\\n\\n
More than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
\\n\\nOur breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
\\n\\n“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
\\n\\nAdditionally, each book published by IntechOpen contains original content and research findings.
\\n\\nWe are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
\\n\\n\\n\\n
\\n"}]',published:!0,mainMedia:{caption:"IntechOpen Maintains",originalUrl:"/media/original/113"}},components:[{type:"htmlEditorComponent",content:'
Simba Information has released its Open Access Book Publishing 2020 - 2024 report and has again identified IntechOpen as the world’s largest Open Access book publisher by title count.
\n\nSimba Information is a leading provider for market intelligence and forecasts in the media and publishing industry. The report, published every year, provides an overview and financial outlook for the global professional e-book publishing market.
\n\nIntechOpen, De Gruyter, and Frontiers are the largest OA book publishers by title count, with IntechOpen coming in at first place with 5,101 OA books published, a good 1,782 titles ahead of the nearest competitor.
\n\nSince the first Open Access Book Publishing report published in 2016, IntechOpen has held the top stop each year.
\n\n\n\nMore than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
\n\nOur breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
\n\n“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
\n\nAdditionally, each book published by IntechOpen contains original content and research findings.
\n\nWe are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
\n\n\n\n
\n'}],latestNews:[{slug:"intechopen-supports-asapbio-s-new-initiative-publish-your-reviews-20220729",title:"IntechOpen Supports ASAPbio’s New Initiative Publish Your Reviews"},{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"}]},book:{item:{type:"book",id:"5280",leadTitle:null,fullTitle:"Actual Problems of Emergency Abdominal Surgery",title:"Actual Problems of Emergency Abdominal Surgery",subtitle:null,reviewType:"peer-reviewed",abstract:'The book "Actual Problems of Emergency Abdominal Surgery" was written by an international team of authors with extensive practical experience. It contains literature reviews describing some of the diseases and pathological conditions that occur in emergency surgical practice. The problems described are relevant for emergency abdominal surgery. We hope that the materials of the book will be of interest to anyone who considers it his or her specialty.',isbn:"978-953-51-2647-8",printIsbn:"978-953-51-2646-1",pdfIsbn:"978-953-51-7308-3",doi:"10.5772/61892",price:119,priceEur:129,priceUsd:155,slug:"actual-problems-of-emergency-abdominal-surgery",numberOfPages:218,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:"0066026ae4b85af070d3b62ba4de1d60",bookSignature:"Dmitry Victorovich Garbuzenko",publishedDate:"September 21st 2016",coverURL:"https://cdn.intechopen.com/books/images_new/5280.jpg",numberOfDownloads:32524,numberOfWosCitations:7,numberOfCrossrefCitations:9,numberOfCrossrefCitationsByBook:0,numberOfDimensionsCitations:19,numberOfDimensionsCitationsByBook:0,hasAltmetrics:1,numberOfTotalCitations:35,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"November 10th 2015",dateEndSecondStepPublish:"December 1st 2015",dateEndThirdStepPublish:"March 20th 2016",dateEndFourthStepPublish:"June 18th 2016",dateEndFifthStepPublish:"July 18th 2016",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"108808",title:"Prof.",name:"Dmitry",middleName:"Victorovich",surname:"Garbuzenko",slug:"dmitry-garbuzenko",fullName:"Dmitry Garbuzenko",profilePictureURL:"https://mts.intechopen.com/storage/users/108808/images/system/108808.png",biography:"Dmitry Victorovich Garbuzenko graduated from Chelyabinsk State Medical Institute in 1985. From 1985 to 1987, he was a clinical intern. From 1987 to 1990, he was a post-graduate student of the Hospital Surgery Department in Chelyabinsk State Medical Academy. He obtained his Ph.D. in 1991. He was an assistant professor of the Department of Hospital Surgery from 1991 to 1996. Since 1996, he has served as an assistant professor, an associate professor (2003), and a full professor (2006) in the Department of Faculty Surgery, South Ural State Medical University. He obtained his DMedSc in 2008. Dr. Garbuzenko is a member of the Russian Society of Surgeons. His practical activities are associated with emergency abdominal surgery. He is the author of nearly 200 publications.",institutionString:"South Ural State Medical University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"4",totalChapterViews:"0",totalEditedBooks:"5",institution:{name:"South Ural State Medical University",institutionURL:null,country:{name:"Russia"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"1138",title:"Abdominal Surgery",slug:"abdominal-surgery"}],chapters:[{id:"50645",title:"The Dilemma of Acute Appendicitis",doi:"10.5772/63097",slug:"the-dilemma-of-acute-appendicitis",totalDownloads:2205,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:1,abstract:"Acute appendicitis is one of a relatively dwindling number of conditions in which a decision to operate may be based solely on clinical findings. Regular re-assessment of patients and making use of the investigative options available will meet the standard of care expected by patients with acute abdominal pain. In this article, the greater importance of history and examination over investigations in the early diagnosis of acute appendicitis is emphasized. The ability to identify the presence of peritoneal inflammation probably has the greatest influence on the final surgical decision.",signatures:"Elroy Patrick Weledji",downloadPdfUrl:"/chapter/pdf-download/50645",previewPdfUrl:"/chapter/pdf-preview/50645",authors:[{id:"182373",title:"Dr.",name:"Elroy",surname:"Weledji",slug:"elroy-weledji",fullName:"Elroy Weledji"}],corrections:null},{id:"51332",title:"Management of Intestinal Obstruction",doi:"10.5772/63156",slug:"management-of-intestinal-obstruction",totalDownloads:5354,totalCrossrefCites:1,totalDimensionsCites:2,hasAltmetrics:1,abstract:"Objective: Intestinal obstruction is a blockage of the intestinal content through bowel. The block must be complete and permanent. Obstruction may be mechanical, simple or strangulated, and paralytic. The purpose of this chapter is to clarify, also evaluating our surgical experience, the steps to diagnose and the ways to treat intestinal obstructions.",signatures:"Vincenzo Neri",downloadPdfUrl:"/chapter/pdf-download/51332",previewPdfUrl:"/chapter/pdf-preview/51332",authors:[{id:"170938",title:"Prof.",name:"Vincenzo",surname:"Neri",slug:"vincenzo-neri",fullName:"Vincenzo Neri"}],corrections:null},{id:"50845",title:"Risk Factors and Predictive Models for Conversion of Laparoscopic Cholecystectomy to Open Surgery, and Surgical Quality Outcome Measures",doi:"10.5772/63648",slug:"risk-factors-and-predictive-models-for-conversion-of-laparoscopic-cholecystectomy-to-open-surgery-an",totalDownloads:2020,totalCrossrefCites:1,totalDimensionsCites:2,hasAltmetrics:0,abstract:"Background: Laparoscopic cholecystectomy is the preferred surgical operation for symptomatic gallstone disease. Conversion of laparoscopic cholecystectomy to open surgery is used to prevent intra-abdominal organ injury, for open common bile duct exploration and to repair intra-abdominal organ injury.",signatures:"Andrei M. Beliaev and Michael Booth",downloadPdfUrl:"/chapter/pdf-download/50845",previewPdfUrl:"/chapter/pdf-preview/50845",authors:[{id:"183966",title:"Ph.D.",name:"Andrei",surname:"Beliaev",slug:"andrei-beliaev",fullName:"Andrei Beliaev"},{id:"186923",title:"Mr.",name:"Michael",surname:"Booth",slug:"michael-booth",fullName:"Michael Booth"}],corrections:null},{id:"51869",title:"Diagnosis and Management of Rectosigmoid Perforations",doi:"10.5772/64383",slug:"diagnosis-and-management-of-rectosigmoid-perforations",totalDownloads:2437,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Rectosigmoid colon, starting from the descending colon to the anus, having the peritoneal and retroperitoneal parts, is provided through the superior mesenteric artery and the inferior mesenteric artery. Many etiological reasons may be responsible for the perforation of the rectosigmoid colon, which may be usually perforated due to causes of iatrogenic and traumatic origins. The rectosigmoid perforations, which can be diagnosed preoperatively through examination, laboratory, and radiological examinations, may not be detected even in the intraoperative period sometimes. In its treatment, applications, such as conservative approaches, endoclip, laparoscopy, and open surgery, can be performed.",signatures:"Alper Yavuz, Çiğdem Hacifazlioğlu, Gökhan Akkurt, Altan Aydin\nand Hakan Ataş",downloadPdfUrl:"/chapter/pdf-download/51869",previewPdfUrl:"/chapter/pdf-preview/51869",authors:[{id:"182955",title:"Dr.",name:"Alper",surname:"Yavuz",slug:"alper-yavuz",fullName:"Alper Yavuz"},{id:"186830",title:"Dr.",name:"Çiğdem",surname:"Hacifazlioğlu",slug:"cigdem-hacifazlioglu",fullName:"Çiğdem Hacifazlioğlu"},{id:"186831",title:"Dr.",name:"Gökhan",surname:"Akkurt",slug:"gokhan-akkurt",fullName:"Gökhan Akkurt"},{id:"186832",title:"Dr.",name:"Altan",surname:"Aydın",slug:"altan-aydin",fullName:"Altan Aydın"},{id:"186833",title:"Dr.",name:"Hakan",surname:"Ataş",slug:"hakan-atas",fullName:"Hakan Ataş"}],corrections:null},{id:"50792",title:"Gastrointestinal Foreign Bodies",doi:"10.5772/63464",slug:"gastrointestinal-foreign-bodies",totalDownloads:2508,totalCrossrefCites:3,totalDimensionsCites:5,hasAltmetrics:0,abstract:"Retained foreign bodies within the gastrointestinal tract (GIT) are common emergency presentations. The majority will pass spontaneously or be removed endoscopically, but a few selected cases may require emergency surgery for removal. This chapter reviews the management of foreign bodies within the GIT including both instances of foreign body ingestions and foreign body insertions. The scope of this chapter is not limited to evidence‐based data on selection of cases for conservative management but also includes data on endoscopic and surgical management.",signatures:"Obinna Obinwa, David Cooper, James M. O’Riordan and Paul Neary",downloadPdfUrl:"/chapter/pdf-download/50792",previewPdfUrl:"/chapter/pdf-preview/50792",authors:[{id:"37650",title:"Prof.",name:"Paul",surname:"Neary",slug:"paul-neary",fullName:"Paul Neary"},{id:"183235",title:"Mr.",name:"Obinna",surname:"Obinwa",slug:"obinna-obinwa",fullName:"Obinna Obinwa"},{id:"186845",title:"Dr.",name:"David",surname:"Cooper",slug:"david-cooper",fullName:"David Cooper"},{id:"186846",title:"Mr.",name:"James",surname:"O'Riordan",slug:"james-o'riordan",fullName:"James O'Riordan"}],corrections:null},{id:"51526",title:"Non-Surgical Causes of Acute Abdominal Pain",doi:"10.5772/64176",slug:"non-surgical-causes-of-acute-abdominal-pain",totalDownloads:2962,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:1,abstract:"Abdominal pain constitutes 5% of the causes of emergency admissions and is an important part in the practice of emergency services in all centers. Patients may suffer from acute surgical abdomen, acute abdomen with nonsurgical diseases or acute problems of chronic diseases. Abdominal pain is sometimes associated with acute trauma. Clinical assessment is a process where diagnosis and treatment must be done quickly and must be well managed. We have tried here to discuss the non-surgical causes of abdominal pain.",signatures:"Ferdane Sapmaz, Sebahat Başyiğit, Murat Başaran and Selim\nDemirci",downloadPdfUrl:"/chapter/pdf-download/51526",previewPdfUrl:"/chapter/pdf-preview/51526",authors:[{id:"177011",title:"Dr.",name:"Sebahat",surname:"Basyigit",slug:"sebahat-basyigit",fullName:"Sebahat Basyigit"},{id:"177012",title:"Dr.",name:"Ferdane",surname:"Sapmaz",slug:"ferdane-sapmaz",fullName:"Ferdane Sapmaz"},{id:"186809",title:"Dr.",name:"Murat",surname:"Başaran",slug:"murat-basaran",fullName:"Murat Başaran"},{id:"186811",title:"Dr.",name:"Selim",surname:"Demirci",slug:"selim-demirci",fullName:"Selim Demirci"}],corrections:null},{id:"51163",title:"Physiotherapy Following Emergency Abdominal Surgery",doi:"10.5772/63969",slug:"physiotherapy-following-emergency-abdominal-surgery",totalDownloads:3358,totalCrossrefCites:1,totalDimensionsCites:5,hasAltmetrics:0,abstract:"Physiotherapy following elective abdominal surgery has been well documented, but following emergency abdominal surgery, despite poorer outcomes and increased complication rates, physiotherapy interventions for this patient group remain largely uninvestigated. The most common complication following upper abdominal surgery is the development of a post-operative pulmonary complication (PPC). Risk factors for the development of PPCs include duration of anaesthesia, emergency upper abdominal surgery, current smoker status, respiratory comorbidities, obesity, increased age and multiple surgeries. Physiotherapy interventions aim to prevent or remediate PPCs and post-operative complications associated with the sequelae of immobility such as venothrombotic events and to facilitate recovery from surgery and a return to normal activities of daily living and function. Physiotherapy interventions after major surgery include early mobilisation and respiratory physiotherapy techniques. Respiratory therapies include deep breathing and coughing exercises, positive expiratory pressure devices, incentive spirometry and non-invasive ventilation. Early mobilisation has been demonstrated to be safe and efficacious following elective abdominal surgery and for patients who are critically ill. This chapter reviews the evidence in these populations and propose that, until further studies are available to direct care, this evidence is extrapolated to patients following emergency abdominal surgery. As abdominal surgery impacts on physical recovery and health-related quality of life, post-discharge rehabilitation programmes may improve long-term outcomes; however, rehabilitation following major cavity surgery is in its infancy. This chapter investigates post-operative rehabilitation research to date in this population in an attempt to determine the effectiveness of such programmes and make recommendations for future practice.",signatures:"Kate Sullivan, Julie Reeve, Ianthe Boden and Rebecca Lane",downloadPdfUrl:"/chapter/pdf-download/51163",previewPdfUrl:"/chapter/pdf-preview/51163",authors:[{id:"159822",title:"Dr.",name:"Julie",surname:"Reeve",slug:"julie-reeve",fullName:"Julie Reeve"},{id:"182271",title:"Dr.",name:"Ianthe",surname:"Boden",slug:"ianthe-boden",fullName:"Ianthe Boden"},{id:"189317",title:"Ms.",name:"Kate",surname:"Sullivan",slug:"kate-sullivan",fullName:"Kate Sullivan"},{id:"189318",title:"Dr.",name:"Rebecca",surname:"Lane",slug:"rebecca-lane",fullName:"Rebecca Lane"}],corrections:null},{id:"51647",title:"Traumatic Bile Duct Injuries",doi:"10.5772/64535",slug:"traumatic-bile-duct-injuries",totalDownloads:2557,totalCrossrefCites:0,totalDimensionsCites:2,hasAltmetrics:0,abstract:"The vast majority of bile duct injuries is iatrogenic and occurs during abdominal surgeries or other interventions such as endoscopic or percutaneous cannulation of the biliary tree. Accidental traumas are responsible only for 1–5% of the total number of biliary injuries. The diagnosis of non-iatrogenic traumatic bile duct injuries is challenging as current cross-sectional imaging tests are not very specific. Therefore, most of the patients are diagnosed when they undergo early explorative laparotomy or when they develop late complications. Among all patients who experience traumatic bile duct injuries, 80–90% are victims of penetrating traumas from stab or gunshot wounds. On the other hand, bile duct lesions due to blunt traumas are predominantly caused by traffic accidents (compression by safety belt or airbag), falls, kicks, or work accidents. Iatrogenic bile duct injuries have been extensively covered in many other papers. In this chapter, we will focus our attention only on traumatic bile duct injuries.",signatures:"Michele Molinari",downloadPdfUrl:"/chapter/pdf-download/51647",previewPdfUrl:"/chapter/pdf-preview/51647",authors:[{id:"182909",title:"Dr.",name:"Michele",surname:"Molinari",slug:"michele-molinari",fullName:"Michele Molinari"}],corrections:null},{id:"52045",title:"Liver Trauma",doi:"10.5772/64543",slug:"liver-trauma-2016-09-08",totalDownloads:2413,totalCrossrefCites:1,totalDimensionsCites:1,hasAltmetrics:0,abstract:"Objective: The aim of this section is to assess the evolution in the management of liver injuries during the last two decades.",signatures:"Marco Massani, Luca Bonariol, Bruno Pauletti, Cesare Ruffolo,\nRoberta Bonariol, Ezio Caratozzolo and Nicolo’ Bassi",downloadPdfUrl:"/chapter/pdf-download/52045",previewPdfUrl:"/chapter/pdf-preview/52045",authors:[{id:"183231",title:"Dr.",name:"Marco",surname:"Massani",slug:"marco-massani",fullName:"Marco Massani"},{id:"189217",title:"Dr.",name:"Luca",surname:"Bonariol",slug:"luca-bonariol",fullName:"Luca Bonariol"},{id:"189218",title:"Dr.",name:"Bruno",surname:"Pauletti",slug:"bruno-pauletti",fullName:"Bruno Pauletti"},{id:"189219",title:"Dr.",name:"Cesare",surname:"Ruffolo",slug:"cesare-ruffolo",fullName:"Cesare Ruffolo"},{id:"189220",title:"Dr.",name:"Roberta",surname:"Bonariol",slug:"roberta-bonariol",fullName:"Roberta Bonariol"},{id:"189221",title:"Dr.",name:"Ezio",surname:"Caratozzolo",slug:"ezio-caratozzolo",fullName:"Ezio Caratozzolo"},{id:"189222",title:"Prof.",name:"Nicolo'",surname:"Bassi",slug:"nicolo'-bassi",fullName:"Nicolo' Bassi"}],corrections:null},{id:"51381",title:"Damage Control Surgery",doi:"10.5772/64326",slug:"damage-control-surgery",totalDownloads:2459,totalCrossrefCites:2,totalDimensionsCites:2,hasAltmetrics:0,abstract:"Objective: The basis of damage control surgery rests on quick control of life-threatening bleeding, injuries, and septic sources in the appropriate patients before restoring their physiological reserves as a first step followed by ensuring of the physiological reserves and control of acidosis, coagulopathy, and hypothermia prior to complementary surgery.",signatures:"Burhan Hakan Kanat, Mehmet Bugra Bozan, Seyfi Emir, Ilhan Bali,\nSelim Sozen, Burak Dal and Fatih Erol",downloadPdfUrl:"/chapter/pdf-download/51381",previewPdfUrl:"/chapter/pdf-preview/51381",authors:[{id:"90616",title:"Associate Prof.",name:"Selim",surname:"Sözen",slug:"selim-sozen",fullName:"Selim Sözen"},{id:"169977",title:"Dr.",name:"Seyfi",surname:"Emir",slug:"seyfi-emir",fullName:"Seyfi Emir"},{id:"169979",title:"Dr.",name:"Ilhan",surname:"Bali",slug:"ilhan-bali",fullName:"Ilhan Bali"},{id:"183319",title:"Associate Prof.",name:"Burhan",surname:"Kanat",slug:"burhan-kanat",fullName:"Burhan Kanat"},{id:"183321",title:"M.D.",name:"Mehmet",surname:"Bozan",slug:"mehmet-bozan",fullName:"Mehmet Bozan"},{id:"186916",title:"Dr.",name:"Mehmet Burak",surname:"Dal",slug:"mehmet-burak-dal",fullName:"Mehmet Burak Dal"},{id:"192715",title:"Dr.",name:"Fatih",surname:"Erol",slug:"fatih-erol",fullName:"Fatih Erol"}],corrections:null},{id:"51446",title:"Emergency Abdominal Surgery in Infants and Children",doi:"10.5772/63649",slug:"emergency-abdominal-surgery-in-infants-and-children",totalDownloads:1881,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"The term acute abdomen refers to sudden severe abdominal pain with unclear etiology that is less than 24 h in duration. In children, acute abdominal pain presents a diagnostic dilemma. Although many cases of acute abdominal pain are benign, some of them need rapid diagnosis and treatment to minimize morbidity. The present chapter provides an overview of abdominal surgical emergencies in children and discusses the most common disorders that cause surgical acute abdomen.",signatures:"Mehrdad Hosseinpour and Bahareh Ahmadi",downloadPdfUrl:"/chapter/pdf-download/51446",previewPdfUrl:"/chapter/pdf-preview/51446",authors:[{id:"85579",title:"Dr.",name:"Mehrdad",surname:"Hosseinpour",slug:"mehrdad-hosseinpour",fullName:"Mehrdad Hosseinpour"}],corrections:null},{id:"51227",title:"Anesthetic Management of Neonatal Emergency Abdominal Surgery",doi:"10.5772/63567",slug:"anesthetic-management-of-neonatal-emergency-abdominal-surgery",totalDownloads:2377,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Anesthetic management of neonatal surgical emergencies presents serious difficulties and challenges for the anesthesiologist and is associated with increased risks of morbidity and mortality. Therefore, in these patients, anesthetic assessment should be directed to the patient's current disease and associated anomalies. The provision of safe anesthesia and perioperative management of these cases also depends on a clear understanding of the physiologic and hemodynamic variables of the preterm and term infants and a precise knowledge of the pathophysiology of disease states likely to affect the neonate. This chapter describes physiology and pathophysiology‐based view on the neonatal abdominal emergency surgeries. General principles of surgery and anesthetic management of specific neonatal emergencies that include congenital diaphragmatic hernia (CDH), abdominal wall defects, necrotizing enterocolitis, and esophageal atresia are reviewed and discussed.",signatures:"Esra Caliskan",downloadPdfUrl:"/chapter/pdf-download/51227",previewPdfUrl:"/chapter/pdf-preview/51227",authors:[{id:"183347",title:"Associate Prof.",name:"Esra",surname:"Caliskan",slug:"esra-caliskan",fullName:"Esra Caliskan"}],corrections:null}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},subseries:null,tags:null},relatedBooks:[{type:"book",id:"1224",title:"Portal Hypertension",subtitle:"Causes and Complications",isOpenForSubmission:!1,hash:"c1e06d98ce373a844e14eb8914a9ba63",slug:"portal-hypertension-causes-and-complications",bookSignature:"Dmitry V. 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\r\n\tDuring the last decade, many unconventional yeast species and strains have been identified and further characterised by using molecular and biochemical approaches. This resulted in the identification of novel platforms for the bio-transformation of industrial residues into valuable products, which represents a major advance toward sustainability. The overall goal of this book is to present and discuss the recent advances in metabolic engineering and bioprospecting of yeast for industrial applications in white biotechnology. Thus, this book will cover three different topics, including 1) Yeast bioprospecting for industrial biotechnology, 2) Metabolic engineering of yeast, and 3) Synthetic biology of yeast. The first topic will cover the identification of novel/unconventional yeast species and strains that can be used to produce valuable products (e.g., biofuels, flavours, and bioactive compounds). The second topic will discuss the current advances in metabolic engineering of yeast with the use of recombinant DNA technology. Finally, the third topic will summarise the current cutting-edge technologies that can be used to engineer yeast-based synthetic biofactories to produce valuable compounds and their social, economic, and environmental implications.
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He is currently working as a researcher at the Leibniz Institute of Plant Biochemistry, Halle (Saale), Germany. He is recently awarded the Georg Forster Research Fellowship for postdoctoral researchers from the Alexander von Humboldt Foundation.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"158295",title:"Dr.",name:"Miguel",middleName:null,surname:"Fernández-Niño",slug:"miguel-fernandez-nino",fullName:"Miguel Fernández-Niño",profilePictureURL:"https://mts.intechopen.com/storage/users/158295/images/system/158295.png",biography:"Dr. Miguel Fernández-Niño is a biologist from The National University of Colombia with a master’s degree in Biochemistry from the same institution and a Ph.D. in Biochemical Engineering from Jacobs University, Bremen, Germany. He is currently working as a researcher at the Leibniz Institute of Plant Biochemistry, Halle (Saale), Germany. 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These proteins create transmembrane pores through which inorganic ions, mainly Na+, K+, Ca2+ or Cl−, permeate according to their electrochemical gradient. Selectivity of the channels for particular ions, mechanisms of their activation and kinetic characteristics are greatly variable. This variability underlines involvement of ion channels in very diverse fundamental physiological processes such as generation of the membrane potential, regulation of cell electrical excitability, propagation of the action potential along neurons and muscle cells, synaptic release of neurotransmitters, generation of postsynaptic response, and calcium signaling. Ion channels are indispensable in multicellular organisms. They are also found in various bacteria and even some viruses [1]. Ion channels are targets for numerous endogenous ligands including hormones and neurotransmitters, as well as for multiple exogenous toxins and medically important and illicit drugs. Due to these roles, ion channels are key objects in pharmacology and toxicology.
This functional importance of ion channels motivates their intensive studies in academia and industry. A large body of experimental data is accumulated on selectivity and permeability characteristics of different channels, physiological mechanisms of their activation by different factors, including membrane voltage, various endogenous and exogenous ligands, metal ions, temperature, pH, and membrane tension. Selective sensitivity of ion channels to various pharmacological agents allowed to reveal their presence in various organs and tissues, cellular localization, and specific roles in physiological and pathological processes. The next big step was understanding molecular characteristics of ion channels due to methodological advancements in molecular genetics and molecular biology. Currently we know sequences of many channels, their subunit composition, stoichiometry, and transmembrane topology. These studies have demonstrated that, unlike many other classes of proteins, which are involved in fundamental physiological functions (e.g. G protein coupled receptors), ion channels do not have a common ancestor. Surprisingly, there is no correlation between functional properties and molecular organization of ion channels. For example, proton-activated channels belong to families of trimetric ASIC channels and tetrameric TRPV channels. Chloride selectivity is observed in voltage-gated ClC channels, which are homodimers with a gated pore in each subunit [2], and in pentameric glycine-gated and GABA-gated channels. On the other hand, close relatives of the latter channels, nAChR receptors, are selective for cations. Besides pentameric nAChRs, cationic selectivity is a fundamental property of tetrameric glutamate-gated channels, trimetric ATP-gated P2X channels, ASIC channels, and certain mechanosensitive channels. Both tetrameric cation-selective channels and pentameric Cys-loop channels are gated by glutamate, the major neurotransmitter in the central nervous system. The potassium selectivity is observed in five clades of potassium channels superfamily, which includes voltage-gated channels, calcium-activated channels, Kir channels, mechanosensitive two-pore (K2P) channels, and CNG/HCN channels [3]. Thus, among ion channels we can see examples of divergent evolution and examples of evolutionary homology and functional analogy. Therefore, understanding of the evolutionary history is crucially important in studies of ion channels. For example, the presence of proton-activated currents in different types of cells does not necessarily mean that these currents are mediated by the same or even evolutionary related channels. And
Until the pioneering publication of the first X-ray structure of a prokaryotic potassium channel, KcsA [4], 3D structures of ion channels were unknown and only indirect evidences about some features of their spatial structures were available. The lack of experimental high-resolution 3D structures greatly hindered research in the field of ion channels, including analysis of their origin and evolution. The reason for rather late appearance of 3D structures of ion channels is problems of crystallization of proteins that have both membrane-spanning and water-exposed parts. For example, MacKinnon and colleagues used bioinformatics tools to find extremely stable potassium channel in thermophilic bacteria and removed flexible cytoplasmic segments [4]. For this and subsequent seminal crystallographic studies of ion channels Roderick MacKinnon was awarded the 2003 Nobel Prize in chemistry.
Since then, many 3D structures of ion channels have been published. Most of the structures were obtained by the X-ray crystallography, but recently the amazing progress in the Cryo-EM methodology has provided high-resolution structures of different channels including open and closed states of the TRPV1 channel [5] and glycine receptor [6]. A complex of heteromeric eukaryotic calcium channel with ancillary subunits is now available [7]. The ongoing revolution in structural studies of ion channels advances research in different fields, in particular, molecular evolution of ion channels. Below we describe several representative examples.
The basic ion-conducting function of ion channels dictates that they have a transmembrane pore-forming domain. This domain is usually assembled from different subunits, which surround the central ion-conducting pore. In most of the channels the pore is lined by alpha-helical segments, but some channels have the beta-barrel structures. 3D structures show different organization of the pore-forming domains (Figure 1). The big variations in the number of transmembrane subunits, transmembrane topology and other structural peculiarities indicate that the domains have different evolutionary origins. In other words, various pore domains are examples of analogies rather than homologies. This conclusion is obvious in view of high-resolution structures, but before such structures become available, discrimination between analogies and homologies was by far not a trivial task.
Diversity of pore-forming domains in ion channels. Extracellular (left) and side (right) views. (A) A potassium channel representing the family of tetrameric P-loop channels. (B) GABAA receptor channel representing pentameric channels. (C) Trimeric acid-sensing channel. (D) Dimeric chloride channel. (E) Beta-barrel structure of the hemolysin channel-forming toxin. (F) A mechanosensitive channel.
An instructive example is the discovery of evolutionary origin of ionotropic receptors of glutamate (for review see [8]), which is the most widespread excitatory neurotransmitter in the central nervous system of vertebrates. The physiological characteristics of the glutamate receptors are similar to those of nicotinic acetylcholine receptors. Both receptor classes are ligand-gated channels, which are permeable to potassium, sodium, and, to some extent, calcium. Both receptor classes are involved in the fast synaptic transmission. In vertebrates glutamate is responsible mainly for excitation in the CNS and acetylcholine mainly provides excitation in skeletal muscles. In contrast, insects have cholinergic transmission in ganglia and glutamatergic neuromuscular transmission. These indirect evidences suggested a common origin for the superfamily of ligand-gated ion channels, including acetylcholine receptors and glutamate receptors. Comparison of the amino acid sequences of ionotropic acetylcholine and glutamate receptors reinforced this view. Indeed, in both types of receptors the neurotransmitter molecules interact with the N-terminal parts of the proteins, which are located extracellularly. Analysis of the hydrophobicity profiles revealed four putative transmembrane segments in both channel proteins. Furthermore, according to mutational data the ion selectivity and interactions with channel blockers in both channel types are controlled by residues belonging to the second potentially transmembrane segment. Thus, the idea of evolutionary homology between ionotropic receptors of glutamate and acetylcholine was supported by solid evidences [8].
However, this idea turned out to be wrong. Increasing data on location of individual amino acid residues provided evidence that the M2 segment of the glutamate receptor does not span the entire membrane, but forms a membrane-reentrant loop both ends of which are exposed to the cytoplasm [9]. Since the transmembrane topology is one of the most conserved characteristics of membrane proteins, the hypothesis on homology between ionotropic receptors of acetylcholine and glutamate was rejected [10]. On the other hand, it is well known that the voltage-gated potassium, sodium, and potassium channels have extracellular membrane-diving loops (P-loops). Another critical series of studies demonstrated that, unlike pentameric receptors of acetylcholine, GABA and glycine, glutamate receptors have four subunits, and by this characteristic they are close to tetrameric potassium channels [11]. The final proofs were provided by the discovery an evolutionary transitional channel type in prokaryotes, which are usually difficult to find among presently existing organisms [12]. The discovery was a potassium channel activated by glutamate. This protein (named GluR0) has a ligand-binding domain, which is highly homologous to the ligand-binding domains of eukaryotic glutamate receptors. The selectivity filter of the GluR0 channel has the TVGYG sequence, which is a fingerprint of potassium channels. Importantly, the GluR0 receptor was first found by searching the database of protein sequences and then was studied experimentally [12]. Thus, glutamate receptors and voltage-gated channels inherited the pore domains from a common ancestor. This conclusion is absolutely clear from comparing 3D structures, which are available now (Figure 2). However, large efforts were required to draw this conclusion before 3D structures become available.
Different organization of glutamate (A–C) and acetylcholine (D–F) receptors. (A) In the ionotropic glutamate receptor four extracellular N-terminal domains (top), four extracellular glutamate-binding domains (middle) and a single transmembrane pore-forming domain (bottom) are connected by flexible linkers. (B) Glutamate binding domains in an ionotropic receptor (left) and in a bacterial non-channel glutamine-binding protein (right) are structurally similar. Ligands are space-filled. (C) Architecture of the pore-forming domains (only two subunits are shown for clarity) is similar in a glutamate-gated channel (left) and a voltage-gated channel (right). Note the opposite orientation of the domains: The P-loop dives into membrane from the cytoplasm in glutamate receptor and from the extracellular space in the voltage-gated channel. (D) In the nicotinic acetylcholine receptor the extracellular ligand-binding domain (top), transmembrane pore-forming domain (middle) and intracellular domain (bottom) are connected by flexible linkers. (E) Ligand-binding domains in the nicotinic acetylcholine receptor (left) and in a non-channel acetylcholine binding protein (right) are structurally similar. (F) Pore-forming domains of the cation-selective nicotinic acetylcholine receptor (right) and in the anion-selective GABAA receptor (left) are similar.
The ligand-binding domain of glutamate receptors also has homologs among bacterial proteins (Figure 2B), which are glutamate-binding periplasmic proteins. Their crystal structure has been determined [13] and found to be remarkably similar to the glutamate binding domain in eukaryotic ionotropic receptors [14]. Probably, it is the extracellular localization of the ligand-binding domain that determines the “inverted” transmembrane topology of glutamate receptors as compared to voltage-gated channels. Nicotinic acetylcholine receptors belong to the structurally different family of so-called Cys-loop pentameric receptors, which also include channels gated by GABA, glycine and serotonin (Figure 2). Pore forming domains of these channels are markedly similar [15, 16, 17]. Neurotransmitter-binding domain of nicotinic acetylcholine receptors also originated from proteins that are not ion channels [18] (Figure 2E).
Like other ion channels of modular architecture, voltage-gated ion channels have the pore domain and four voltage-sending domains, which are believed to be of independent evolutionary origin. Indeed, some voltage-dependent enzymes (phosphatases) have voltage-sensing domains that are similar to those in ion channels. Interestingly, fusion of the voltage-sensing domains from the evolutionary unrelated phosphatase (a marine invertebrate) and a simple viral potassium channel that lacks any voltage-sensing or ligand-binding domains produced a functional voltage-gated potassium channel, which combines the pore properties of the contributing channel and the voltage dependence of the contributing phosphatase [19].
Besides the pore-forming domains and domains, which are responsible for the channel activation by specific stimuli (e.g., voltage or ligands), there are other domains involved in the channel regulation (Figure 2A and D). Regulatory functions may be performed not only by domains, but also by ancillary subunits, which are tightly associated with the channel proteins. The regulatory domains or subunits are typical characteristic of eukaryotic channels, which are involved in complex physiological systems and multiple interactions with other proteins.
Thus, various ion-channel proteins of modular organization may be assembled from domains, which originated from evolutionary and functionally distant protein families. Growing knowledge on the domain organization of ion channels shows that existent classifications of ion channels (e.g. according to the gating mechanism or the principle permeant ion) does not reflect their evolutionary history. Evolutionary studies would benefit from classification that also involves domain architecture, which is evolutionary much more conserved than physiological, biochemical or pharmacological properties.
Certainly, evolutionary changes are not limited to domain organization. Homologous ionotropic receptors diverge the sensitivities to specific ligands as a result of local changes in the ligand-recognition domains. An interesting example is TRPV channels, which share with voltage-sensing P-loop channels folding of the pore domain and four “voltage-sensing” domains with apparently very similar structural organization. However, TRPV channels are not sensitive to voltage and can be activated by various stimuli, including temperature, pH, and ligands that bind to distinct sites [20]. Unexpectedly, these specific features appeared in evolution without incorporation of specific domains. Capsaicin, an active component of chili pepper, and related compounds bind in the interface between the “voltage-sensing” domain and the pore domain. Sensitivity of TRPV channels to pH is due to protonation of several residues in the extracellular loops, which have nothing in common with proton-binding domains in proton-gated ASIC channels. Thus, TRPV channels are an example, where specific properties appeared without incorporation of additional domains.
One of the most important features of pore-forming domains is their ion selectivity. Usually the selectivity is governed by a local region in the narrow part of the pore, which is named the selectivity filter. This rather small part of the channel allows very fast passing of specific types of ions and rejects other ions. Concrete mechanisms of selectivity are different, but in any case, they involve specific interactions of the permeant ions with the pore-facing amino acids.
Classical example is opposite selectivity (cationic or anionic) within the family of Cys-loop channels. The 3D structures of the pore domain are very similar (Figure 2F), but acetylcholine and 5-hydroxytryptamine receptors are cationic channels, whereas Glycine and GABAA receptors are anionic channels. Experiments demonstrated that just few mutations can convert the cationic selectivity to the anionic one and
The big and diverse family of P-loop channels includes transmembrane proteins, which permeate different types of cations. The group includes potassium, sodium, calcium channels and less selective glutamate-gated and TRP channels. Multiple studies strongly suggest that the pore-forming domains of all these channels have a common ancestor from which the folding is inherited (see above section), while specific families evolved through gene duplication and gene divergence [21]. According to 3D structures, in all these channels the ion selectivity is governed by rather small number of pore-lining residues downstream from the P-loop turns (Figure 3). Potassium selectivity is governed by the highly conserved VGYG motif found in various organisms including prokaryotes (Figure 3A). Four potassium binding sites are present in the selectivity filter (Figure 3B). Unlike potassium channels, in which high selectivity is achieved due to tight binding of potassium ions to the backbone carbonyls, in sodium and calcium channels the selectivity is achieved by side chains of residues, which are located in the same region. Such evolutionary divergence from a common ancestor, which was driven by the necessity of more complex electrophysiological signaling, is accompanied by local refolding of the selectivity-filter region, which is seen in 3D structures as the appearance of so-called P2 helices in sodium and calcium channels (Figure 3C). However, evolution of eukaryotic sodium channels from their prokaryotic ancestors includes not only replacements in the selectivity filter. Although experimental high-resolution structures of eukaryotic sodium channels are still lacking, analysis of various data suggests deletions in non-matching positions of the four repeats in the selectivity-filter region [22, 23] (Figure 3A).
Selectivity in P-loop channels. (A) Sequence alignment of P-loops with the selectivity filter residues highlighted. (B–D) Available 3D structures with the ion binding sites and the selectivity filter highlighted.
The structure of the selectivity filter of glutamate receptors, which include NMDA-, AMPA-, and kainate-gated channels, is still unavailable, but mutational analysis suggests that selectivity is governed by the ring of Asn, Gln, or Arg residues [24]. AMPA channels, which have glutamine residues in the selectivity filter, are the most ancient among this group of channels; they are permeable for monovalent cations and calcium. NMDA channels, which have asparagine residues in the selectivity filter, are more selective for calcium ions and are blocked by Mg2+. Both these properties determine physiological roles of NMDA receptors in synaptic regulation and plasticity in the glutamatergic system. On the other hand, in the GluR2 subunit of AMPA receptors Gln is replaced by Arg. This substitution completely eliminates calcium permeation. Thus, existence of three types of glutamate receptors enables different degree of coupling between electrical synaptic signaling due to permeability for sodium and potassium ions and calcium signaling, which regulates various biochemical processes within the neuron.
Phylogenetic studies involving protein sequences are broadly used to understand molecular evolution. The first and most critical step in these studies is multiple sequence alignment of proteins. Regrettably, in the field of ion channels the standard sequence alignment tools work only within families of closely related channels, e.g., voltage-gated potassium channels [21]. However, attempts to align structurally conserved elements of the pore domains of potassium, calcium, sodium, glutamate-gated and TRP channels (all of which are P-loop channels) yielded contradictory results. Correct alignments, which later have been confirmed by comparing experimental 3D structures, were elaborated by careful analysis of a large body of data on individual residues. When X-ray structures of various P-loop channels become available, the channels were found to have rather conserved folding despite vastly different sequences. Superposition of 3D structures allowed to adjust the sequence alignments, which provide much better basis for phylogenetic studies.
Alignments of residues in sequences and respective 3D structures do not necessarily coincide. For example, the sequence alignment of P-loops unambiguously shows the TVGYGDL motif of potassium channels and TVGMGDL motif of the TRPV channel in the matching positions and other positions within the P-loops do not suggest any alternative alignment (Figure 4A). However, in the superposed 3D structures of the TRPV and potassium channels the residues, which are in the matching positions of P-helix sequence alignment, occur at the opposite faces of the helices and thus would play different roles in the protein folding and function. In contrast, the 3D alignment, which is proposed to maximize the 3D similarity of the P-loops, shows the above residues in mismatching positions [25]. Thus, during evolution homologous residues may have changed their role and disposition, whereas the general domain folding did not change. The evolutionary mechanisms of such changes are unclear.
Mismatched sequence and 3D alignments of Kv1.2 and TRPV1 channels. (A) Alignment mismatch in P-loops. Underlined residues in matching positions have different localization in 3D structures and thus different functions. (B) Alignment mismatch in S6 segments. Underlined Leu residues in mismatching positions have the same spatial orientation due to the presence of pi-helix element.
Transmembrane segments of ion channels are usually alpha-helices because in this secondary structure the polar groups of the backbones are hidden from the lipid environment. On the other hand, probability of possible evolutionary changes within alpha-helical structures is relatively small. Indeed, any insertion/deletion within a helical structure results in a big reorientation of other helical residues. Such reorientations would affect folding-stabilizing intersegment contacts and the exposure of functionally important groups into the aqueous pore or lipids. Therefore, the chances of acceptance of respective insertions/deletions during evolution would be small because so dramatic structural changes would result in the loss of the channel function. However, there are structural mechanisms that may provide tolerance of helical structures to insertions/deletions. The most common helical structure is an alpha-helix, which has H-bonds between residues in positions
Multiple sequence alignments reveal conserved and variable residues. Conserved residues may be indispensable for protein folding or have crucial roles in the protein function. But it is only the 3D view that allows to really understand specific role of conserved residues. An appealing example is exceptionally conserved tryptophans in the selectivity filter region in sodium and calcium channels. It was proposed that the tryptophans are involved in the folding stabilization [26], but it is the X-ray structure of a bacterial sodium channel [27], which has revealed atomic details of H-bonds that stabilize the folding (Figure 5B). Tryptophan is an amino acid with the largest side chain, which can also donate an H-bond. These two factors allow tryptophan residues to simultaneously participate in a large number of specific interactions. That is why tryptophans are often found to have important structural roles as folding stabilizers. For example, in the pore helix of potassium channels side chains of two adjacent tryptophans are oriented toward neighboring segments and form multiple contacts, thus forming cyclic motifs (Figure 5A) in the 3D structure [25].
Conserved tryptophan residues as folding stabilizers. (A) Two Trp residues in the pore helix of potassium channel (see
Asparagine residues in the middle of the pore-lining helices are highly conserved in TRPV, sodium and calcium channels. Engineered substitutions of the asparagines in sodium and calcium channels affect gating properties as well as interactions with pore-targeting ligands. Available 3D structures of sodium and calcium channels show involvement of the asparagines in inter-segment contacts, but do not allow to make an unambiguous conclusion about their functional roles. A modeling study suggests that these asparagines stabilize the open channel state [28]. Another example of highly conserved residues is positively charged arginines or lysines in every third sequential position of some transmembrane helices in voltage-gated ion channels. These positively charged residues are “signatures” of the S4 helices within the voltage-sensing domains of ion channels. At the negative resting membrane potential, the positively charged S4 helices are attracted to the cytoplasmic side of the membrane and the channels are closed. Upon membrane depolarization, the S4 helices shift in the extracellular direction thus initiating the process of the channel activation (opening).
The structural and/or functional importance of conserved residues is obvious. Non-conserved residues may be not critical for folding or function, but sometimes such residues play key roles in determining specific properties of the proteins. For example, variable hydrophilic residues, such as lysines, arginines, glutamines or asparagines in a matching position may indicate exposure of respective position in the aqueous environment rather than specific functional roles. However, sometimes this conclusion may be wrong. For example, asparagine, glutamine, or arginine (N/Q/R) residues determine permeability of glutamate receptor subtypes for specific cations [24]. The mechanism of selectivity was suggested in a modeling study [29], but experimental 3D structures of the N/Q/R site are still unavailable.
Evolutionary changes are observable in phylogenetic studies, but driving forces for these changes remain largely unclear. Local adaptive changes of animal ion channels, which are exposed to toxins, are easy to reveal. An interesting example of the constrained convergence during evolution is resistance of snake species around the globe, which feed on newts that possess sodium channel blocker, tetrodotoxin [30]. Some garter snake populations around the globe have evolved resistance to extremely high levels of TTX [31]. Amino acid substitutions are observed in the selectivity-filter region of sodium channels and structural explanation for the acquired resistance has been proposed [26]. Interestingly, such changes are seen in the sodium channel paralogs, which are expressed in the skeletal muscle and peripheral nervous system of snakes and thus should be exposed to the ingested tetrodotoxin. In contrast, sodium channel paralogs, which are expressed solely in the central nervous system, showed no evidence of the TTX resistance, indicating that the blood-brain barrier protects from the toxin [32]. The observed genetic changes represent only a small fraction of the experimentally validated mutations known to increase the sodium channels resistance to TTX. These results suggest that evolutionary convergence at the molecular level results from the compromise between ion channel function and resistance to toxin. Thus, the natural selection may be constrained to produce similar genetic outcomes even in independent lineages.
An example of genetic adaptation of large practical importance is acquired resistance of insects to sodium channel-targeting insecticides [33]. Well known insecticides such as DDT and pyrethroids are sodium channel activators, which disturb the normal processes in the nervous system. Many insect populations worldwide mutated to elaborate residence to DDT and the earlier generation of pyrethroids. Such adaptive genetic changes are called kdr (knock-down resistance) mutations. In various inset populations many kdr mutations within sodium channel are found. Additional studies involving molecular modeling, mutational analysis and electrophysiology led to discovery of two pyrethroid binding sites in insect sodium channels [34, 35]. The receptors are located within the pore domain, in the lipid-exposed interfaces between individual channel segments whose mutual disposition changes upon the channel gating. This fast adaptive evolution of ion channels presents a big economical problem and requires development of new insecticides whose action would not be abolished by known kdr mutations. Structure-based design of new insecticides is hardly possible without knowledge of the sodium channels 3D structures.
A goal of research in the fields of molecular evolution in general and ion channels in particular is to understand how functional diversity of proteins is related to genetic changes. A traditional approach uses amino acid sequences to build phylogenetic trees and relate these with known functional characteristics of ion channels. Obviously, the amino acid sequence determines the 3D structure and functional characteristics of a protein. Nowadays, properties of small molecules are reliably predictable from their chemical structures. However, a general approach to predict 3D structures and properties of proteins just from their amino acid sequences is still lacking. Successful predictions are based on the knowledge of proteins that have similar sequences. For example, the presence of the VGYGD motif allows to predict that respective protein is a potassium channel, but such predictions are based on the fact that many channels that have this “signature sequence” have been previously studied experimentally and were found to have the potassium selectivity. It is the knowledge of 3D structures of proteins that helps to link genetic and functional data. In this work we presented examples of how the rapidly growing body of experimental data on 3D structures of ion channels influences progress in understanding their molecular evolution.
Obviously, besides molecular evolution, knowledge of 3D structures of ion channels is important in other fields. Ion channels are among the prime targets for many different drugs and toxins. This determines large demand for practical applications of knowledge on ion channels in chemistry, medicine, toxicology, and pharmacology. Structure-based analysis of action of existent drugs and toxins and design of new channel-targeting molecules requires knowledge of 3D structures of the target proteins. Available experimental 3D structures still do not represent the large diversity of ion channels and multiplicity of their functional states (open, close, inactivated, etc.). Even nowadays any new experimental 3D structure of an ion channels is an important event in the field, which is usually reported in a high-impact journal. Comparative (homology) molecular modeling is an approach to fill the gap between the numbers of desired and available 3D structures of ion channels. A key assumption of homology modeling is that the evolutionary close ion channels have similar 3D structures. Homology modeling of an ion channel involves selections of structural templates (available 3D structures of relative proteins), sequence alignment between the templates and the query protein, computer-assisted building and optimization of the model 3D structure, and analysis of possible structural deviations of the model from the templates. The choice of an incorrect template or even one-position misalignment between the template and the query protein may result in entirely incorrect model. Understanding mechanisms of molecular evolution of ion channels is necessary to avoid such errors. This is an example of how basic evolutionary studies can be translated to practical applications.
This work was supported by State budget funding by Federal Agency of Scientific Organizations Russia (Neurophysiological regulatory mechanisms and their evolution).
AMPA | α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid [receptor] |
ASIC | acid-sensing ion channel |
Cryo-EM | cryo-electron microscopy |
ClC | chloride channel |
CNG | cyclic nucleotide-gated [channels] |
GABA | gamma-aminobutyric acid |
HCN | hyperpolarization-activated cyclic nucleotide-modulated [channels] |
Kir | inward-rectifying potassium [channels] |
nAChR | nicotinic acetylcholine receptor |
NMDA | N-methyl-D-aspartate [receptor] |
TRPV | transient receptor potential vanilloid [channel] |
KcsA | prokaryotic potassium channel from the soil bacteria Streptomyces lividans |
TTX | tetrodotoxin |
Herbal or phyto-based medicines are in the mainstream of present pharmacological world [1]. Nearly two-thirds of the medicines throughout the world is plant based, the rest being the conventional ones [2]. The main reasons behind the preference of herbal drugs over the synthetic ones are that they have negligible side effects, are cost-effective, and easily available [3]. Also, the knowledge of herbal sources has led to the formation of base for many modern medicines. Some examples mentioned by Vickers and Zellman [4] are aspirin taken from willow bark, digoxin from foxglove, and morphine from opium poppy. Many researchers have also stated the development of resistance to allopathic drugs after a long medicament leading to becoming ineffective [5]. Thus, a documentation of medicinal plants and its herbal aspect becomes the first step toward a “botanical healing.”
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He also obtained an MSc in Molecular and Genetic Medicine, and a Ph.D. in Clinical Immunology and Human Genetics from the University of Sheffield, UK. He also completed a short-term fellowship in Pediatric Clinical Immunology and Bone Marrow Transplantation at Newcastle General Hospital, England. Dr. Rezaei is a Full Professor of Immunology and Vice Dean of International Affairs and Research, at the School of Medicine, Tehran University of Medical Sciences, and the co-founder and head of the Research Center for Immunodeficiencies. He is also the founding president of the Universal Scientific Education and Research Network (USERN). Dr. Rezaei has directed more than 100 research projects and has designed and participated in several international collaborative projects. He is an editor, editorial assistant, or editorial board member of more than forty international journals. He has edited more than 50 international books, presented more than 500 lectures/posters in congresses/meetings, and published more than 1,100 scientific papers in international journals.",institutionString:"Tehran University of Medical Sciences",institution:{name:"Tehran University of Medical Sciences",country:{name:"Iran"}}},{id:"180733",title:"Dr.",name:"Jean",middleName:null,surname:"Engohang-Ndong",slug:"jean-engohang-ndong",fullName:"Jean Engohang-Ndong",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/180733/images/system/180733.png",biography:"Dr. Jean Engohang-Ndong was born and raised in Gabon. After obtaining his Associate Degree of Science at the University of Science and Technology of Masuku, Gabon, he continued his education in France where he obtained his BS, MS, and Ph.D. in Medical Microbiology. He worked as a post-doctoral fellow at the Public Health Research Institute (PHRI), Newark, NJ for four years before accepting a three-year faculty position at Brigham Young University-Hawaii. Dr. Engohang-Ndong is a tenured faculty member with the academic rank of Full Professor at Kent State University, Ohio, where he teaches a wide range of biological science courses and pursues his research in medical and environmental microbiology. Recently, he expanded his research interest to epidemiology and biostatistics of chronic diseases in Gabon.",institutionString:"Kent State University",institution:{name:"Kent State University",country:{name:"United States of America"}}},{id:"188773",title:"Prof.",name:"Emmanuel",middleName:null,surname:"Drouet",slug:"emmanuel-drouet",fullName:"Emmanuel Drouet",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/188773/images/system/188773.png",biography:"Emmanuel Drouet, PharmD, is a Professor of Virology at the Faculty of Pharmacy, the University Grenoble-Alpes, France. As a head scientist at the Institute of Structural Biology in Grenoble, Dr. Drouet’s research investigates persisting viruses in humans (RNA and DNA viruses) and the balance with our host immune system. He focuses on these viruses’ effects on humans (both their impact on pathology and their symbiotic relationships in humans). He has an excellent track record in the herpesvirus field, and his group is engaged in clinical research in the field of Epstein-Barr virus diseases. He is the editor of the online Encyclopedia of Environment and he coordinates the Universal Health Coverage education program for the BioHealth Computing Schools of the European Institute of Science.",institutionString:null,institution:{name:"Grenoble Alpes University",country:{name:"France"}}},{id:"131400",title:"Prof.",name:"Alfonso J.",middleName:null,surname:"Rodriguez-Morales",slug:"alfonso-j.-rodriguez-morales",fullName:"Alfonso J. Rodriguez-Morales",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/131400/images/system/131400.png",biography:"Dr. Rodriguez-Morales is an expert in tropical and emerging diseases, particularly zoonotic and vector-borne diseases (especially arboviral diseases). He is the president of the Travel Medicine Committee of the Pan-American Infectious Diseases Association (API), as well as the president of the Colombian Association of Infectious Diseases (ACIN). He is a member of the Committee on Tropical Medicine, Zoonoses, and Travel Medicine of ACIN. He is a vice-president of the Latin American Society for Travel Medicine (SLAMVI) and a Member of the Council of the International Society for Infectious Diseases (ISID). Since 2014, he has been recognized as a Senior Researcher, at the Ministry of Science of Colombia. He is a professor at the Faculty of Medicine of the Fundacion Universitaria Autonoma de las Americas, in Pereira, Risaralda, Colombia. He is an External Professor, Master in Research on Tropical Medicine and International Health, Universitat de Barcelona, Spain. He is also a professor at the Master in Clinical Epidemiology and Biostatistics, Universidad Científica del Sur, Lima, Peru. In 2021 he has been awarded the “Raul Isturiz Award” Medal of the API. Also, in 2021, he was awarded with the “Jose Felix Patiño” Asclepius Staff Medal of the Colombian Medical College, due to his scientific contributions to COVID-19 during the pandemic. He is currently the Editor in Chief of the journal Travel Medicine and Infectious Diseases. His Scopus H index is 47 (Google Scholar H index, 68).",institutionString:"Institución Universitaria Visión de las Américas, Colombia",institution:null},{id:"332819",title:"Dr.",name:"Chukwudi Michael",middleName:"Michael",surname:"Egbuche",slug:"chukwudi-michael-egbuche",fullName:"Chukwudi Michael Egbuche",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/332819/images/14624_n.jpg",biography:"I an Dr. Chukwudi Michael Egbuche. I am a Senior Lecturer in the Department of Parasitology and Entomology, Nnamdi Azikiwe University, Awka.",institutionString:null,institution:{name:"Nnamdi Azikiwe University",country:{name:"Nigeria"}}},{id:"284232",title:"Mr.",name:"Nikunj",middleName:"U",surname:"Tandel",slug:"nikunj-tandel",fullName:"Nikunj Tandel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/284232/images/8275_n.jpg",biography:'Mr. Nikunj Tandel has completed his Master\'s degree in Biotechnology from VIT University, India in the year of 2012. He is having 8 years of research experience especially in the field of malaria epidemiology, immunology, and nanoparticle-based drug delivery system against the infectious diseases, autoimmune disorders and cancer. He has worked for the NIH funded-International Center of Excellence in Malaria Research project "Center for the study of complex malaria in India (CSCMi)" in collaboration with New York University. The preliminary objectives of the study are to understand and develop the evidence-based tools and interventions for the control and prevention of malaria in different sites of the INDIA. Alongside, with the help of next-generation genomics study, the team has studied the antimalarial drug resistance in India. Further, he has extended his research in the development of Humanized mice for the study of liver-stage malaria and identification of molecular marker(s) for the Artemisinin resistance. At present, his research focuses on understanding the role of B cells in the activation of CD8+ T cells in malaria. Received the CSIR-SRF (Senior Research Fellow) award-2018, FIMSA (Federation of Immunological Societies of Asia-Oceania) Travel Bursary award to attend the IUIS-IIS-FIMSA Immunology course-2019',institutionString:"Nirma University",institution:{name:"Nirma University",country:{name:"India"}}},{id:"334383",title:"Ph.D.",name:"Simone",middleName:"Ulrich",surname:"Ulrich Picoli",slug:"simone-ulrich-picoli",fullName:"Simone Ulrich Picoli",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/334383/images/15919_n.jpg",biography:"Graduated in Pharmacy from Universidade Luterana do Brasil (1999), Master in Agricultural and Environmental Microbiology from Federal University of Rio Grande do Sul (2002), Specialization in Clinical Microbiology from Universidade de São Paulo, USP (2007) and PhD in Sciences in Gastroenterology and Hepatology (2012). She is currently an Adjunct Professor at Feevale University in Medicine and Biomedicine courses and a permanent professor of the Academic Master\\'s Degree in Virology. She has experience in the field of Microbiology, with an emphasis on Bacteriology, working mainly on the following topics: bacteriophages, bacterial resistance, clinical microbiology and food microbiology.",institutionString:null,institution:{name:"Universidade Feevale",country:{name:"Brazil"}}},{id:"229220",title:"Dr.",name:"Amjad",middleName:"Islam",surname:"Aqib",slug:"amjad-aqib",fullName:"Amjad Aqib",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/229220/images/system/229220.png",biography:"Dr. Amjad Islam Aqib obtained a DVM and MSc (Hons) from University of Agriculture Faisalabad (UAF), Pakistan, and a PhD from the University of Veterinary and Animal Sciences Lahore, Pakistan. Dr. Aqib joined the Department of Clinical Medicine and Surgery at UAF for one year as an assistant professor where he developed a research laboratory designated for pathogenic bacteria. Since 2018, he has been Assistant Professor/Officer in-charge, Department of Medicine, Manager Research Operations and Development-ORIC, and President One Health Club at Cholistan University of Veterinary and Animal Sciences, Bahawalpur, Pakistan. He has nearly 100 publications to his credit. His research interests include epidemiological patterns and molecular analysis of antimicrobial resistance and modulation and vaccine development against animal pathogens of public health concern.",institutionString:"Cholistan University of Veterinary and Animal Sciences",institution:{name:"University of Agriculture Faisalabad",country:{name:"Pakistan"}}},{id:"333753",title:"Dr.",name:"Rais",middleName:null,surname:"Ahmed",slug:"rais-ahmed",fullName:"Rais Ahmed",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/333753/images/20168_n.jpg",biography:null,institutionString:null,institution:{name:"University of Agriculture Faisalabad",country:{name:"Pakistan"}}},{id:"62900",title:"Prof.",name:"Fethi",middleName:null,surname:"Derbel",slug:"fethi-derbel",fullName:"Fethi Derbel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/62900/images/system/62900.jpeg",biography:"Professor Fethi Derbel was born in 1960 in Tunisia. He received his medical degree from the Sousse Faculty of Medicine at Sousse, University of Sousse, Tunisia. He completed his surgical residency in General Surgery at the University Hospital Farhat Hached of Sousse and was a member of the Unit of Liver Transplantation in the University of Rennes, France. He then worked in the Department of Surgery at the Sahloul University Hospital in Sousse. Professor Derbel is presently working at the Clinique les Oliviers, Sousse, Tunisia. His hospital activities are mostly concerned with laparoscopic, colorectal, pancreatic, hepatobiliary, and gastric surgery. He is also very interested in hernia surgery and performs ventral hernia repairs and inguinal hernia repairs. He has been a member of the GREPA and Tunisian Hernia Society (THS). During his residency, he managed patients suffering from diabetic foot, and he was very interested in this pathology. For this reason, he decided to coordinate a book project dealing with the diabetic foot. Professor Derbel has published many articles in journals and collaborates intensively with IntechOpen Access Publisher as an editor.",institutionString:"Clinique les Oliviers",institution:null},{id:"300144",title:"Dr.",name:"Meriem",middleName:null,surname:"Braiki",slug:"meriem-braiki",fullName:"Meriem Braiki",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/300144/images/system/300144.jpg",biography:"Dr. Meriem Braiki is a specialist in pediatric surgeon from Tunisia. She was born in 1985. She received her medical degree from the University of Medicine at Sousse, Tunisia. She achieved her surgical residency training periods in Pediatric Surgery departments at University Hospitals in Monastir, Tunis and France.\r\nShe is currently working at the Pediatric surgery department, Sidi Bouzid Hospital, Tunisia. Her hospital activities are mostly concerned with laparoscopic, parietal, urological and digestive surgery. She has published several articles in diffrent journals.",institutionString:"Sidi Bouzid Regional Hospital",institution:null},{id:"229481",title:"Dr.",name:"Erika M.",middleName:"Martins",surname:"de Carvalho",slug:"erika-m.-de-carvalho",fullName:"Erika M. de Carvalho",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/229481/images/6397_n.jpg",biography:null,institutionString:null,institution:{name:"Oswaldo Cruz Foundation",country:{name:"Brazil"}}},{id:"186537",title:"Prof.",name:"Tonay",middleName:null,surname:"Inceboz",slug:"tonay-inceboz",fullName:"Tonay Inceboz",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/186537/images/system/186537.jfif",biography:"I was graduated from Ege University of Medical Faculty (Turkey) in 1988 and completed his Med. PhD degree in Medical Parasitology at the same university. I became an Associate Professor in 2008 and Professor in 2014. I am currently working as a Professor at the Department of Medical Parasitology at Dokuz Eylul University, Izmir, Turkey.\n\nI have given many lectures, presentations in different academic meetings. I have more than 60 articles in peer-reviewed journals, 18 book chapters, 1 book editorship.\n\nMy research interests are Echinococcus granulosus, Echinococcus multilocularis (diagnosis, life cycle, in vitro and in vivo cultivation), and Trichomonas vaginalis (diagnosis, PCR, and in vitro cultivation).",institutionString:"Dokuz Eylül University",institution:{name:"Dokuz Eylül University",country:{name:"Turkey"}}},{id:"71812",title:"Prof.",name:"Hanem Fathy",middleName:"Fathy",surname:"Khater",slug:"hanem-fathy-khater",fullName:"Hanem Fathy Khater",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/71812/images/1167_n.jpg",biography:"Prof. Khater is a Professor of Parasitology at Benha University, Egypt. She studied for her doctoral degree, at the Department of Entomology, College of Agriculture, Food and Natural Resources, University of Missouri, Columbia, USA. She has completed her Ph.D. degrees in Parasitology in Egypt, from where she got the award for “the best scientific Ph.D. dissertation”. She worked at the School of Biological Sciences, Bristol, England, the UK in controlling insects of medical and veterinary importance as a grant from Newton Mosharafa, the British Council. Her research is focused on searching of pesticides against mosquitoes, house flies, lice, green bottle fly, camel nasal botfly, soft and hard ticks, mites, and the diamondback moth as well as control of several parasites using safe and natural materials to avoid drug resistances and environmental contamination.",institutionString:null,institution:{name:"Banha University",country:{name:"Egypt"}}},{id:"99780",title:"Prof.",name:"Omolade",middleName:"Olayinka",surname:"Okwa",slug:"omolade-okwa",fullName:"Omolade Okwa",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/99780/images/system/99780.jpg",biography:"Omolade Olayinka Okwa is presently a Professor of Parasitology at Lagos State University, Nigeria. She has a PhD in Parasitology (1997), an MSc in Cellular Parasitology (1992), and a BSc (Hons) Zoology (1990) all from the University of Ibadan, Nigeria. She teaches parasitology at the undergraduate and postgraduate levels. She was a recipient of a Commonwealth fellowship supported by British Council tenable at the Centre for Entomology and Parasitology (CAEP), Keele University, United Kingdom between 2004 and 2005. She was awarded an Honorary Visiting Research Fellow at the same university from 2005 to 2007. \nShe has been an external examiner to the Department of Veterinary Microbiology and Parasitology, University of Ibadan, MSc programme between 2010 and 2012. She is a member of the Nigerian Society of Experimental Biology (NISEB), Parasitology and Public Health Society of Nigeria (PPSN), Science Association of Nigeria (SAN), Zoological Society of Nigeria (ZSN), and is Vice Chairperson of the Organisation of Women in Science (OWSG), LASU chapter. She served as Head of Department of Zoology and Environmental Biology, Lagos State University from 2007 to 2010 and 2014 to 2016. She is a reviewer for several local and international journals such as Unilag Journal of Science, Libyan Journal of Medicine, Journal of Medicine and Medical Sciences, and Annual Research and Review in Science. \nShe has authored 45 scientific research publications in local and international journals, 8 scientific reviews, 4 books, and 3 book chapters, which includes the books “Malaria Parasites” and “Malaria” which are IntechOpen access publications.",institutionString:"Lagos State University",institution:{name:"Lagos State University",country:{name:"Nigeria"}}},{id:"273100",title:"Dr.",name:"Vijay",middleName:null,surname:"Gayam",slug:"vijay-gayam",fullName:"Vijay Gayam",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/273100/images/system/273100.jpeg",biography:"Dr. Vijay Bhaskar Reddy Gayam is currently practicing as an internist at Interfaith Medical Center in Brooklyn, New York, USA. He is also a Clinical Assistant Professor at the SUNY Downstate University Hospital and Adjunct Professor of Medicine at the American University of Antigua. He is a holder of an M.B.B.S. degree bestowed to him by Osmania Medical College and received his M.D. at Interfaith Medical Center. His career goals thus far have heavily focused on direct patient care, medical education, and clinical research. He currently serves in two leadership capacities; Assistant Program Director of Medicine at Interfaith Medical Center and as a Councilor for the American\r\nFederation for Medical Research. As a true academician and researcher, he has more than 50 papers indexed in international peer-reviewed journals. He has also presented numerous papers in multiple national and international scientific conferences. His areas of research interest include general internal medicine, gastroenterology and hepatology. He serves as an editor, editorial board member and reviewer for multiple international journals. His research on Hepatitis C has been very successful and has led to multiple research awards, including the 'Equity in Prevention and Treatment Award” from the New York Department of Health Viral Hepatitis Symposium (2018) and the 'Presidential Poster Award” awarded to him by the American College of Gastroenterology (2018). He was also awarded 'Outstanding Clinician in General Medicine” by Venus International Foundation for his extensive research expertise and services, perform over and above the standard expected in the advancement of healthcare, patient safety and quality of care.",institutionString:"Interfaith Medical Center",institution:{name:"Interfaith Medical Center",country:{name:"United States of America"}}},{id:"93517",title:"Dr.",name:"Clement",middleName:"Adebajo",surname:"Meseko",slug:"clement-meseko",fullName:"Clement Meseko",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/93517/images/system/93517.jpg",biography:"Dr. Clement Meseko obtained DVM and PhD degree in Veterinary Medicine and Virology respectively. He has worked for over 20 years in both private and public sectors including the academia, contributing to knowledge and control of infectious disease. Through the application of epidemiological skill, classical and molecular virological skills, he investigates viruses of economic and public health importance for the mitigation of the negative impact on people, animal and the environment in the context of Onehealth. \r\nDr. Meseko’s field experience on animal and zoonotic diseases and pathogen dynamics at the human-animal interface over the years shaped his carrier in research and scientific inquiries. He has been part of the investigation of Highly Pathogenic Avian Influenza incursions in sub Saharan Africa and monitors swine Influenza (Pandemic influenza Virus) agro-ecology and potential for interspecies transmission. 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His research work has been published in various high-impact factor journals (Science, PNAS, Nature Medicine) with a high number of citations. He has received many awards and honors in India and abroad including various Young Scientist Awards, BBSRC India Partnering Award, and Dr. JC Bose National Award of Department of Biotechnology, Min. of Science and Technology, Govt. of India. Dr. Saxena is a fellow of various international societies/academies including the Royal College of Pathologists, United Kingdom; Royal Society of Medicine, London; Royal Society of Biology, United Kingdom; Royal Society of Chemistry, London; and Academy of Translational Medicine Professionals, Austria. He was named a Global Leader in Science by The Scientist. 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