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Barely three months into the new year and we are happy to announce a monumental milestone reached - 150 million downloads.
\n\nThis achievement solidifies IntechOpen’s place as a pioneer in Open Access publishing and the home to some of the most relevant scientific research available through Open Access.
\n\nWe are so proud to have worked with so many bright minds throughout the years who have helped us spread knowledge through the power of Open Access and we look forward to continuing to support some of the greatest thinkers of our day.
\n\nThank you for making IntechOpen your place of learning, sharing, and discovery, and here’s to 150 million more!
\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:"3226",leadTitle:null,fullTitle:"Abiotic Stress - Plant Responses and Applications in Agriculture",title:"Abiotic Stress",subtitle:"Plant Responses and Applications in Agriculture",reviewType:"peer-reviewed",abstract:'"This book is not intended to cover all known abiotic stresses or every possible technique used to understand plant tolerance but, instead, to describe some of the widely used approaches to addressing such major abiotic stresses as drought, salinity, extreme temperature, cold, light, calcareous soils, excessive irradiation, ozone, ultraviolet radiation,\r\nand flooding, and to describe major or newly emerging techniques employed in understanding and improving plant tolerance. Among the strategies for plant stress survival, examples of both avoidance and tolerance are presented in detail and comprehensive case studies of progress and directions in several agricultural crops such as apple, walnut, grape and\r\nwheat are included."',isbn:null,printIsbn:"978-953-51-1024-8",pdfIsbn:"978-953-51-4254-6",doi:"10.5772/45842",price:139,priceEur:155,priceUsd:179,slug:"abiotic-stress-plant-responses-and-applications-in-agriculture",numberOfPages:420,isOpenForSubmission:!1,isInWos:1,isInBkci:!0,hash:"8063f7215a8655b897424c418ed0f4bc",bookSignature:"Kourosh Vahdati and Charles Leslie",publishedDate:"March 13th 2013",coverURL:"https://cdn.intechopen.com/books/images_new/3226.jpg",numberOfDownloads:59574,numberOfWosCitations:355,numberOfCrossrefCitations:187,numberOfCrossrefCitationsByBook:29,numberOfDimensionsCitations:480,numberOfDimensionsCitationsByBook:36,hasAltmetrics:1,numberOfTotalCitations:1022,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"April 4th 2012",dateEndSecondStepPublish:"April 25th 2012",dateEndThirdStepPublish:"July 30th 2012",dateEndFourthStepPublish:"October 28th 2012",dateEndFifthStepPublish:"November 27th 2012",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6,8,9",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"59106",title:"Dr.",name:"Kourosh",middleName:null,surname:"Vahdati",slug:"kourosh-vahdati",fullName:"Kourosh Vahdati",profilePictureURL:"https://mts.intechopen.com/storage/users/59106/images/3773_n.jpg",biography:"Kourosh Vahdati received his Ph.D. in Horticultural Science, Fruit Breeding and Biotechnology, from the University of Tehran in 2002 and is now a professor at the University of Tehran specializing in walnut research, particularly genetic transformation and rootstock breeding for resistance to abiotic stresses. He was a visiting scholar at the University of California-Davis in 2000-2001 and returned in 2010-2011 as associate visiting professor and worked on tissue culture and genetic transformation of walnut. Dr. Vahdati teaches pomology, breeding and biotechnology of fruit and nut trees, supervises graduate students, has published more than 50 research articles and book chapters, and has served on the editorial boards of several journals. He also serves as Chairman of the ISHS Walnut Working Group and of the Iranian Center of Excellence for Walnut Improvement and Technology, and has made numerous contributions worldwide to the fields of walnut breeding and biotechnology.",institutionString:null,position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"1",institution:{name:"University of Tehran",institutionURL:null,country:{name:"Iran"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:{id:"151921",title:"Dr.",name:"Charles",middleName:null,surname:"Leslie",slug:"charles-leslie",fullName:"Charles Leslie",profilePictureURL:"https://mts.intechopen.com/storage/users/151921/images/system/151921.jpg",biography:"Charles Leslie earned his B.S. in Zoology from Oregon State University in 1973 and his M.S. degree in Plant Physiology from the University of California – Davis in 1985. He worked in private sector forestry research as a wildlife biologist, entomologist and tissue culture specialist, has 25 years of experience at UC Davis in tissue culture, genetic engineering, and walnut breeding, and is current Director of the UC-Davis Walnut improvement Program. His research includes application of genomics to breeding walnut scion cultivars, enhancing efficiency of in vitro walnut propagation and clonal rootstock production, and developing hybrid walnut rootstocks with resistance to soil-borne disease, pathogens and abiotic stresses. 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Garrido, D. Blanco, M.L. Munoz, L. Moreno and M. Abderrahim",reviewType:"peer-reviewed",authors:[null]},{id:"151",type:"chapter",title:"Effective Method for Autonomous Simultaneous Localization and Map Building in Unknown Indoor Environments",slug:"effective_method_for_autonomous_simultaneous_localization_and_map_building_in_unknown_indoor_environ",totalDownloads:2491,totalCrossrefCites:0,signatures:"Y.L. Ip, A.B. Rad and Y.K. 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Habib",reviewType:"peer-reviewed",authors:[null]},{id:"155",type:"chapter",title:"Intelligent Control of AC Induction Motors",slug:"intelligent_control_of_ac_induction_motors",totalDownloads:4282,totalCrossrefCites:0,signatures:"Hosein Marzi",reviewType:"peer-reviewed",authors:[null]},{id:"156",type:"chapter",title:"Optimal Path Planning of Multiple Mobile Robots for Sample Collection on a Planetary Surface",slug:"optimal_path_planning_of_multiple_mobile_robots_for_sample_collection_on_a_planetary_surface",totalDownloads:2056,totalCrossrefCites:2,signatures:"J.C. Cardema and P.K.C. Wang",reviewType:"peer-reviewed",authors:[null]},{id:"157",type:"chapter",title:"Multi Robotic Conflict Resolution by Cooperative Velocity and Direction Control",slug:"multi_robotic_conflict_resolution_by_cooperative_velocity_and_direction_control",totalDownloads:2392,totalCrossrefCites:0,signatures:"Satish Pedduri and K. Madhava Krishna",reviewType:"peer-reviewed",authors:[null]},{id:"158",type:"chapter",title:"Robot Collaboration for Simultaneous Map Building and Localization",slug:"robot_collaboration_for_simultaneous_map_building_and_localization",totalDownloads:2372,totalCrossrefCites:1,signatures:"M. Oussalah and D. Wilson",reviewType:"peer-reviewed",authors:[null]}]},relatedBooks:[{type:"book",id:"3622",title:"Climbing and Walking Robots",subtitle:null,isOpenForSubmission:!1,hash:null,slug:"climbing-and-walking-robots",bookSignature:"Behnam Miripour",coverURL:"https://cdn.intechopen.com/books/images_new/3622.jpg",editedByType:"Edited by",editors:[{id:"5507",title:"Dr.",name:"Behnam",surname:"Miripour-Fard",slug:"behnam-miripour-fard",fullName:"Behnam Miripour-Fard"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"},chapters:[{id:"10079",title:"A Survey of Technologies and Applications for Climbing Robots Locomotion and Adhesion",slug:"a-survey-of-technologies-and-applications-for-climbing-robots-locomotion-and-adhesion",signatures:"Manuel F. Silva and J. A. 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Berenguer",authors:[null]},{id:"10090",title:"Quadrupedal Gait Generation Based on Human Feeling for Animal Type Robot",slug:"quadrupedal-gait-generation-based-on-human-feeling-for-animal-type-robot",signatures:"Hidekazu Suzuki and Hitoshi Nishi",authors:[null]},{id:"10095",title:"Gait Based Directional Bias Detection of Four-Legged Walking Robots",slug:"gait-based-directional-bias-detection-of-four-legged-walking-robots",signatures:"Wei-Chung Teng and Ding-Jie Huang",authors:[null]},{id:"10075",title:"Locomotion Analysis of Hexapod Robot",slug:"locomotion-analysis-of-hexapod-robot",signatures:"Xilun Ding, Zhiying Wang, Alberto Rovetta and J.M. Zhu",authors:[null]},{id:"10091",title:"In Situ Self-Reconfiguration of Hexapod Robot OSCAR Using Biologically Inspired Approaches",slug:"in-situ-self-reconfiguration-of-hexapod-robot-oscar-using-biologically-inspired-approaches",signatures:"Bojan Jakimovski and Erik Maehle",authors:[null]},{id:"10082",title:"Softly Stable Walk Using Phased Compliance Control with Virtual Force for Multi-Legged Walking Robot",slug:"softly-stable-walk-using-phased-compliance-control-with-virtual-force-for-multi-legged-walking-robot",signatures:"Qingjiu Huang",authors:[null]},{id:"10073",title:"Biohybrid Walking Microrobot with Self-Assembled Cardiomyocytes",slug:"biohybrid-walking-microrobot-with-self-assembled-cardiomyocytes",signatures:"Jinseok Kim, Eui-Sung Yoon and Sukho Park",authors:[null]},{id:"10083",title:"Theoretical and Experimental Study for Queueing System with Walking Distance",slug:"theoretical-and-experimental-study-for-queueing-system-with-walking-distance",signatures:"Daichi Yanagisawa, Yushi Suma, Akiyasu Tomoeda, Ayako Kimura, Kazumichi Ohtsuka and Katsuhiro Nishinari",authors:[null]},{id:"10088",title:"Intention-Based Walking Support for Paraplegia Patients with Robot Suit HAL",slug:"intention-based-walking-support-for-paraplegia-patients-with-robot-suit-hal",signatures:"Kenta Suzuki, Gouji Mito, Hiroaki Kawamoto, Yasuhisa Hasegawa and Yoshiyuki Sankai",authors:[null]},{id:"10084",title:"Development of Vision Based Person Following Module for Mobile Robots in RT-Middleware",slug:"development-of-vision-based-person-following-module-for-mobile-robots-in-rt-middleware",signatures:"Hiroshi Takemura, Zentaro Nemoto, Keita Ito and Hiroshi Mizoguchi",authors:[null]},{id:"12295",title:"A-B Autonomy of a Shape-shifting Robot 'AMOEBA-I' for USAR",slug:"a-b-autonomy-of-a-shape-shifting-robot-amoeba-i-for-usar",signatures:"Yuechao Wang, Jinguo Liu and Bin Li",authors:[null]},{id:"12296",title:"The Rh-1 Full-Size Humanoid Robot: Control System Design and Walking Pattern Generation",slug:"the-rh-1-full-size-humanoid-robot-control-system-design-and-walking-pattern-generation",signatures:"Mario Arbulu, Dmitry Kaynov and Carlos Balaguer",authors:[null]}]}],publishedBooks:[{type:"book",id:"6109",title:"Mobile Robots",subtitle:"Perception & Navigation",isOpenForSubmission:!1,hash:"8118f1daeb4d79aa1a234ae61a1fbf55",slug:"mobile_robots_perception_navigation",bookSignature:"Sascha Kolski",coverURL:"https://cdn.intechopen.com/books/images_new/6109.jpg",editedByType:"Edited by",editors:[{id:"150980",title:"Dr.",name:"Sascha",surname:"Kolski",slug:"sascha-kolski",fullName:"Sascha Kolski"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}],publishedBooksByAuthor:[]},onlineFirst:{chapter:{type:"chapter",id:"66740",title:"Bacteriophages: Their Structural Organisation and Function",doi:"10.5772/intechopen.85484",slug:"bacteriophages-their-structural-organisation-and-function",body:'\nAll living systems have many diseases that are often caused by small organisms such as bacteria or infectious particles consisting of proteins, nucleic acids and sometimes lipids. These particles are called viruses, use the resources of living cells for their own propagation and can be transmitted from one organism to another. Each type of particle infects its own host cells, and they can survive outside living organisms in very harsh conditions. some of them continue to replicate with cells despite the host’s defence mechanisms and remain dormant (latent) in their host cell, e.g. herpesviruses which reactivate at a later date to produce further attacks of the disease if the host’s defence system weakens [1].
\nBacteriophages (or phages) are viruses that infect and use bacterial resources for their own reproduction. They are characterised by a high specificity to bacteria at infection and are very common in all environments. Their number is directly related to the number of bacteria present. It is estimated that there are more than 1030 tailed phages in the biosphere [2]. Phages are common in soil and readily isolated from faeces and sewage, as well as being very abundant in freshwater and oceans with an estimate of more than 10 million virus-like particles in 1 mL of seawater [3, 4].
\nWhy study the structure-function relationship of phages? Currently, there are substantial problems with diseases caused by bacteria, especially in hospitals. Many pathogenic bacteria exist such as
A powerful method to circumvent this resistance is the use of phages in the treatment of bacterial infections [9]. Most current studies of phage therapy have focussed on acute infections in animals [10]. In order to regulate the mechanisms of phage infection, we need to know not only the phage structure but also the phage-cell surface interaction mechanism and the process of switching the cell replication machinery for phage propagation. One important factor that has to be considered is how phages are reproduced. Phages have two ways of propagation: lytic and lysogenic [11]. In the first case, phages cause the compete lysis of a cell, where it breaks open and subsequently dies after phage replication. In the second type of replication, a phage integrates its genome into the host bacterium’s genome or forms a circular replicon in the bacterial cytoplasm. The bacterium then continues to live and reproduce normally, but the phage genome is transmitted to progeny cells at each subsequent cell division. Changes in cell conditions such as radiation or certain chemicals can release the phage genome, causing proliferation of new phages via the lytic cycle. Therefore, for medical treatments we need to use only lytic phages, so they will exist in an organism, while the pathogenic bacteria are around but only infect those bacteria that have the appropriate receptors in the outer membrane. This is an important factor that can be used to affect specific bacteria without harming those ones that are essential for the health of humans and animals [10]. In this review we will focus on tailed phages as they are abundant and well studied and could be beneficial to medicine [12]. We will describe the general organisation and structural features of their components revealed by current structural methods.
\nVirus classification is based on characteristics such as morphology, type of nucleic acid, replication mode, host organism and type of disease. The International Committee on Taxonomy of Viruses (ICTV) has produced an ordered system for classifying viruses (https://talk.ictvonline.org/taxonomy/). Phages are found in a variety of morphologies: filamentous phages, phages with a lipid-containing envelope and phages with lipids in the particle shell (Figure 1A). They have a genome, either DNA or RNA, which can be single or double stranded, and contain information on the proteins that constitute the particles, additional proteins that are responsible for switching cell molecular metabolism in favour of viruses and, therefore, the information on the self-assembly process. The genome can be one or multipartite and is located inside the phage capsid. Nearly 5500 bacterial viruses have been characterised by electron microscopy (EM) [15]. The shape of viruses is closely related to their genome, and a large genome indicates a large capsid and therefore a more complex organisation. The most studied group of phages is the tailed phages (order
(A) Representation of prokaryote bacteriophage morphotypes [
The first ideas on how viruses infect cells were based on results obtained by microbiology and bacteriology during the last century. Understanding the function of viruses and how this can be regulated and modified requires knowledge of their structural organisation. However, investigation of structure-function relationships needs a combination of different techniques. Microbiology has identified viruses as infectious agents, while bacteriology and light microscopy enabled us to identify specificity between viruses and host cell interactions and to recognise a level of survival of bacteria in the presence of different phages. In order to understand interactions at the molecular level, one needs to know the structural features of the viruses and their components at an atomic level. Different structural techniques are often utilised for smaller components, and the results fitted into larger EM structures.
\nX-ray crystallography was the first method used to study proteins at the atomic level, which is essential to reveal protein-ligand interactions that can boost or suppress protein activity. It is based on the principles of beam scattering within a crystal. By using specific software packages, a 3D electron density map of the protein that forms the crystal can be calculated [16]. However, to produce protein crystals, we need solutions of a protein at high concentration. The proteins have to be stable, and often mutations are made to remove their flexible parts, but this may produce different conformations to those that are required for their natural activity.
\nX-ray analysis is an efficient tool for analysis of protein complexes from a few kDa to hundreds of kDa in size. In order to study the structure of a large protein or a complex of several proteins, the process of crystallisation becomes a more challenging step. The development of cryoprotection in X-ray crystallography, where the crystals are flash frozen, has improved the quality of the data and often resulted in higher resolution. Nowadays, many structures of large protein complexes (up to 2–3 MDa) have been determined by X-ray analysis, but these projects have required decades to obtain high-quality crystals [17].
\nViruses are much bigger particles and often have flexible components. The large size of the complexes results in significantly bigger unit cells, which results in technical challenges in obtaining fine structural details. Viruses with a rigid icosahedral lattice of the capsid have been studied successfully by X-ray crystallography at near-atomic resolution. The first viral structure was that of the
Nuclear magnetic resonance (NMR) is an important technique that resolves structures of small proteins that are not suitable for crystallisation due to their flexibility. This method is based on exploiting the electrical charges and spins of the nuclei in a molecule. If an external magnetic field is applied, energy is transferred to the nuclei changing their state from the level of base energy to a higher energy. This energy is emitted when the spin returns back to its base level at a frequency corresponding to radio frequencies1. The signal that matches this transfer is measured and processed in order to yield a NMR spectrum [17, 20]. This technique is typically used for proteins of less than 200 amino acids and an upper weight limit of about 50 kDa, so it is unsuitable for the structural determination of complete viruses. However, it can be used to analyse flexibility of bigger complexes [21]. The NMR structures can be docked into low-resolution cryo-EM structures.
\nLight microscopy has been used for several centuries to study objects that are hardly visible to the naked eye. In conventional microscopy, resolution is mostly restricted according to the theoretical context of the Rayleigh criterion [22]. This limit is defined by the diffraction properties of light in lenses and has restricted our view to objects bigger than 250 nm. New developments in technology and advances in optical quality, electronics and software have delivered new options and extended the field of applications for electron microscopes allowing visualisation of single molecules. Electron microscopes use a beam of electrons (wavelength of less than 0.1 nm) instead of visible light
At the very beginning of EM evolvement, a method called negative staining was used for visualisation of biological complexes. In this case a drop of biocomplex solution is placed on a support grid and embedded in a heavy atom salt, usually uranyl acetate [24]. Since the specific density of the negative stain is much higher than the density of the biological molecules in the microscope, we can see the cast of the molecule merged into the surrounding stain. Where the stain did not penetrate into the molecule, one can see light spots in the image as the stain has blocked electrons. Sample preparation is fast and produces very high contrast. However, this technique does not allow fine details to be seen, and the particle becomes distorted due to the drying procedure required. The stain has a relatively large grain (up to 1.5 nm) that obscures details of the molecules under study.
\nNearly four decades ago, a cryo-technique for sample preparation was introduced that allows biocomplexes to be kept at nearly native conditions. A thin layer of sample on a grid is flash frozen at liquid nitrogen temperatures, thus trapping molecules in a native, hydrated state within a thin layer of amorphous ice [25]. This technique is used to study the structural organisation of biocomplexes by cryo-electron microscopy (cryo-EM) or electron tomography (cryo-ET). Until two decades ago, all data in EM was collected on films that had to be developed and digitised, which was time-consuming. The advent of charge-coupled devices (CCDs) allowed direct digital acquisition of images and the collection of large numbers of particles giving rise to structures of higher resolution. Later, direct electron detectors were introduced into EM and are now used in all high-end electron microscopes [26]. Together with new approaches in microtechnology and the automation of data collection, the results from image analysis have improved tremendously. Cryo-EM is now approaching the near-atomic resolution that had only been achieved by X-ray crystallography. New maps obtained by cryo-EM provide information on the main polypeptide chains and often reveal the positions of side chains. The current highest resolution of structures currently deposited in the EMDB is 1.5 Å [27], with many others at a resolution between 3.5 and 4 Å. At this resolution atomic models can be built and refined using the crystallographic methods.
\nIn cryo-ET the samples are also flash frozen, but data is collected by tilting the grid with the sample between −60 and 60° around the horizontal axis (perpendicular to the optical axis of the microscope) with an increment typically of 2°. The 2D images taken at each angle are combined to calculate a 3D map of the object. The limitation in the range of the tilt results in a cone of missing data [28]. The resolution in structures obtained by cryo-ET is lower than that in single-particle analysis. However, this approach allows visualisation of important organelles within cells. If there are multiple small structures such as ribosomes or viruses, then each structure can be extracted and averaged. This is called subtomogram averaging and will give higher-resolution structures [29].
\nPhages may have different shapes and sizes (Figure 1A). The most studied group is that of tailed phages with a dsDNA genome, and it also represents the largest group (Figure 1B). The tailed phages have three major components: a capsid where the genome is packed, a tail that serves as a pipe during infection to secure transfer of genome into host cell and a special adhesive system (adsorption apparatus) at the very end of the tail that will recognise the host cell and penetrate its wall. Cell resources are used for the phage reproduction.
\nThe functional phage is a result of a multistep process that starts with all the necessary proteins produced by the host cell after infection: capsid, portal, tail, scaffolding, terminase, etc. (Figure 2). The capsids of the dsDNA phages often have fivefold or icosahedral symmetries [30], which are broken at one of the fivefold axes by the head-to-tail interface (HTI). The main component of the HTI is a dodecameric portal protein (PP) within the capsid. The PP represents the DNA-packaging motor, which is the crucial part of these nano-machines. The HTI also includes oligomeric rings of head completion proteins that play dual roles: (1) making an additional interface to molecules of ATP which provide energy for DNA packaging and (2) then connecting the portal protein and the tail. Some HTIs also serve as valves that close the exit channel preventing leakage of genome from the capsid but opening as soon as the phage is attached to the host cell. However, symmetries other than dodecameric have been found for nearly all PPs in vitro if the PPs are assembled under naive conditions, without any other phage protein components [31, 32, 33, 34, 35]. Typically, the main phage proteins have conservative folds despite low sequence similarity, although they may have different additional domains [36, 37].
\nSelf-assembly pathway of phages. Multiple copies of the capsid/scaffold complex bind the portal protein to form the procapsid; then, the scaffold proteins are ejected, and DNA is packaged into the procapsid, which expands to the size of the mature capsid. The head completion proteins (the stopper and the adaptor) are bound to the portal complex preventing DNA leakage. Next, decoration proteins bind to the capsid, and the tail, assembled separately or after DNA packaging, is attached; thus, the final infectious phage is produced. The preassembled tail attaches in
The phage tail is the structural component of the phage that is essential during infection. Its adsorption apparatus located on the distal end of the tail recognises a receptor, or the envelope chemistry, of the host cell and ensures genome delivery to the cell cytoplasm. In
The capsid of a phage has a precursor formation, named the procapsid, during the assembly process (Figure 2). Scaffolding proteins (SPs) drive the assembly process by chaperoning major capsid protein (MCP) subunits to build an icosahedral procapsid that is later filled with dsDNA. The SPs are bound to the portal complex during formation of a procapsid with scaffolding inside. The sequence of conformational changes from a procapsid to the phage capsid where genome has been packed is named as the maturation process and goes through a series of intermediates [19, 38, 39, 40]. Some phages like HK97 and T5 do not have a separate SP; instead, the capsid protein is fused with a scaffolding domain at the N-terminus. As soon as the procapsid is assembled, the scaffolding domain is cleaved off and then like the separate SP will be removed from the capsid to make room for the genome [38, 39]. Structures of procapsids and mature virions have been determined for a number of phages (Table 1). The spherical capsid shell expands during maturation and becomes thinner due to alterations in the inter- and intra-subunit contacts.
\nPhage | \nType of phage | \nCapsid protein | \nNo. of residues | \nM. Mass (kDa) | \nResolution (Å) | \nStructure analysis | \n
---|---|---|---|---|---|---|
HK97 | \ngp5 | \n385 282 (AC) | \n42 | \n3.44 (C) 12 (PC) | \nX-ray [42] EM [51] | \n|
Т5 | \npb8 | \n458 299 (AC) | \n51 | \n9 (C) | \nEM [52] | \n|
λ | \ngpE | \n341 | \n38 | \n6.8 (C),13.3 (PC) | \nEM [47] | \n|
SPP1 | \ngp13 | \n324 | \n35 | \n8.8 (C) | \nEM [53] | \n|
TP901-1 | \nORF36 | \n272 | \n29 | \n15 | \nEM [54] | \n|
TW1 | \ngp57* | \n352 | \n39 | \n7 | \nEM [55] | \n|
φ29 | \ngp8 | \n448 | \n50 | \n8 | \nEM [56] | \n|
T7 | \ngp10 | \n345 | \n37 | \n4.6 (PC) 3.6 (C) | \nEM [57] | \n|
P22 | \ngp5 | \n430 | \n47 | \n3.8 (PC) 4.0 (C) 3.3 (C) | \nEM [58, 59, 60] | \n|
ε15 | \ngp7 | \n335 | \n37 | \n4.5 | \nEM [50] | \n|
T4 | \ngp24 gp24* gp23 gp23* | \n427 417 (AC) 521 456 (AC) | \n47 44 56 49 | \n2.9 (monomer) 3.3 (EM) | \nX-ray [61] EM [62] | \n|
HSV-1 | \nVP5 | \n1374 | \n149 | \n4.2 (C) | \nEM [63] | \n
Phage procapsids and capsids.
AC—after cleavage; C—capsid; PC—procapsid
Most tailed phages have capsids of an icosahedral shape formed by multiple copies of one or more proteins. Icosahedral capsids are characterised by 12× fivefold, 20× threefold and 30× twofold axes, which give rise to 60 copies of the major independent parts [41]. A triangulation number (T number) describes the number of copies of the same protein within the independent part of the icosahedral lattice. The overall number of proteins in the virus corresponds to the T number multiplied by 60; for example, a T = 3 virus has 180 subunits [41]. Oligomers of the proteins that are located on the fivefold axes are referred to as pentons, while those complexes that are located on the faces of the icosahedron and form oligomers from six subunits are named as hexons.
\nStructural organisation of the major capsid proteins. (A) Siphophage HK97 (1OHG). The catalytic residues are shown in brown and circled. (B) Podophage ε15 (3 J40). (C) Podophage P22 (5UU5). (D) MyophageT4 gp23* (5VF3). The N-arm is dark blue, the P-domain is red, the A-domain is light blue and the E-loop is yellow. Extra inserted domains seen in P22 and T4 are magenta. The yellow linker in T4 is topologically equivalent to the E-loop seen in the other phages.
Crystal structures were obtained for the Hoc protein from the T4-like phage RB49 with the capsid-binding C-terminal domain 4 missing [71] and Soc protein from the T4-like phage RB49 [72]. The Soc molecules, which are required for capsid stability, interact with three gp23* subunits [62] although not all binding sites were fully occupied possibly due to differences in the gp23* I-domain linkers. The immunogenic outer capsid Hoc protein was found in two different sites within the asymmetric unit: at the centre of the hexon near the icosahedral threefold axis and in the hexon close to the fivefold axis [62]. The density of Hoc near the threefold axis was less interpretable than that near the fivefold axis.
\nIn phages and herpesviruses, one of the fivefold vertices of the capsid is replaced by a
All currently known PPs are homo-dodecamers when extracted from the viral capsids, as that symmetry is imposed during self-assembly in vivo. However, naive assemblies in vitro of the PP complexes have some variations in their rotational symmetry with 13-mers being observed for SPP1, T7 and HK97 [31, 33, 74]. HSV has been shown to have 11-fold, 12-fold, 13-fold and sometimes even 14-fold symmetry [34]. While monomers of the different PPs vary in size, all of them share a common fold—shown by EM and X-ray structures that were obtained for the φ29, SPP1 and P22 portals [75, 76, 77, 78] and by cryo-EM for T7 and T4 (Table 2) [69, 79]. All known PP monomers are characterised by four domains: clip, stem, wing and crown (Figure 4) [77]. The clip domain is exposed to the capsid exterior and involved in binding to the terminase for DNA packaging [75, 80, 81] and later to a head completion protein during the HTI assembly [82]. The first high-resolution structure of a phage PP was obtained for the φ29 phage (Figure 4A, [75]). The clip domain is linked to the wing region through a stem that comprises typically two α-helices and the outer loops (Figure 4B,C). X-ray structures of PP from φ29 and SPP1 phages revealed major helical components that form the central channel through which DNA enters and exits the capsid. The structures of other PPs obtained later have confirmed that this is a conserved element characteristic for all known PPs. The wing domain radiates outwards from the central axis and has an α-helix, which is the longest one and serves as a spine of the wing. It has an α/β sub-fold at its periphery [77]. The crown domain consists of α-helices and is relatively small in SPP1 and surprisingly long (213 aa) in phage P22 (Figure 4B,D, Table 2).
\nPhage | \nPP | \nNo. of residues | \nM. Mass (kDa) | \nResolution (Å) | \nStructure analysis | \n
---|---|---|---|---|---|
HK97 | \ngp3 | \n424 | \n47 | \n\n | none | \n
T5 | \npb7 | \n403 | \n45 | \n\n | none | \n
λ | \ngpB | \n533 | \n59 | \n\n | none | \n
SPP1 | \ngp6 | \n503 | \n57 | \n3.4 (X-ray), ~7 (EM) | \nX-ray [77], EM [82] | \n
TP901-1 | \nORF32 | \n452 | \n52 | \n20 | \nEM [54] | \n
TW1 | \ngp24 | \n459 | \n51 | \n21 | \nEM [55] | \n
φ29 | \ngp10 | \n309 | \n36 | \n2.1 | \nX-ray [76] | \n
T7 | \ngp8 | \n536 | \n59 | \n8, 12 | \nEM [87] | \n
P22 | \ngp1 | \n725 | \n83 | \n10.5 (EM) 3.25 (X-ray) | \nEM [88] X-ray [78] | \n
ε15 | \ngp4 | \n556 | \n61 | \n20 | \nEM [89] | \n
T4 | \ngp20 | \n524 | \n61 | \n3.6 | \nEM [69] | \n
HSV-1 | \npUL6 | \n676 | \n74.2 | \n8 | \nEM [90] | \n
Phage portal proteins.
Structures of portal proteins. One chain of the PP is highlighted in red. (A) gp10 of φ29 (1FOU). (B) gp6 of SPP1 (2JES). (C) A gp6 SPP1 monomer with the crown, stem, wing and clip domains indicated. (D) gp1 of P22 (3LJ5). (E) gp8 of T7 (3J4A). (F) gp24 of T4 (3JA7).
Structures of the HTI. (A) The cryo-EM map of the SPP1 HTI coloured according to protein with the gp6 PP (blue), adaptor gp15 (brown) and stopper (purple) (EMD-1021 [
The tail organisation in phages depends on their type:
Phage | \nTail proteins | \nNo. of residues | \nM. Mass kDa | \nResolution (Å) | \nStructure analysis | \n
---|---|---|---|---|---|
HK97 | \nputative tail-component IPR010064, gp10 | \nnot defined | \nnot known | \nn/a | \nNone | \n
Т5 | \npb6 | \n464 | \n50 | \n2.2 6 | \nX-ray [97] EM [97] | \n
λ | \ngpV (TP) gpH (TMP) gpU (terminator) | \n246 853 131 | \n26 92 15 | \nn/a 2.7 | \nNMR [98, 102] X-ray [103] | \n
SPP1 | \ngp17 (TP) gp17* (TP) gp18 (TMP) | \n134 264 1032 | \n15 28 111 | \nn/a 14 | \nNMR (gp17) [104] EM [85] | \n
TW1 | \ngp12 (TP) gp14 (TMP) | \nNF 675 | \n18 72 | \n23 | \nEM [55] | \n
φ29 | \ngp9 (knob) gp12 (tailspike) | \n599 854 | \n68 92 | \n2.04 1.8–2.05 7.8 | \nX-ray [105, 106] EM [56] | \n
T7 | \ngp11 (TP) gp12 (TP) gp17 (fibres) | \n196 794 553 | \n22 89 62 | \n12.0 2.0 (X-ray) | \nEM (gp11,12,17) [87] X-ray (gp17) [107] | \n
P22 | \ngp10 (hub) gp9 (tailspike) | \n472 667 | \n52 72 | \n9.4 2.0 | \nEM, tomography [88, 91], X-ray [108, 109] | \n
ε15 | \ngp20 (tailspike) | \n1070 | \n116 | \n20n/r | \nEM [89, 110] | \n
T4 | \ngp19 (TP) gp15 (terminator) | \n163 272 | \n18 32 | \n4.11 3.4 15.0 3.2 | \nEM [111, 112] X-ray [113] | \n
HSV | \ndoes not have the tail | \nn/a | \nn/a | \nn/a | \nn/a | \n
Phage tail structures.
Bacteriophage tails. (A) The crystal structure of a monomer of T5 pb6 (5NGJ). The extra immunoglobulin domain is coloured yellow. (B) A slice of the combined EM map of T5 (EMD-3692) showing the fold symmetry of the tail. (C) The crystal structure of the N-terminal domain of the P22 TP gpV (2K4Q). (D) Cryo-EM map of SPP1 tails (gp17.1). (E) Cryo-EM map of SPP1 tails (gp17.1*). The protrusions are the size of an immunoglobulin domain. (F) The T4 cryo-EM map (EMD-8767) with fitted coordinates (5W5F). Alternate subunits in the central ring are coloured red and blue. The red circle in B and rectangles in D, E and F indicate the inner tail tube, γ—rotation between adjacent tail rings.
Most
Adsorption apparatus. (A) The EM map (EMD-5051) of P22 coloured according to the constituent proteins. The PP (gp1), the gp4 12-mer, the gp10 6-mer, the gp9 tailspikes and the gp26 cell-puncturing needle are in purple, green, red, blue and brown, respectively. (B) The crystal structures for the N-terminal head-binding domain (1LKT) and the C-terminal receptor-binding domain (1TYU) of P22 gp9 docked into the cryo-EM density (EMDB-5051). (C) The receptor-binding carboxy-terminal domain of T5 tail fibre pb1 (5AQ5). The five different domain regions are labelled. The N- and C-termini are indicated. (D) The EM map (EMD- 8868) of the TW1 tail showing the TP gp12 (in blue), gp15 (in green), gp16, gp18, gp27 (together in light brown) and the gp19 tailspikes (in purple). (E) The φ29 tailspike protein gp12 (3SUC). The four domains D1*, D2, D3 and D4 are labelled. (F) The crystal structure (1 K28) of the cell-puncturing device of T4 (gp27 ± gp5* ± gp5C)3. Each monomer within in the gp5 trimer is coloured in blue, green and orange, and each one in gp27 is coloured in magenta, red and cyan.
The structure of the T4 baseplate was assembled in vitro from gp10, gp7, gp8, gp6 and gp53, and the crystal structure was determined (4.2 Å) [141]. This indicated interesting differences compared to the structures when they are separately crystallised. However, about two-thirds of the structure was missing, but a cryo-EM structure of the same construct (3.8 Å) provided the positions of these missing parts [142]. The structures of T4 baseplate in its pre- and post-host attachment states were determined at 4.11 and 6.77 Å, respectively, by cryo-EM [111]. By combining high-resolution structures of the individual baseplate proteins, the authors were able to build a pseudo-atomic model for the baseplate proteins. The crystal structure at 2.9 Å of the gp5–gp27 cell-puncturing device was fitted into the EM structure (Figure 7F) [143]. Positions of gp27, gp5C (the C-terminal β-helix domain of gp5) and gp5* (the N-terminal OB-fold domain and the lysozyme middle domain) were identified. A monomeric protein gp5.4 caps the tip of the gp5 β-helix to sharpen the central spike [144]. During infection this spike punctures the cell membrane, and the lysozyme domain of gp5 digests the peptidoglycan in the
Structural studies of the currently known tailed phages have shown a common organisation, which implies that they have a single ancestor and diversity has arisen through evolution [37]. All phages have a similar pathway of self-assembly: a procapsid formed with the help of a SP (or sometimes a scaffolding domain); conformational changes induced by release of the SP create a space for the DNA, and assisted by DNA terminases, the genome is packaged into the procapsid. This step is typically named as the maturation of the capsid. The tail is then attached or assembled on the capsid to form the infectious virion. The MCPs are characterised by the HK97 capsid protein fold. However, phages have a very low sequence similarity, which leads to differences in how the capsid stability is arranged to withstand the high inner pressure of the genome. In some phages like HK97 and SPP1, the interactions between capsid proteins are strong and hold the capsid intact. In many phages the process of capsid maturation is linked to attachment of additional proteins that are named as auxiliary or decoration proteins. They are often essential to enhance the capsid stability. The HK97 capsid is held together by chain mail covalent links between the MCPs; in SPP1 and T5, the decoration proteins enhance stability of the capsid, but in λ, T4 and ε15 phages, these proteins are essential for keeping DNA inside the capsid [19, 52, 53].
\nThe HTIs play an important role in all tailed phages as they provide a channel for DNA to enter and exit the capsid and at the same time provide a covalent connection to either the preassembled tails or tails assembled on the capsid. They all contain a dodecameric PP positioned within the capsid at one of the fivefold vertices and that acts as a gatekeeper holding the DNA within the capsid even in very harsh environments. Like the capsid proteins, the PPs have a common fold with the conserved elements being involved in interactions with DNA [145]. They have mostly α-helical domains in their central part and β-layers in the wing domains that interact with the capsid to fix the PP position. Head completion proteins below the PP also have similar folds to each other.
\nA much higher level of divergence is reflected in phage tail structures. The most common feature in all long-tailed phages is a central tube with a large number (30–40) of three- or sixfold circular rings of the major TPs. There is structural similarity between these major TPs: they have a similar fold of a β-sandwich flanked by alpha-helices and loops that provide links between adjacent rings. The helical tails have a typical rise of about 40 Å and rotation of around 20° between adjacent rings. Some tails also have appendages, which appear to have an immunoglobulin-like fold. Very little is known about the organisation of tail sheaths that have some similarities with type VI secretion systems, but sometimes they have extra appendages like immunoglobulin domains to help phages recognise their host cells. There is also some structural similarity of the TP with the tail terminator proteins and proteins in the T4 sheath.
\nEven higher diversity is found in the adsorption apparatus which are responsible for the recognition of the host cells and signalling the opening of the gate for the genome release. The tip of phage SPP1 recognises its receptor; induces the tail to be attached to the outer membrane of the host cell after disconnection of the tip. At the same time this interaction generates a signal that open the PP gate keeper. The T4 phage has a significantly more complex system of a baseplate which undergoes several steps of complex conformational changes.
\nInterestingly, the receptor-binding proteins also a have similar organisation: they are all trimers, usually intertwined with β-helical regions, and use their N-terminal domain to bind to the phage. Spikes and fibres are also found in many phages. However, the number of spikes or fibres varies significantly between phages. Podophages have trimeric tailspikes to recognise the specific host cell for infection. Like other phage components, they vary from six fibres in phage T7 to 12 in phage φ29, but they all have a β-helical fold. The fibres can have different roles within a phage, for instance, T4 has six long fibres that serve as host recognition and six short fibres which then extend and bind to the cell.
\nAntibiotics (especially of the broad-spectrum type) are very effective at killing infectious bacteria; however, they kill typically multiple bacterial species indiscriminately, thus destroying beneficial bacteria of the host microbiome as well. Since phages are specific to one species of bacteria, they are unlikely to perturb microbiome bacterial species. Current problems with antibiotic resistance require new approaches, and here phages can be used [12]. For medicinal purposes it is necessary to design a phage that will recognise the specific bacteria we want to eliminate [146]. Phages can be modified for high specificity in the recognition of pathogens. The high level of phage specificity is based on recognition of receptor characteristic for a given type of bacteria which is where the differences in the adsorption systems of different phages play a crucial role. The important task in studying phages is to find those that are able to kill only antibiotic-resistant bacteria. Here, the lytic phages are of most interest, since rather than stopping bacteria from producing a certain type of protein that will slow down the bacterium proliferation, like in the case of antibiotics, these phages destroy the bacteria’s cell wall and cell membrane completely. In addition, many bacteria develop biofilm—a thick layer of viscous materials that protect them from antibiotics. Some phages are equipped with tools that can digest this biofilm [147]. There are some problems with phages, since they are easy to use for topical applications, but often specific medications have to be administered internally. For phages to be used for delivery of drugs, they need to be more precise in their action. Consequently, we need to modify them so that the infectivity will be efficient by replacing the genome with DNA encoding specific enzymes and the adsorption apparatus made more effective. To develop these medical approaches, we need to know the phage organisation and the interactions between protein components at the atomic level. To achieve this hybrid, methods should be used including structural biology, biochemistry and microbiology [21].
\nThe authors are grateful to Dr. D. Houldershaw and Mr. Y. Goudetsidis for their computer support. The authors apologise for the incomplete coverage of known phage structures and have drawn on a limited subset, owing to space constraints.
\nThe authors declare no conflict of interest.
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\n\nOut of all of the publishing options available to researchers, why choose to contribute your research to an IntechOpen Edited Volume? The reasons are simple. IntechOpen has worked exceptionally hard over the past years to fine tune the Open Access book publishing process and we continue to work hard to deliver the best for all of our contributors. The quality of published content is of utmost importance to us, followed closely by speed, and of course, availability and accessibility. To view current Open Access book projects that are Open for Submissions visit us here.
\n\nQUALITY CONTENT
\n\nOver the years we have learned what is important. What makes a difference to the researchers that work with us, what they value. Something that is very high not only on their lists, but our own, is the quality of the published content.
\n\nOur books contain scientific content written by two Nobel Prize winners, two Breakthrough Prize winners and 73 authors who are in the top 1% Most Cited.
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\n\nIn addition to BKCI, IntechOpen covers a number of important discipline specific databases as well, such as Thomson Reuters’ BIOSIS Previews.
\n\nACCESS
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He is also a member of the editorial boards of the Journal of Electrical Engineering, Electronics, Control and Computer Science and Sustainability. Dr. Gaiceanu has been General Chairman of the IEEE International Symposium on Electrical and Electronics Engineering in the last six editions.",institutionString:'"Dunarea de Jos" University of Galati',institution:{name:'"Dunarea de Jos" University of Galati',country:{name:"Romania"}}},{id:"4519",title:"Prof.",name:"Jaydip",middleName:null,surname:"Sen",slug:"jaydip-sen",fullName:"Jaydip Sen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/4519/images/system/4519.jpeg",biography:"Jaydip Sen is associated with Praxis Business School, Kolkata, India, as a professor in the Department of Data Science. His research areas include security and privacy issues in computing and communication, intrusion detection systems, machine learning, deep learning, and artificial intelligence in the financial domain. He has more than 200 publications in reputed international journals, refereed conference proceedings, and 20 book chapters in books published by internationally renowned publishing houses, such as Springer, CRC press, IGI Global, etc. Currently, he is serving on the editorial board of the prestigious journal Frontiers in Communications and Networks and in the technical program committees of a number of high-ranked international conferences organized by the IEEE, USA, and the ACM, USA. He has been listed among the top 2% of scientists in the world for the last three consecutive years, 2019 to 2021 as per studies conducted by the Stanford University, USA.",institutionString:"Praxis Business School",institution:null},{id:"320071",title:"Dr.",name:"Sidra",middleName:null,surname:"Mehtab",slug:"sidra-mehtab",fullName:"Sidra Mehtab",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00002v6KHoQAM/Profile_Picture_1584512086360",biography:"Sidra Mehtab has completed her BS with honors in Physics from Calcutta University, India in 2018. She has done MS in Data Science and Analytics from Maulana Abul Kalam Azad University of Technology (MAKAUT), Kolkata, India in 2020. Her research areas include Econometrics, Time Series Analysis, Machine Learning, Deep Learning, Artificial Intelligence, and Computer and Network Security with a particular focus on Cyber Security Analytics. Ms. Mehtab has published seven papers in international conferences and one of her papers has been accepted for publication in a reputable international journal. She has won the best paper awards in two prestigious international conferences – BAICONF 2019, and ICADCML 2021, organized in the Indian Institute of Management, Bangalore, India in December 2019, and SOA University, Bhubaneswar, India in January 2021. Besides, Ms. Mehtab has also published two book chapters in two books. Seven of her book chapters will be published in a volume shortly in 2021 by Cambridge Scholars’ Press, UK. Currently, she is working as the joint editor of two edited volumes on Time Series Analysis and Forecasting to be published in the first half of 2021 by an international house. Currently, she is working as a Data Scientist with an MNC in Delhi, India.",institutionString:"NSHM College of Management and Technology",institution:{name:"Association for Computing Machinery",country:{name:"United States of America"}}},{id:"226240",title:"Dr.",name:"Andri Irfan",middleName:null,surname:"Rifai",slug:"andri-irfan-rifai",fullName:"Andri Irfan Rifai",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/226240/images/7412_n.jpg",biography:"Andri IRFAN is a Senior Lecturer of Civil Engineering and Planning. He completed the PhD at the Universitas Indonesia & Universidade do Minho with Sandwich Program Scholarship from the Directorate General of Higher Education and LPDP scholarship. He has been teaching for more than 19 years and much active to applied his knowledge in the project construction in Indonesia. His research interest ranges from pavement management system to advanced data mining techniques for transportation engineering. He has published more than 50 papers in journals and 2 books.",institutionString:null,institution:{name:"Universitas Internasional Batam",country:{name:"Indonesia"}}},{id:"314576",title:"Dr.",name:"Ibai",middleName:null,surname:"Laña",slug:"ibai-lana",fullName:"Ibai Laña",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/314576/images/system/314576.jpg",biography:"Dr. Ibai Laña works at TECNALIA as a data analyst. He received his Ph.D. in Artificial Intelligence from the University of the Basque Country (UPV/EHU), Spain, in 2018. He is currently a senior researcher at TECNALIA. His research interests fall within the intersection of intelligent transportation systems, machine learning, traffic data analysis, and data science. He has dealt with urban traffic forecasting problems, applying machine learning models and evolutionary algorithms. He has experience in origin-destination matrix estimation or point of interest and trajectory detection. Working with large volumes of data has given him a good command of big data processing tools and NoSQL databases. He has also been a visiting scholar at the Knowledge Engineering and Discovery Research Institute, Auckland University of Technology.",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"314575",title:"Dr.",name:"Jesus",middleName:null,surname:"L. Lobo",slug:"jesus-l.-lobo",fullName:"Jesus L. Lobo",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/314575/images/system/314575.png",biography:"Dr. Jesús López is currently based in Bilbao (Spain) working at TECNALIA as Artificial Intelligence Research Scientist. In most cases, a project idea or a new research line needs to be investigated to see if it is good enough to take into production or to focus on it. That is exactly what he does, diving into Machine Learning algorithms and technologies to help TECNALIA to decide whether something is great in theory or will actually impact on the product or processes of its projects. So, he is expert at framing experiments, developing hypotheses, and proving whether they’re true or not, in order to investigate fundamental problems with a longer time horizon. He is also able to design and develop PoCs and system prototypes in simulation. He has participated in several national and internacional R&D projects.\n\nAs another relevant part of his everyday research work, he usually publishes his findings in reputed scientific refereed journals and international conferences, occasionally acting as reviewer and Programme Commitee member. Concretely, since 2018 he has published 9 JCR (8 Q1) journal papers, 9 conference papers (e.g. ECML PKDD 2021), and he has co-edited a book. He is also active in popular science writing data science stories for reputed blogs (KDNuggets, TowardsDataScience, Naukas). Besides, he has recently embarked on mentoring programmes as mentor, and has also worked as data science trainer.",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"103779",title:"Prof.",name:"Yalcin",middleName:null,surname:"Isler",slug:"yalcin-isler",fullName:"Yalcin Isler",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRyQ8QAK/Profile_Picture_1628834958734",biography:"Yalcin Isler (1971 - Burdur / Turkey) received the B.Sc. degree in the Department of Electrical and Electronics Engineering from Anadolu University, Eskisehir, Turkey, in 1993, the M.Sc. degree from the Department of Electronics and Communication Engineering, Suleyman Demirel University, Isparta, Turkey, in 1996, the Ph.D. degree from the Department of Electrical and Electronics Engineering, Dokuz Eylul University, Izmir, Turkey, in 2009, and the Competence of Associate Professorship from the Turkish Interuniversity Council in 2019.\n\nHe was Lecturer at Burdur Vocational School in Suleyman Demirel University (1993-2000, Burdur / Turkey), Software Engineer (2000-2002, Izmir / Turkey), Research Assistant in Bulent Ecevit University (2002-2003, Zonguldak / Turkey), Research Assistant in Dokuz Eylul University (2003-2010, Izmir / Turkey), Assistant Professor at the Department of Electrical and Electronics Engineering in Bulent Ecevit University (2010-2012, Zonguldak / Turkey), Assistant Professor at the Department of Biomedical Engineering in Izmir Katip Celebi University (2012-2019, Izmir / Turkey). He is an Associate Professor at the Department of Biomedical Engineering at Izmir Katip Celebi University, Izmir / Turkey, since 2019. In addition to academics, he has also founded Islerya Medical and Information Technologies Company, Izmir / Turkey, since 2017.\n\nHis main research interests cover biomedical signal processing, pattern recognition, medical device design, programming, and embedded systems. He has many scientific papers and participated in several projects in these study fields. He was an IEEE Student Member (2009-2011) and IEEE Member (2011-2014) and has been IEEE Senior Member since 2014.",institutionString:null,institution:{name:"Izmir Kâtip Çelebi University",country:{name:"Turkey"}}},{id:"339677",title:"Dr.",name:"Mrinmoy",middleName:null,surname:"Roy",slug:"mrinmoy-roy",fullName:"Mrinmoy Roy",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/339677/images/16768_n.jpg",biography:"An accomplished Sales & Marketing professional with 12 years of cross-functional experience in well-known organisations such as CIPLA, LUPIN, GLENMARK, ASTRAZENECA across different segment of Sales & Marketing, International Business, Institutional Business, Product Management, Strategic Marketing of HIV, Oncology, Derma, Respiratory, Anti-Diabetic, Nutraceutical & Stomatological Product Portfolio and Generic as well as Chronic Critical Care Portfolio. A First Class MBA in International Business & Strategic Marketing, B.Pharm, D.Pharm, Google Certified Digital Marketing Professional. Qualified PhD Candidate in Operations and Management with special focus on Artificial Intelligence and Machine Learning adoption, analysis and use in Healthcare, Hospital & Pharma Domain. Seasoned with diverse therapy area of Pharmaceutical Sales & Marketing ranging from generating revenue through generating prescriptions, launching new products, and making them big brands with continuous strategy execution at the Physician and Patients level. Moved from Sales to Marketing and Business Development for 3.5 years in South East Asian Market operating from Manila, Philippines. Came back to India and handled and developed Brands such as Gluconorm, Lupisulin, Supracal, Absolut Woman, Hemozink, Fabiflu (For COVID 19), and many more. In my previous assignment I used to develop and execute strategies on Sales & Marketing, Commercialization & Business Development for Institution and Corporate Hospital Business portfolio of Oncology Therapy Area for AstraZeneca Pharma India Ltd. Being a Research Scholar and Student of ‘Operations Research & Management: Artificial Intelligence’ I published several pioneer research papers and book chapters on the same in Internationally reputed journals and Books indexed in Scopus, Springer and Ei Compendex, Google Scholar etc. Currently, I am launching PGDM Pharmaceutical Management Program in IIHMR Bangalore and spearheading the course curriculum and structure of the same. I am interested in Collaboration for Healthcare Innovation, Pharma AI Innovation, Future trend in Marketing and Management with incubation on Healthcare, Healthcare IT startups, AI-ML Modelling and Healthcare Algorithm based training module development. I am also an affiliated member of the Institute of Management Consultant of India, looking forward to Healthcare, Healthcare IT and Innovation, Pharma and Hospital Management Consulting works.",institutionString:null,institution:{name:"Lovely Professional University",country:{name:"India"}}},{id:"310576",title:"Prof.",name:"Erick Giovani",middleName:null,surname:"Sperandio Nascimento",slug:"erick-giovani-sperandio-nascimento",fullName:"Erick Giovani Sperandio Nascimento",position:null,profilePictureURL:"https://intech-files.s3.amazonaws.com/0033Y00002pDKxDQAW/ProfilePicture%202022-06-20%2019%3A57%3A24.788",biography:"Prof. Erick Sperandio is the Lead Researcher and professor of Artificial Intelligence (AI) at SENAI CIMATEC, Bahia, Brazil, also working with Computational Modeling (CM) and HPC. He holds a PhD in Environmental Engineering in the area of Atmospheric Computational Modeling, a Master in Informatics in the field of Computational Intelligence and Graduated in Computer Science from UFES. He currently coordinates, leads and participates in R&D projects in the areas of AI, computational modeling and supercomputing applied to different areas such as Oil and Gas, Health, Advanced Manufacturing, Renewable Energies and Atmospheric Sciences, advising undergraduate, master's and doctoral students. He is the Lead Researcher at SENAI CIMATEC's Reference Center on Artificial Intelligence. In addition, he is a Certified Instructor and University Ambassador of the NVIDIA Deep Learning Institute (DLI) in the areas of Deep Learning, Computer Vision, Natural Language Processing and Recommender Systems, and Principal Investigator of the NVIDIA/CIMATEC AI Joint Lab, the first in Latin America within the NVIDIA AI Technology Center (NVAITC) worldwide program. He also works as a researcher at the Supercomputing Center for Industrial Innovation (CS2i) and at the SENAI Institute of Innovation for Automation (ISI Automação), both from SENAI CIMATEC. He is a member and vice-coordinator of the Basic Board of Scientific-Technological Advice and Evaluation, in the area of Innovation, of the Foundation for Research Support of the State of Bahia (FAPESB). He serves as Technology Transfer Coordinator and one of the Principal Investigators at the National Applied Research Center in Artificial Intelligence (CPA-IA) of SENAI CIMATEC, focusing on Industry, being one of the six CPA-IA in Brazil approved by MCTI / FAPESP / CGI.br. He also participates as one of the representatives of Brazil in the BRICS Innovation Collaboration Working Group on HPC, ICT and AI. He is the coordinator of the Work Group of the Axis 5 - Workforce and Training - of the Brazilian Strategy for Artificial Intelligence (EBIA), and member of the MCTI/EMBRAPII AI Innovation Network Training Committee. He is the coordinator, by SENAI CIMATEC, of the Artificial Intelligence Reference Network of the State of Bahia (REDE BAH.IA). He leads the working group of experts representing Brazil in the Global Partnership on Artificial Intelligence (GPAI), on the theme \"AI and the Pandemic Response\".",institutionString:"Manufacturing and Technology Integrated Campus – SENAI CIMATEC",institution:null},{id:"1063",title:"Prof.",name:"Constantin",middleName:null,surname:"Volosencu",slug:"constantin-volosencu",fullName:"Constantin Volosencu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/1063/images/system/1063.png",biography:"Prof. Dr. Constantin Voloşencu graduated as an engineer from\nPolitehnica University of Timișoara, Romania, where he also\nobtained a doctorate degree. He is currently a full professor in\nthe Department of Automation and Applied Informatics at the\nsame university. Dr. Voloşencu is the author of ten books, seven\nbook chapters, and more than 160 papers published in journals\nand conference proceedings. He has also edited twelve books and\nhas twenty-seven patents to his name. He is a manager of research grants, editor in\nchief and member of international journal editorial boards, a former plenary speaker, a member of scientific committees, and chair at international conferences. His\nresearch is in the fields of control systems, control of electric drives, fuzzy control\nsystems, neural network applications, fault detection and diagnosis, sensor network\napplications, monitoring of distributed parameter systems, and power ultrasound\napplications. He has developed automation equipment for machine tools, spooling\nmachines, high-power ultrasound processes, and more.",institutionString:'"Politechnica" University Timişoara',institution:null},{id:"221364",title:"Dr.",name:"Eneko",middleName:null,surname:"Osaba",slug:"eneko-osaba",fullName:"Eneko Osaba",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/221364/images/system/221364.jpg",biography:"Dr. Eneko Osaba works at TECNALIA as a senior researcher. He obtained his Ph.D. in Artificial Intelligence in 2015. He has participated in more than twenty-five local and European research projects, and in the publication of more than 130 papers. He has performed several stays at universities in the United Kingdom, Italy, and Malta. Dr. Osaba has served as a program committee member in more than forty international conferences and participated in organizing activities in more than ten international conferences. He is a member of the editorial board of the International Journal of Artificial Intelligence, Data in Brief, and Journal of Advanced Transportation. He is also a guest editor for the Journal of Computational Science, Neurocomputing, Swarm, and Evolutionary Computation and IEEE ITS Magazine.",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"275829",title:"Dr.",name:"Esther",middleName:null,surname:"Villar-Rodriguez",slug:"esther-villar-rodriguez",fullName:"Esther Villar-Rodriguez",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/275829/images/system/275829.jpg",biography:"Dr. Esther Villar obtained a Ph.D. in Information and Communication Technologies from the University of Alcalá, Spain, in 2015. She obtained a degree in Computer Science from the University of Deusto, Spain, in 2010, and an MSc in Computer Languages and Systems from the National University of Distance Education, Spain, in 2012. Her areas of interest and knowledge include natural language processing (NLP), detection of impersonation in social networks, semantic web, and machine learning. Dr. Esther Villar made several contributions at conferences and publishing in various journals in those fields. Currently, she is working within the OPTIMA (Optimization Modeling & Analytics) business of TECNALIA’s ICT Division as a data scientist in projects related to the prediction and optimization of management and industrial processes (resource planning, energy efficiency, etc).",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"49813",title:"Dr.",name:"Javier",middleName:null,surname:"Del Ser",slug:"javier-del-ser",fullName:"Javier Del Ser",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/49813/images/system/49813.png",biography:"Prof. Dr. Javier Del Ser received his first PhD in Telecommunication Engineering (Cum Laude) from the University of Navarra, Spain, in 2006, and a second PhD in Computational Intelligence (Summa Cum Laude) from the University of Alcala, Spain, in 2013. He is currently a principal researcher in data analytics and optimisation at TECNALIA (Spain), a visiting fellow at the Basque Center for Applied Mathematics (BCAM) and a part-time lecturer at the University of the Basque Country (UPV/EHU). His research interests gravitate on the use of descriptive, prescriptive and predictive algorithms for data mining and optimization in a diverse range of application fields such as Energy, Transport, Telecommunications, Health and Industry, among others. In these fields he has published more than 240 articles, co-supervised 8 Ph.D. theses, edited 6 books, coauthored 7 patents and participated/led more than 40 research projects. He is a Senior Member of the IEEE, and a recipient of the Biscay Talent prize for his academic career.",institutionString:"Tecnalia Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"278948",title:"Dr.",name:"Carlos Pedro",middleName:null,surname:"Gonçalves",slug:"carlos-pedro-goncalves",fullName:"Carlos Pedro Gonçalves",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRcmyQAC/Profile_Picture_1564224512145",biography:'Carlos Pedro Gonçalves (PhD) is an Associate Professor at Lusophone University of Humanities and Technologies and a researcher on Complexity Sciences, Quantum Technologies, Artificial Intelligence, Strategic Studies, Studies in Intelligence and Security, FinTech and Financial Risk Modeling. He is also a progammer with programming experience in:\n\nA) Quantum Computing using Qiskit Python module and IBM Quantum Experience Platform, with software developed on the simulation of Quantum Artificial Neural Networks and Quantum Cybersecurity;\n\nB) Artificial Intelligence and Machine learning programming in Python;\n\nC) Artificial Intelligence, Multiagent Systems Modeling and System Dynamics Modeling in Netlogo, with models developed in the areas of Chaos Theory, Econophysics, Artificial Intelligence, Classical and Quantum Complex Systems Science, with the Econophysics models having been cited worldwide and incorporated in PhD programs by different Universities.\n\nReceived an Arctic Code Vault Contributor status by GitHub, due to having developed open source software preserved in the \\"Arctic Code Vault\\" for future generations (https://archiveprogram.github.com/arctic-vault/), with the Strategy Analyzer A.I. module for decision making support (based on his PhD thesis, used in his Classes on Decision Making and in Strategic Intelligence Consulting Activities) and QNeural Python Quantum Neural Network simulator also preserved in the \\"Arctic Code Vault\\", for access to these software modules see: https://github.com/cpgoncalves. He is also a peer reviewer with outsanding review status from Elsevier journals, including Physica A, Neurocomputing and Engineering Applications of Artificial Intelligence. Science CV available at: https://www.cienciavitae.pt//pt/8E1C-A8B3-78C5 and ORCID: https://orcid.org/0000-0002-0298-3974',institutionString:"University of Lisbon",institution:{name:"Universidade Lusófona",country:{name:"Portugal"}}},{id:"241400",title:"Prof.",name:"Mohammed",middleName:null,surname:"Bsiss",slug:"mohammed-bsiss",fullName:"Mohammed Bsiss",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/241400/images/8062_n.jpg",biography:null,institutionString:null,institution:null},{id:"276128",title:"Dr.",name:"Hira",middleName:null,surname:"Fatima",slug:"hira-fatima",fullName:"Hira Fatima",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/276128/images/14420_n.jpg",biography:"Dr. Hira Fatima\nAssistant Professor\nDepartment of Mathematics\nInstitute of Applied Science\nMangalayatan University, Aligarh\nMobile: no : 8532041179\nhirafatima2014@gmal.com\n\nDr. Hira Fatima has received his Ph.D. degree in pure Mathematics from Aligarh Muslim University, Aligarh India. Currently working as an Assistant Professor in the Department of Mathematics, Institute of Applied Science, Mangalayatan University, Aligarh. She taught so many courses of Mathematics of UG and PG level. Her research Area of Expertise is Functional Analysis & Sequence Spaces. She has been working on Ideal Convergence of double sequence. She has published 17 research papers in National and International Journals including Cogent Mathematics, Filomat, Journal of Intelligent and Fuzzy Systems, Advances in Difference Equations, Journal of Mathematical Analysis, Journal of Mathematical & Computer Science etc. She has also reviewed few research papers for the and international journals. She is a member of Indian Mathematical Society.",institutionString:null,institution:null},{id:"414880",title:"Dr.",name:"Maryam",middleName:null,surname:"Vatankhah",slug:"maryam-vatankhah",fullName:"Maryam Vatankhah",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Borough of Manhattan Community College",country:{name:"United States of America"}}},{id:"414879",title:"Prof.",name:"Mohammad-Reza",middleName:null,surname:"Akbarzadeh-Totonchi",slug:"mohammad-reza-akbarzadeh-totonchi",fullName:"Mohammad-Reza Akbarzadeh-Totonchi",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Ferdowsi University of Mashhad",country:{name:"Iran"}}},{id:"414878",title:"Prof.",name:"Reza",middleName:null,surname:"Fazel-Rezai",slug:"reza-fazel-rezai",fullName:"Reza Fazel-Rezai",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"American Public University System",country:{name:"United States of America"}}},{id:"426586",title:"Dr.",name:"Oladunni A.",middleName:null,surname:"Daramola",slug:"oladunni-a.-daramola",fullName:"Oladunni A. Daramola",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Federal University of Technology",country:{name:"Nigeria"}}},{id:"357014",title:"Prof.",name:"Leon",middleName:null,surname:"Bobrowski",slug:"leon-bobrowski",fullName:"Leon Bobrowski",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Bialystok University of Technology",country:{name:"Poland"}}},{id:"302698",title:"Dr.",name:"Yao",middleName:null,surname:"Shan",slug:"yao-shan",fullName:"Yao Shan",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Dalian University of Technology",country:{name:"China"}}},{id:"354126",title:"Dr.",name:"Setiawan",middleName:null,surname:"Hadi",slug:"setiawan-hadi",fullName:"Setiawan Hadi",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Padjadjaran University",country:{name:"Indonesia"}}},{id:"125911",title:"Prof.",name:"Jia-Ching",middleName:null,surname:"Wang",slug:"jia-ching-wang",fullName:"Jia-Ching Wang",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"National Central University",country:{name:"Taiwan"}}},{id:"332603",title:"Prof.",name:"Kumar S.",middleName:null,surname:"Ray",slug:"kumar-s.-ray",fullName:"Kumar S. Ray",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Indian Statistical Institute",country:{name:"India"}}},{id:"415409",title:"Prof.",name:"Maghsoud",middleName:null,surname:"Amiri",slug:"maghsoud-amiri",fullName:"Maghsoud Amiri",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Allameh Tabataba'i University",country:{name:"Iran"}}},{id:"357085",title:"Mr.",name:"P. Mohan",middleName:null,surname:"Anand",slug:"p.-mohan-anand",fullName:"P. Mohan Anand",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Indian Institute of Technology Kanpur",country:{name:"India"}}},{id:"356696",title:"Ph.D. Student",name:"P.V.",middleName:null,surname:"Sai Charan",slug:"p.v.-sai-charan",fullName:"P.V. Sai Charan",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Indian Institute of Technology Kanpur",country:{name:"India"}}},{id:"357086",title:"Prof.",name:"Sandeep K.",middleName:null,surname:"Shukla",slug:"sandeep-k.-shukla",fullName:"Sandeep K. Shukla",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Indian Institute of Technology Kanpur",country:{name:"India"}}}]}},subseries:{item:{id:"17",type:"subseries",title:"Metabolism",keywords:"Biomolecules Metabolism, Energy Metabolism, Metabolic Pathways, Key Metabolic Enzymes, Metabolic Adaptation",scope:"Metabolism is frequently defined in biochemistry textbooks as the overall process that allows living systems to acquire and use the free energy they need for their vital functions or the chemical processes that occur within a living organism to maintain life. Behind these definitions are hidden all the aspects of normal and pathological functioning of all processes that the topic ‘Metabolism’ will cover within the Biochemistry Series. 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