Phage procapsids and capsids.
\r\n\tSynthetic zeolites can be formed from different raw materials and among these many wastes represent some interesting sources due to their chemical and mineralogical composition. Today, a large number of different types of waste resulting from many human activities are produced in the world (e.g. industrial, municipal, agricultural waste) and most of them are deposed of in landfills thus determining a great environmental problem.
\r\n\r\n\tThis book intends to provide the reader with a comprehensive overview of the current state-of-the-art on the possibility to transform the different types of waste materials into useful products, zeolites, through conventional processes and innovative methods. The aim is to demonstrate that waste can be a problem or a resource depending on how it is managed.
",isbn:"978-1-80356-426-5",printIsbn:"978-1-80356-425-8",pdfIsbn:"978-1-80356-427-2",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,isSalesforceBook:!1,isNomenclature:!1,hash:"3ed0dfd842de9cd1143212415903e6ad",bookSignature:"Dr. Claudia Belviso",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11561.jpg",keywords:"Structure, Properties, Natural Material, Synthetic Product, Type, Composition, Production, Disposal, Hydrothermal Method, Pre-fusion Process, Sonication, Multiple Steps",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"February 25th 2022",dateEndSecondStepPublish:"March 25th 2022",dateEndThirdStepPublish:"May 24th 2022",dateEndFourthStepPublish:"August 12th 2022",dateEndFifthStepPublish:"October 11th 2022",dateConfirmationOfParticipation:null,remainingDaysToSecondStep:"3 months",secondStepPassed:!0,areRegistrationsClosed:!0,currentStepOfPublishingProcess:4,editedByType:null,kuFlag:!1,biosketch:"Since 2002, Dr. Claudia Belviso has been carrying out research activity in the field of mineralogy and geochemistry aimed at environmental protection. She is responsible for the research activity on zeolite synthesis from waste materials and natural sources which has allowed her to be the inventor of an International Patent, publish numerous scientific articles in peer-reviewed journals, and carry out scientific research in national and international projects.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"61457",title:"Dr.",name:"Claudia",middleName:null,surname:"Belviso",slug:"claudia-belviso",fullName:"Claudia Belviso",profilePictureURL:"https://mts.intechopen.com/storage/users/61457/images/system/61457.jpg",biography:"Claudia Belviso is a researcher at the Institute of Methodologies of Environmental Analysis (IMAA) of CNR. After graduating in Geological Sciences and qualifying as a professional geologist, she earned a Ph.D. in Earth Sciences. Since 2002 has been carrying out her research activity in the field of mineralogy and geochemistry aimed at environmental protection. She is responsible for the research activity on zeolite synthesis from waste materials and natural sources as well as their application to solving environmental problems and as new raw material. These research activities have allowed her to be the inventor of an International Patent, publish numerous scientific articles in peer-reviewed journals, participate in national and international conferences, take part in the organization of international congresses, and carry out scientific research in national and international projects.",institutionString:"National Research Council",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"1",institution:{name:"National Research Council",institutionURL:null,country:{name:"Italy"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"8",title:"Chemistry",slug:"chemistry"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"453622",firstName:"Tea",lastName:"Jurcic",middleName:null,title:"Ms.",imageUrl:"//cdnintech.com/web/frontend/www/assets/author.svg",email:"tea@intechopen.com",biography:null}},relatedBooks:[{type:"book",id:"5306",title:"Zeolites",subtitle:"Useful Minerals",isOpenForSubmission:!1,hash:"eec7f864baf093058440c0f56072a7cf",slug:"zeolites-useful-minerals",bookSignature:"Claudia Belviso",coverURL:"https://cdn.intechopen.com/books/images_new/5306.jpg",editedByType:"Edited by",editors:[{id:"61457",title:"Dr.",name:"Claudia",surname:"Belviso",slug:"claudia-belviso",fullName:"Claudia Belviso"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1591",title:"Infrared Spectroscopy",subtitle:"Materials Science, Engineering and Technology",isOpenForSubmission:!1,hash:"99b4b7b71a8caeb693ed762b40b017f4",slug:"infrared-spectroscopy-materials-science-engineering-and-technology",bookSignature:"Theophile Theophanides",coverURL:"https://cdn.intechopen.com/books/images_new/1591.jpg",editedByType:"Edited by",editors:[{id:"37194",title:"Dr.",name:"Theophile",surname:"Theophanides",slug:"theophile-theophanides",fullName:"Theophile Theophanides"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3161",title:"Frontiers in Guided Wave Optics and Optoelectronics",subtitle:null,isOpenForSubmission:!1,hash:"deb44e9c99f82bbce1083abea743146c",slug:"frontiers-in-guided-wave-optics-and-optoelectronics",bookSignature:"Bishnu Pal",coverURL:"https://cdn.intechopen.com/books/images_new/3161.jpg",editedByType:"Edited by",editors:[{id:"4782",title:"Prof.",name:"Bishnu",surname:"Pal",slug:"bishnu-pal",fullName:"Bishnu Pal"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3092",title:"Anopheles mosquitoes",subtitle:"New insights into malaria vectors",isOpenForSubmission:!1,hash:"c9e622485316d5e296288bf24d2b0d64",slug:"anopheles-mosquitoes-new-insights-into-malaria-vectors",bookSignature:"Sylvie Manguin",coverURL:"https://cdn.intechopen.com/books/images_new/3092.jpg",editedByType:"Edited by",editors:[{id:"50017",title:"Prof.",name:"Sylvie",surname:"Manguin",slug:"sylvie-manguin",fullName:"Sylvie Manguin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"371",title:"Abiotic Stress in Plants",subtitle:"Mechanisms and Adaptations",isOpenForSubmission:!1,hash:"588466f487e307619849d72389178a74",slug:"abiotic-stress-in-plants-mechanisms-and-adaptations",bookSignature:"Arun Shanker and B. Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"72",title:"Ionic Liquids",subtitle:"Theory, Properties, New Approaches",isOpenForSubmission:!1,hash:"d94ffa3cfa10505e3b1d676d46fcd3f5",slug:"ionic-liquids-theory-properties-new-approaches",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/72.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"314",title:"Regenerative Medicine and Tissue Engineering",subtitle:"Cells and Biomaterials",isOpenForSubmission:!1,hash:"bb67e80e480c86bb8315458012d65686",slug:"regenerative-medicine-and-tissue-engineering-cells-and-biomaterials",bookSignature:"Daniel Eberli",coverURL:"https://cdn.intechopen.com/books/images_new/314.jpg",editedByType:"Edited by",editors:[{id:"6495",title:"Dr.",name:"Daniel",surname:"Eberli",slug:"daniel-eberli",fullName:"Daniel Eberli"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"57",title:"Physics and Applications of Graphene",subtitle:"Experiments",isOpenForSubmission:!1,hash:"0e6622a71cf4f02f45bfdd5691e1189a",slug:"physics-and-applications-of-graphene-experiments",bookSignature:"Sergey Mikhailov",coverURL:"https://cdn.intechopen.com/books/images_new/57.jpg",editedByType:"Edited by",editors:[{id:"16042",title:"Dr.",name:"Sergey",surname:"Mikhailov",slug:"sergey-mikhailov",fullName:"Sergey Mikhailov"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1373",title:"Ionic Liquids",subtitle:"Applications and Perspectives",isOpenForSubmission:!1,hash:"5e9ae5ae9167cde4b344e499a792c41c",slug:"ionic-liquids-applications-and-perspectives",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/1373.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"2270",title:"Fourier Transform",subtitle:"Materials Analysis",isOpenForSubmission:!1,hash:"5e094b066da527193e878e160b4772af",slug:"fourier-transform-materials-analysis",bookSignature:"Salih Mohammed Salih",coverURL:"https://cdn.intechopen.com/books/images_new/2270.jpg",editedByType:"Edited by",editors:[{id:"111691",title:"Dr.Ing.",name:"Salih",surname:"Salih",slug:"salih-salih",fullName:"Salih Salih"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{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.
The canine elbow joint is a complex joint, whose musculoskeletal anatomy is well investigated. However, the in vivo function of the elbow joint, the individual movement of the humerus, radius and ulna relative to each other and the load distribution within the joint is still subject of present and future research. Especially pathophysiological motion of the elbow joint, leading to a mechanical overload of certain joint compartments, is not well understood and an interesting field of present veterinary research. Canine developmental elbow disease (DED), in particular medial coronoid disease (MCD), is one of the most common reasons for forelimb lameness in the dog and therefore this topic has not only academic, but also clinical relevance.
The canine elbow joint is composed of the humerus proximally and the radius and ulna distally, and can be divided into three joint compartments: the humero-ulnar, humero-radial and proximal radio-ulnar joint [1, 2]. The humero-ulnar joint is formed by the humeral trochlea and intercondylar region of the condyle and the ulnar trochlear notch, which extends from the anconeal process to the radial incisure, and continues to the medial coronoid process of the ulna. The humero-radial joint is formed by the capitulum of the humeral condyle and the radial head. The radial incisure and the medial aspect of the radial head form the proximal radio-ulnar joint. Altogether the elbow joint acts as a hinge joint (ginglymus) with extension and flexion being the main motion pattern and some amount of pronation and supination, mainly taken over by the radio-ulnar joint [1].
In healthy canine elbows the radio-ulnar joint shows a congruent shape without any step formation between the ulnar and radial joint surface, at least under static conditions. However, the humero-ulnar joint is not perfectly congruent even in healthy dogs [3, 4, 5, 6]. The radii of curvature of the humeral condyle and ulnar trochlear notch show different values along their curvilinear course, resulting in reduced contact in the central notch region [3, 4, 5, 6, 7]. The trochlear notch shows a slightly elliptical shape, so that the anconeal process and distal aspect of the notch as well as the coronoid process are in contact with the humeral condyle. This kind of physiological humero-ulnar incongruence was first described in humans and could be detected in the canine elbow joint, too [4, 5, 6, 8, 9].
The maximum range of motion (ROM) varies between 110 to 150 degrees, with breed-specific maximum flexion of 25 to 49 degrees and maximum extension of 155 to 175 degrees [10, 11, 12, 13, 14]. The main extensor muscle of the elbow joint is the triceps brachii muscle [1]. Further this muscle prevents flexion of the elbow during the stance phase. The anconeal and tensor fasciae antebrachii muscles are additional extensors of the elbow joint. Flexion is performed by the biceps brachii and brachial muscles. The extensor carpi radialis muscle contributes to flexor function to some amount. The canine antebrachium can be pronated 17 to 50 degrees and supinated 31 to 70 degrees [10, 15]. The supinator and brachioradial muscles are responsible for supination of the antebrachium. The latter contributes only minimal to supination and is missing in some individuals [16]. The pronator teres and pronator quadratus muscles are responsible for pronation and the pronator teres muscle is supposed to contribute to elbow joint flexion as well [1, 2].
Four ligaments support the elbow joint: the medial and lateral collateral ligament, the annular ligament and interosseous ligament/interosseous membrane [1, 2]. The medial and lateral collateral ligaments origin from the medial and lateral humeral epicondyle. The medial collateral divides into two crura. The cranial one is weaker and attaches at the radius, while the stronger caudal one attaches mainly at the ulna and to some amount at the radius. The lateral collateral ligament consists of two crura as well. The cranial part attaches to the radius, and the caudal part attaches to the ulna and colligates with the annular ligament, which can contain a sesamoid bone [2]. The annular ligament runs transversely around the radial head spanning from the lateral to the medial aspect of the radial incisure of the ulna. It runs underneath the medial and lateral collateral ligaments. The radius and ulna are further attached to each other by the interosseous ligament and interosseous membrane, which spans the interosseous space. Distally the radius and ulna are connected to each other by the radioulnar ligament.
Kinematics describe the motion of body segments without measuring the forces acting onto that segments. Kinematic analysis allows evaluation of the range of motion, angular velocities, segmental velocities of each portion of the limb, stride frequency and stride length [17]. Depending on the technique used for the kinematic analysis, motion of bones and joints can be measured with a submillimeter accuracy [18, 19, 20].
Generally two forms of kinematic analysis can be differentiated: the video-kinematography, based on a video motion capture system, and the radiostereometric kinematic analysis (RSA), based on a radiographic system, coupled with high speed video cameras. Video motion capture kinematic systems use skin markers, attached to specific body areas, which are tracked in the generated videos of the moving animal and allow for calculation of the aforementioned parameters. Radiostereometric analysis can be marker based or performed without bone markers [21, 22, 23, 24, 25, 26, 27, 28, 29, 30]. Furthermore, both kinematic analysis systems can be used to evaluate motion in the two or three dimensional (2D, 3D) space, depending on the technical setup [17].
The most commonly used technique is a video motion capture system based analysis. This technique is non-invasive and allows for evaluation of overall limb, limb segment or body segment motion. However, skin mounted markers do not match exactly the movement of the underlying bones. Movement of the soft tissues results in skin motion artifacts [21, 28, 31, 32, 33, 34, 35], with a difference of 0.4 to 1.2 cm between the skin marker and respective underlying bony landmark in small animals [33]. Especially in the proximal joints of the forelimb skin marker based data differ significantly from fluoroscopically gained kinematic data [28]. Comparison of biplanar fluoroscopy and video-kinematography in hindlimb kinematics revealed significant differences between both techniques, too [21]. Skin marker based data tend to project different trajectories and smaller amplitudes compared to fluoroscopic kinematography with particularly contradictory results, especially in proximal joints, where increased soft tissues can be found [21].
Radiostereometric analysis, also called fluoroscopic kinematography, allows for the most accurate kinematic data acquisition [19, 21, 22, 23, 24, 28, 30]. One or two fluoroscopic units, coupled with high speed video cameras, take x-ray movies of the moving object. Based on these x-ray movies bone movement can be calculated and transferred onto 3D bone models generated from CT scans of the individual animal. Bone motion analysis can be performed using implanted bone markers, which are tracked in one (uniplanar, 2D evaluation) or both (biplanar, 3D evaluation) x-ray movies and 3D coordinates of each marker are then transferred onto the 3D bone models. Alternatively, scientific rotoscoping or autoscoping techniques can be used to track bone movement and transfer this in vivo bone motion from the fluoroscopic images onto 3D bone models [18, 20, 36]. These techniques do not rely on bone markers, rather the shape and edges of each bone are used to project digitally reconstructed radiographs (DRR), generated from the CT scans of each bone, onto the respective bone in the fluoroscopic image. By that the 3D bone model is aligned and animated along the x-ray movies. Scientific rotoscoping is performed manually, while autoscoping is a completely computerized process. Both techniques can be described as morphology based methods of motion analysis. Marker based tacking is the gold standard of kinematic analysis with an accuracy of 0.1 mm and 0.1 degrees [20]. However, scientific rotoscoping and autoscoping show a high accuracy as well, with values ranging from 0.16 to 0.66 mm in translation and 0.43 to 2.78 degrees rotation for scientific rotoscoping and 0.07 to 1.13 mm translation and 0.01 to 3.0 degrees rotation for autoscoping [18, 37, 38, 39, 40, 41, 42]. Therefore, both techniques result in a highly precise evaluation of bone and joint motion with a substantially reduced invasiveness compared to a bone marker based analysis.
Multiple studies have investigated elbow joint kinematics in healthy dogs and dogs with different joint pathologies. Results have to be interpreted cautiously due to varying breeds, different technical setups and varying gaits and gait velocities, e.g. the walk or the trot, all of which influencing the kinematic pattern. Table 1 gives an overview of previous studies on canine forelimb and elbow joint kinematics.
Study | Technique | Breed | Number of dogs | Gait/Speed |
---|---|---|---|---|
DeCamp et al. [43] | 3D marker based video-kinematography, 2D evaluation (sagittal motion) | Greyhound | 8 | trot, 1.8–2.3 m/s (walkway) |
Allen et al. [44] | 3D marker based video-kinematography, 2D evaluation (sagittal motion) | Mixed breed dogs | 14 | trot, 1.8–2.3 m/s (overground) |
Hottinger et al. [45] | 3D marker based video-kinematography, 2D evaluation (sagittal motion) | Different large breed dogs | 15 | walk, 0.9–1.1. m/s (overground) |
Gillette and Zebas [46] | Uniplanar marker based video-kinematography, 2D evaluation (sagittal motion) | Labrador Retriever | 16 | trot, 2.8 m/s |
Nielsen et al. [47] | 3D marker based video-kinematography, 2D evaluation (sagittal motion), stance phase only | Mixed breed dogs | 6 | walk, 0.8–1.0 m/s (overground) |
Owen et al. [48] | Uniplanar marker based video-kinematography, 2D evaluation (sagittal motion) | Greyhound | 11 | trot, 2.2–2.4 m/s (treadmill) |
Clements et al. [49] | Uniplanar marker based video-kinematography, 2D evaluation (sagittal motion) | Labrador Retriever | 10 | trot, 2.0 m/s (treadmill) |
Feeney et al. [50] | Uniplanar marker based video-kinematography, 2D evaluation (sagittal motion) | Labrador Retriever | 10 | walk, velocity not documented (overground) |
Burton et al. [51] | 3D marker based video-kinematography, 2D evaluation (sagittal motion) | Different mid to large breed dogs | 7 (unilateral elbow disease) | trot, velocity not documented (treadmill) |
Holler et al. [52] | 3D marker based video-kinematography, 2D evaluation (sagittal motion) | Different mid to large breed dogs | 8 | walk, 0.89–1.1 m/s (treadmill, normal, uphill, downhill, obstacle) |
Agostinho et al. [53] | 3D marker based video-kinematography, 2D evaluation (sagittal motion) | Labrador Retriever Rottweiler | 20 (10 each) | trot, 2.1–2.2. m/s (treadmill) |
Guillou et al. [54] | 3D marker based fluoroscopic kinematography | Fox hound | 4 | walk & trot, velocity not documented |
Angle et al. [55] | Uniplanar marker based video-kinematography, 2D evaluation (sagittal motion) | Greyhound | 7 | Movement initiation up to 3.52 m/s (overground) |
Jarvis et al. [56] | 3D marker based video-kinematography, 2D evaluation (sagittal motion), stance phase only | Different breeds | 40 (24 healthy, 16 front limb amputee dogs) | trot, 2.2–2.6 m/s (walkway) |
Brady et al. [57] | 3D marker based video-kinematography, 2D evaluation (sagittal motion) | Different breeds | 16 | trot, 1.8 m/s & 2.5 m/s (walkway) |
Miqueleto et al. [58] | 3D marker based video-kinematography, 2D evaluation (sagittal motion) | German Shepherd | 20 (10 hip dysplasia, 10 healthy dogs) | trot, 2.1–2.2. m/s (treadmill) |
Galindo-Zamora et al. [59] | 3D marker based video-kinematography, 2D evaluation (sagittal motion) | Different mid to large breed dogs | 20 (unilateral elbow disease) | walk, 0.65–1.1 m/s (treadmill) |
Caron et al. [60] | 3D marker based video-kinematography, 3D evaluation | Labrador Retriever | 26 (13 healthy, 13 dogs with coronoid disease) | walk, 0.7 m/s (treadmill) |
Fischer & Lilje, [61] | 3D marker based video- & fluoroscopic kinematography, 2D evaluation (sagittal motion) | 32 different breeds | 327 | walk & trot, 0.54–5.56 m/s (treadmill) |
Catavitello et al. [62] | Uniplanar marker based video-kinematography, 2D evaluation (sagittal motion) | Labrador Retriever Golden Retriever | 6 (3 each breed) | walk, 2 m/s, trot, 4 m/s & running, 9.5 m/s (overground) |
Duerr et al. [63] | Uniplanar marker based video-kinematography, 2D evaluation (sagittal motion) and inertial measurements unit | Different mid to large breed dogs | 16 | trot, 2.4–2.5 m/s (overground) |
Andrada et al. [28] | 3D marker based video- & fluoroscopic kinematography (scientific rotoscoping), 3D evaluation | Beagle | 5 | walk, 0.98 m/s & trot, 2.2 m/s (treadmill) |
Lorke et al. [64] | 3D marker based video-kinematography, 2D evaluation (sagittal motion) | Beagle | 10 | trot, 1.7–1.8 m/s (treadmill) |
Rohwedder et al. [22] | 3D marker based fluoroscopic kinematography (first third of stance phase only) | Different mid to large breed dogs | 11 (5 healthy, 6 dogs with coronoid disease) | walk, 0.6–0.9 m/s (treadmill) |
Kopec et al. [65] | Uniplanar marker based video-kinematography, 2D evaluation (sagittal motion) | Different mid to large breed dogs | 8 | walk, 1.01–1.45 m/s (overground & stair exercise) |
Rohwedder et al. [23] | 3D marker based fluoroscopic kinematography (first third of stance phase only) | Different mid to large breed dogs | 11 (5 healthy, 6 dogs with coronoid disease) | walk, 0.6–0.9 m/s (treadmill) |
Rohwedder et al. [24] | 3D marker based fluoroscopic kinematography & joint contact pattern evaluation | Labrador Retriever | 1 (before and after DPUO*) | walk, 0.6–0.9 m/s (treadmill) |
Humphries et al. [66] | 3D marker based video-kinematography, 2D evaluation (sagittal motion) | Labrador Retriever German Shepherd | 24 (12 each breed) | trot, 2.19–2.45 m/s (walkway) |
De Souza et al. [67] | 3D marker based video-kinematography, 2D evaluation (sagittal motion) | American Pit Bull Terrier | 11 | walk, 1.17 ± 0.17 m/s trot, 2.04 ± 0.33 m/s (overground) |
Summary of studies investigating canine forelimb and/or elbow joint kinematics.
DPUO: dynamic proximal ulnar osteotomy.
Most studies on elbow joint kinematics are based on video-kinematographic analysis and have investigated the motion of the elbow only in the sagittal plane [43, 44, 45, 47, 48, 49, 50, 51, 52, 53, 55, 56, 57, 58, 59, 62, 63, 65, 68, 69]. Caron et al. were the first to describe the real 3D kinematics of the canine forelimb of healthy Labrador retrievers and dogs with medial coronoid disease using video-kinematographic analysis [60]. Another study evaluated the 3D motion of orthopedic healthy canine forelimbs using video-kinematography and compared that data to fluoroscopically gained motion analysis, which was additionally calculated in one of the dogs [28].
One complete gait cycle consists of the swing and the stance phase. The swing phase starts when the paw breaks contact with the ground and ends with first ground contact of the paw. The time between initial ground contact and paw lift is defined as the stance phase. The ratio between swing and stance phase depends from the gait pattern and the dog’s velocity [28, 29, 70, 71]. At the walk the swing phase of the forelimb accounts for 39 to 43% of the whole gait cycle [60] and increases to approximately 50% to two thirds of the whole gait cycle during the trot, depending from the trotting speed [28, 43, 45, 58, 62, 64, 66]. During running the swing phase is further prolonged and accounts for approximately 75% of the gait cycle [62]. Conversely, with increasing speed the stance phase decreases [45, 70, 71].
The sagittal plane range of motion of the elbow joint (flexion-extension) is between 48.1 degrees and 70 degrees during one complete gait cycle when the dog is moving on a flat surface (Table 2), with the majority of motion occurring during the swing phase [28, 43, 44, 45, 47, 48, 49, 50, 52, 53, 56, 57, 58, 59, 60, 61, 63, 64, 65, 66, 67]. Range of motion is influenced by different parameters like breed, limb and body segment length, gait, velocity, exercise, age, contralateral limb amputation and concurrent orthopedic disease. With increasing speed of the gait the range of motion of joints increases [29, 45, 57, 62, 66, 68, 69]. Obese dogs show an increased range of motion as well, especially during the stance phase [57]. However, increasing age leads to an decrease in total range of motion, even in orthopedic healthy dogs [64]. Further, different exercises like descending stairs, uphill and downhill walking influence the range of motion, with descending stairs, obstacle exercises and uphill walking increasing the range of motion, while downhill walking decreases the amount of sagittal motion in the elbow [52, 65].
Study | Breed | Range of motion (°) | Flexion/Extension (°) | Gait/Speed |
---|---|---|---|---|
DeCamp et al. [43] | Greyhound | 53.7 | 86.8/140.5 | trot, 1.8–2.3 m/s (walkway) |
Allen et al. [44] | Mixed breed dogs | 55.8 | 93.7/149.5 | trot, 1.8–2.3 m/s (overground) |
Hottinger et al. [45] | Different large breed dogs | 48.1 | — | walk, 0.9–1.1. m/s (walkway) |
Gillette and Zebas [46] | Labrador Retriever | right: 69.1 left: 66.1 | — | trot, 2.8 m/s |
Nielsen et al. [47] | Mixed breed dogs | — | 111.7 ± 12/136.3 ± 10.4 (stance phase only) | walk, 0.8–1.0 m/s (overground) |
Owen et al. [48] | Greyhound | 49.35–49.59 | 100.98–102.7/150.57–152.05 | trot, 2.2–2.4 m/s (treadmill) |
Clements et al. [49] | Labrador Retriever | 59.3 (SD 5.5) | — | trot, 2.0 m/s (treadmill) |
Feeney et al. [50] | Labrador Retriever | 54.8 ± 17.9 | 91.4/146.3 | walk, velocity not documented(overground) |
Holler et a. [52] | Different mid to large breed dogs | normal: 52.9 ± 7.0 uphill: 54.2 ± 7.4 downhill: 43.1 ± 5.8 obstacle: 57.0 ± 6.9 | — | walk, 0.89–1.1 m/s (treadmill, normal, uphill, downhill, obstacle) |
Agostinho et al. [53] | Labrador Retriever Rottweiler | 63.77 ± 4.83 54.86 ± 5.16 | 90.52 ± 11.66/154.28 ± 9.64 93.99 ± 10.19/148.85 ± 9.15 | trot, 2.1–2.2. m/s (treadmill) |
Jarvis et al. [56] | Different breeds | stance phase only: control: 33.3 ± 8.6 amputee: 39.7 ± 10.4 | control: 123.0 ± 12.9/ 156.4 ± 12.2 amputee: 119.2 ± 12.8/ 158.9 ± 12.5 | trot, 2.2–2.6 m/s (walkway) |
Brady et al. [57] | Different breeds | lean: 52.5 (1.8 m/s) obese: 65.0 (1.8 m/s) lean: 54.0 (2.5 m/s) obese: 62.0 (2.5 m/s) | lean: 95 ± 7/147 ± 17 obese: 90 ± 11/155 ± 9 lean: 93 ± 8/147 ± 9 obese: 88 ± 14/150 ± 18 | trot, 1.8 m/s & 2.5 m/s (walkway) |
Miqueleto et al. [58] | German Shepherd | healthy: 68.15 ± 7.19 hip dysplasia: 63.54 ± 13.53 | healthy: 61.99/131.77 ± 7.60 hip dysplasia: 69.09/133.68 ± 11.37 | trot, 2.1–2.2. m/s (treadmill) |
Galindo-Zamora et al. [59] | Different mid to large breed dogs | healthy: 54.18 ± 8.62 MCD: 51.45 ± 7.27 | healthy: 82.36 ± 6.02/136.54 ± 9.16 MCD: 87.1 ± 10.8/138.55 ± 13.03 | walk, 0.65–1.1 m/s (treadmill) |
Duerr et al. [63] | Different mid to large breed dogs | 63.4 ± 7.7 | 82.1 ± 8.6/145.5 ± 10.8 | trot, 2.4–2.5 m/s (overground) |
Lorke et al. [64] | Beagle | young: 68.8 ± 2.7 old: 62.9 ± 5.1 | young: 83.2/152.0 ± 10.5 old: 76.8/139.6 ± 12.4 | trot, 1.7–1.8 m/s (treadmill) |
Kopec et al. [65] | Different mid to large breed dogs | flat: 65.81 desc. Stair: 80.43 desc. Ramp: 67.95 | 66.23/132.03 34.36/114.79 46.0/113.95 | walk, 1.01–1.45 m/s (overground & stair exercise) |
Humphries et al. [66] | Labrador Retriever German Shepherd | left: 70.63 right: 67.13 left: 67.13 right: 67.94 | 77.21/147.84 77.21/144.34 75.45/142.58 74.37/142.31 | trot, 2.19–2.45 m/s (walkway) |
De Souza et al. [67] | American Pit Bull Terrier | walk: 45.22 trot: 52.39 | walk: 111.25/167.65 trot: 110.14/163.00 | walk, 1.17 ± 0.17 m/s trot, 2.04 ± 0.33 m/s (overground) |
Summary of the values for range of motion in sagittal plane and flexion and extension angles of the canine elbow joint from different kinematic studies. All values are expressed in degrees and were calculated, if necessary, based on data of each study to allow comparison between studies. 180 degrees represent maximum extension and 0 degrees maximum flexion.
The stance phase is mainly characterized by continuous extension of the elbow joint until lifting of the paw from the ground. Some studies have shown flexion of the elbow joint just after weight bearing [43, 45, 47, 53, 58, 60, 64], resulting in two peaks of extension during the gait cycle. The first peak of extension occurs during the late swing phase and the initiation of ground contact and a second peak occurs at the end of the stance phase. The amount of this flexion differs between studies by several degrees. Further, this movement has not been described using fluoroscopic kinematography, what represents the gold standard of kinematic gait analysis [28]. This might be due to breed and inter-individual differences in the gait, due to the different techniques used for kinematic analysis or due to a soft tissue artifact, which occurs with skin mounted markers, and does not represent the in vivo motion of the bony cubital joint, but the movement pattern of the complete limb including the soft tissues [28, 32, 33]. Maximum extension of the elbow joint is reached at the end of the stance phase and is followed by continuous flexion during the swing phase. The peak flexion of the elbow joint is reached at approximately the middle of the swing phase and is followed by continuous extension of the elbow joint as a preparation for paw strike [53, 60, 64].
Besides flexion and extension, which represent the main motion pattern of the elbow joint, supination and pronation of the antebrachium and abduction and adduction of the humerus and antebrachium occur during the regular locomotion. In healthy Labrador retrievers the antebrachium is positioned in mild supination at the initial stance phase and shows minimal pronation during the remainder stance phase with a mean supination of the antebrachium of 3 ± 9 degrees [60]. In healthy Beagle the forelimb is placed onto the ground in mild pronation and is kept in this position during two thirds of the stance phase and then externally rotated during the last third of stance [28]. During the initial swing phase the antebrachium is supinated and maximum supination (mean 19 ± 9 degrees) occurs at the middle of the swing phase, together with maximum flexion of the elbow joint, in healthy Labrador retrievers [60]. In orthopedic sound Beagle a similar motion pattern is present during the swing phase, with supination of the antebrachium occurring during the first third of the swing phase [28]. Prior to foot strike rapid pronation of the antebrachium occurs and the limb is placed on the ground in a slightly supinated position in Labrador retrievers and slight pronation in Beagle [28, 60].
Three dimensional micromotion of the humerus, radius and ulna relative to each other was measured in different studies using marker based fluoroscopic kinematographic analysis [22, 23, 24, 54, 72]. Results of these studies show that the bones of the antebrachium have a complex motion pattern and radius and ulna cannot be seen as one single object. At the walk and the trot an axial movement between radius and ulna occurs in healthy and MCD affected elbows [22, 54]. In healthy canine elbow joints the radius shows an mean axial movement of 0.7 (SD 0.31) mm to 0.8 mm in relation to the ulna. This axial motion was detected in different mid to large breed dogs, like Fox hounds, Australian shepherd, Labrador retriever, Eurasian, German shepherd, Bernese mountain dog and mixed breeds [22, 54]. After the initiation of ground contact the radius moves proximally and remains in a slightly elevated position relative to the ulna, resulting in a dynamic negative radio-ulnar incongruence (RUI) [22, 72]. These results correspond with data from an in vitro study, which investigated the effects of limb loading and flexion and extension onto the radio-ulnar joint conformation and intra articular contact areas and which showed, that elbow extension leads to a relative lowering of the ulna in relation to the radius [73]. Extension is the main motion of the elbow during the weight bearing phase and therefore the induction of a dynamic negative RUI might be seen as a adaption to joint loading [72]. Further, internal and external rotation between the radius and ulna occurs during the walk. Prior to foot strike the radius is in an externally rotated position relative to the ulna und shows internal rotation during the first third of the stance phase. Mean range of motion of the in vivo internal-external radial rotation is 11.4 (SD 2.0) degrees during the initial weight bearing phase [74]. No data exist investigating the in vivo radio-ulnar movement during the later stance phase and the swing. Therefore, the in vivo motion of the antebrachial bones and the dynamic changes within the radio-ulnar joint during the complete gait cycle are still unknown.
The in vivo humero-ulnar micromotion has only been investigated in one study so far [23]. Movement between the humerus and the ulna is characterized by flexion and extension, but rotational movement of the humerus relative to the ulna takes also place during locomotion [23]. At the walk the humerus shows an relative external rotation of 2.9 (SD 1.1) degrees during the first third of the stance phase in healthy humero-ulnar joints [23, 28]. These data imply that the elbow joint is not completely restricted to sagittal motion only. One study, investigating the 3D kinematics of the whole canine forelimb showed, that at the moment of ground contact the humerus is in an internally rotated position, which is slightly less at the trot compared to the walk (mean segment angle, walk: −34 degrees; trot: −25 degrees) [28]. During the walk the humerus shows internal and external rotation and only external rotation during the trot throughout the complete stance and swing phase, with a net external rotational movement during the stance phase [28]. This external rotational motion of the humerus is contrary to the internal rotation (pronation) of the antebrachium, which occurs prior to paw strike and is maintained during the stance [28, 60].
When kinematics of the diseased canine elbow joint are evaluated two different types of changes in the kinematic pattern have to be differentiated. First, changes attributed to pain and lameness, i.e. altered kinematics as a result of the disease. Second, changes in elbow joint kinematics, which represent a causative factor of the disease process.
Due to pain, caused by different joint pathologies in the elbow with DED, multiple adaptive mechanisms occur in the affected forelimb. Decreases in stance time, angular displacement and net joint moments can all be seen in the diseased elbow joint [51].
A reduced range of motion in the sagittal plane (flexion-extension) is present in dogs with MCD [51, 59, 60]. In particular flexion of the joint is decreased and the elbow kept in a more extended position during the gait. In Labrador retrievers with MCD a faster extension of the cubital joint occurs during late swing phase and the elbow is more extended by 9 degrees (mean) during initial ground contact and the early stance phase compared to orthopedically healthy elbows [60]. This more extended gait is a compensating mechanism and aims to reduce pressure at the medial joint compartment [7, 73, 75]. At the end of the stance and beginning of swing phase the elbow joint is more rapidly flexed in affected dogs. However, no active push off occurs at the end of the stance phase indicating that the affected limb is pulled off the ground by the proximal musculature [51]. Reduction in active push off aims to reduce the pressure acting on the joint surface. The elbow is held 16 degrees more externally rotated during the end of swing and initial stance phase and the antebrachium is in average 2 degrees more abducted throughout the gait cycle and 9 degrees more supinated during the paw strike and early stance phase [60]. These changes have to be assumed as compensating mechanisms as well. Supination leads to caudal displacement of the peak pressure at the medial ulnar joint surface and by that to a release of pressure and potentially pain at the diseased medial coronoid process. Besides the Labrador retriever a more extended elbow joint is present in other breeds with MCD, e.g. Rottweiler, Staffordshire Bullterrier, Airdale terrier, Golden retriever, Polish Lowland sheepdog, German wirehaired pointer, Belgian malinois, Irish setter and mixed breed dogs [51, 59, 60]. Therefore, these changes in the kinematic pattern represent a general secondary adaption to intra articular pathologies and the corresponding pain in canine elbow joints with MCD.
Primary changes in the kinematics of the radius, ulna and humerus are assumed to play an role in the pathogenesis of MCD. Altered kinematics in the proximal radio-ulnar joint, were suggested by different researchers to be one potential factor influencing the development of MCD [76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90]. One proposed mechanism was an increased axial translation of the radius relative to the ulna leading to an dynamic radio-ulnar incongruence. Translational movement between the radius and ulna occurs in elbows with and without MCD in vivo [22, 54], with no significant difference in the total amount of movement between both groups [22]. Therefore, increased axial movement between the radius and ulna and induction of a dynamic RUI under weight bearing conditions could be excluded as an primary factor. However, the direction of radial motion is different between normal and diseased joints, with a negative RUI being induced during the initial stance phase in healthy elbows and no significant change in the radio-ulnar joint conformation in MCD affected joints [72]. Based on the results of that study dogs with a static RUI are not able to compensate the radio-ulnar step formation by radio-ulnar translation and dogs with MCD, but without a static RUI, do not show the same amount of negative dynamic RUI as measured in healthy canine elbow joints [72]. The induction of a negative radio-ulnar step during weight bearing might be a protective mechanism in healthy canine elbow joints. Lowering of the ulna or elevation of the radius during extension of the elbow joint was previously described in vitro and leads to a decrease of intra articular pressure at the medial joint compartment [73]. The inability of the diseased canine elbow joint to adjust the radio-ulnar joint conformation during loading might be one potential biomechanical factor in the pathogenesis of MCD. Especially in dogs without a measurable static incongruence, which account for 40% of all patients with MCD [76], the insufficient adaption to intra articular joint loads can lead to mechanical overload at one distinct joint compartment. Increased radio-ulnar rotation was proposed as another potential cause of mechanical overload along the radial incisure of the medial coronoid process and subsequent cartilage and bone damage [82, 87, 88, 89, 90]. The only study comparing in vivo radio-ulnar rotational movement in healthy joints to joints with MCD showed no significant difference in the total amount of radial rotation and in the motion pattern of the radius [74]. The radius starts in an externally rotated position during the late swing phase just before paw strike and rotates internally in relation to the ulna during the early weight bearing phase. At approximately 30 to 40% of the stance phase the radius shows an external rotation again. Values of total rotational movement and internal/external movement of the radius show no significant difference between normal and affected elbow (internal radial rotation, healthy: 5.7 [SD 2.1] degrees; MCD: 5.3 [SD 2.6] degrees; p = 0.1727; external radial rotation, healthy: - 5.8 [SD: 1.3] degrees; MCD: - 4.5 [1.7] degrees; p = 0.7705; total rotation, healthy: 11.4 [SD: 2.0] degrees; MCD: 9.8 [SD: 3.2]; p = 0.2904) [74]. Absence of increased radio-ulnar rotational motion does not exclude an biomechanical overload along the lateral aspect of the medial coronoid process of the ulna caused by interaction with the radial head. An abaxial attachment of the tendon of the biceps brachii muscle at the ulna was detected in dogs with MCD [90]. The pull of the biceps brachii muscle on the ulna could potentially lead to increased pressure between the medial coronoid and the radial head without altering the kinematics. However, no studies have investigated the forces acting between radius and ulna and compared these data between healthy and MCD affected dogs.
Another significant difference can be seen in the humero-ulnar rotational movement between healthy and MCD affected joints. Increased external rotation of the humeral condyle in relation to the ulna occurs at the first third of the stance phase in cubital joints with MCD (humeral rotation, healthy: 2.9 [SD 1.1] degrees; MCD: 5.3 [SD 2.0] degrees; p = 0.0229) [23]. This rotation of the humeral condyle leads to compression of the joint space between the medial coronoid process and the humeral trochlea, and might potentially lead to mechanical overload at the coronoid process and consequently to cartilage and subchondral bone damage (Figure 1). Therefore, increased humero-ulnar rotation has to be considered as one dynamic factor in the pathogenesis of MCD. If this increased humero-ulnar rotational movement is caused by soft tissue laxity, like in the dysplastic hip joint, altered muscle function or due to bony differences altering the joint function has not been investigated so far. The influence of a static positive radio-ulnar incongruence onto the contact areas and pressure distribution within the humero-ulnar joint is known [91, 92, 93]. However, the literature is lacking kinematic analysis investigating the influence of a static RUI on elbow joint motion, particular the humero-radio-ulnar micromotion. In the cited study on humero-ulnar kinematics the MCD group consisted of dogs with and without a static positive RUI [23]. Due to the small sample size no correlation could be found between the presence of static RUI and the amount of humeral rotational motion. Therefore, the influence of this significant bony deformity on the kinematics of the elbow joint remains unknown.
Image sequence of the in vivo humero-ulnar joint motion during the late swing phase (f0), at the moment of weight bearing (f30) and the first third of the stance phase (f60 – f150). (A) Healthy joint; (B) MCD affected joint; relative external rotation of the humerus occurs just after ground contact, when the joint gets loaded. External rotation of the condyle leads to a craniolateral shift of the trochlea, impinging on the lateral aspect of the medial coronoid process [
The mean body weight distribution between fore- and hindlimbs is approximately 60% : 40% in dogs [56, 94]. A large study investigating 123 different breeds found that the grand mean proportion of mass was 60.4% on the forelimbs (range: 47.6 to 74.4%) [94]. Only sex was shown to be a significant factor altering that ratio, with females being below the mean value throughout different breeds [94]. Another study comparing kinematic and kinetic data of orthopedic healthy Labrador retrievers and German shepherds reported that Labrador retrievers carry a higher percentage of the weight on their forelimbs compared to the German shepherd (69% vs. 62%, p < 0.001) [66]. If this breed specific mechanical overload plays a role in the pathogenesis of DED and contributes to the high rate of Labrador retrievers with developmental elbow disease, in particular MCD, is not known.
Within the elbow joint load and forces are not homogenously distributed throughout the whole joint surface. It was believed that the radial joint surface is the main weight bearing surface of the radio-ulnar joint. However, more recent studies have shown, that the radius takes 51 to 52% of load [73, 75, 91]. Therefore the ulna plays a more important role in weight bearing than previously assumed. Despite an overall equal load and force distribution between the radius and the ulna, not every part of the joint surface represents an active joint contact area. Within the combined radio-ulnar joint surface three distinct contact areas can be found: the craniolateral aspect of anconeal process, the joint surface of the radial head, and the medial coronoid process [7, 24, 73]. There is no particular contact at the medial aspect of the anconeal process and the center of the trochlear notch (Figure 2). The latter one might be explained by the slight physiological humero-ulnar incongruence leading to a bicentrical contact pattern [6, 7, 9, 73, 95]. When the elbow joint is loaded the force applied by the humeral condyle is distributed along the anconeal process and the coronoid region. With increasing load the concave ulnar notch is stretched and these pressure forces are partially transformed to traction forces [8, 95, 96, 97]. Therefore this physiological incongruence leads to a more even stress distribution within the humero-ulnar joint. In human elbow joints the proximal and distal contact area confluent when high loads are acting onto the ulnar joint surface [98]. This load dependent change in contact pattern has not been described in canine elbows so far [7].
Colored animation of the in vivo humero-ulnar joint contact pattern at the ulnar joint surface at the beginning of weight bearing in a healthy canine elbow joint (red: Humero-ulnar contact). Joint contact is present along the medial coronoid process and the lateral and proximal aspect of the trochlear notch. The radius is not shown in this animation.
The presence of these three contact areas within the elbow joint is further supported by increased subchondral bone density measurements at these anatomic areas [95, 99]. Bone is a dynamic tissue which has the ability to remodel in response to mechanical load (Wolff’s law) [100]. Therefore, increased bone density can be found in areas with increased load. Increased subchondral bone densities are present at the disto-medial and cranial aspect of the humeral trochlea and in the olecranon fossa, the anconeal and medial coronoid processes of the ulna and the cranio-medial region of the joint surface of the radius [95]. The same study showed a significant age-dependent increase in the subchondral bone density of the joint surfaces of all three bones, representing continuous adaption of the bone to mechanical stress with increasing age [95].
Though increased loading of the ulnar joint surface does not result in confluence of the bicentric contact pattern, other factors can influence the joint contact patterns of the humero-ulnar and humero-radial joint surfaces. An in vitro study investigated the influence of positive radio-ulnar incongruence (short radius) on joint contact patterns. Presence of a positive RUI leads to a shift of the contact area at the medial coronoid process towards the cranio-lateral aspect of the coronoid process and reduction of the anconeal contact area [93]. Other in vitro studies show similar results. After induction of a 1.9 mm positive RUI medial compartment contact area decreases significantly while the lateral contact area increases. Likewise the mean contact pressure and peak contact pressure increase within the medial compartment and decrease in the lateral part [91, 92]. Therefore, presence of a static positive RUI has to be assumed as an important factor in the disease process of developmental elbow disease and a correlation between the severity of cartilage damage and static RUI has been shown in affected elbows [76, 77, 101]. In vivo evaluation of the ulnar joint contact pattern during the walk in a dog with positive static RUI before and after bi-oblique dynamic proximal ulnar osteotomy (DPUO) confirmed the results of different in vitro studies [24]. Following DPUO positive static RUI decreased, leading to a significant increase of the contact area at the medial coronoid process and to a shift of the contact area from the cranio-lateral aspect (tip and radial incisure) towards the medial aspect and the base of the medial coronoid process (Figure 3) [24]. This positive effect of different forms of ulnar and humeral osteotomies onto humero-radio-ulnar contact and force distribution has previously been shown in vitro [75, 91, 92]. Whether a static RUI changes the kinematic pattern of humero-radial, humero-ulnar or radio-ulnar motion and by that the intra articular contact areas and pressure distribution or has a purely mechanical influence without dynamic changes has not been investigated so far.
Humero-ulnar joint contact pattern at the ulnar joint surface at the beginning of weight bearing in a canine elbow joint with MCD (red: Contact area). (A) Contact pattern before bi-oblique DPUO; focal concentration of joint contact at the medial coronoid process (MCP) and slight contact at the medial and lateral aspect of the anconeal process is present. (B) Contact pattern 12 weeks postoperative; joint contact is more homogenously distributed throughout the ulnar joint surface and the craniolateral aspect of the MCP is even not in contact with the corresponding humeral trochlea [
Further, joint contact areas change during the regular locomotion. Pronation leads to reduction of the contact area in the medial and to a lesser amount in the lateral compartment of the radio-ulnar joint surface. The effect of pronation is further influenced by the elbow joint angle, with significant reduction of the medial contact area by 23% at 135 degree of flexion, what represents the average flexion angle during the stance phase [73]. A reduced contact area will result in increased pressure when the same load is applied to the joint. Further, pronation of the antebrachium leads to a shift of the peak contact pressure towards the apex of the medial coronoid process. Otherwise supination of the antebrachium leads to caudal displacement of the peak contact pressure on the medial coronoid process [73, 75]. This might explain that dogs with medial coronoid disease show a more supinated stance to release pressure from the apex of the medial coronoid [60]. Moreover, flexion and extension, the main motion pattern during the normal locomotion, influence the intra articular pressure distribution. Flexion increases peak pressure at the medial radio-ulnar joint compartment and extension decreases pressure [73]. It is assumed that this change is due to dynamic changes within the radio-ulnar joint surface in healthy canine elbows [72, 73]. In a cadaveric study extension of the elbow joint induced lowering of the radius and ulna, however more pronounced in the ulna (3.8 mm) compared to the radius (1.9 mm). This corresponds to findings of the in vivo investigation of the radio-ulnar joint cup conformation in healthy elbow joints during the walk, where a negative RUI (short ulna) was induced during weight bearing [72]. This lowering of the ulna relative to the radius might protect the medial coronoid process from mechanical overload during locomotion in healthy canine elbows. In contrast, altered radio-ulnar kinematics preventing elevation of the radius might lead to continuous excessive mechanical overload and subsequent joint pathologies.
Considering the changes of intra articular contact areas and pressure distribution as a function of limb position might explain the typical clinical signs in dogs with developmental elbow disease. Affected dogs stand with the elbow slightly abducted and the antebrachium in slight external rotation (supination) [102]. Furthermore, the elbow joint is more rapidly extended during the swing phase and kept in a more extended position during weight bearing [60]. This motion pattern aims to reduce the contact and pressure at the medial coronoid process, where most commonly lesions attributed to developmental elbow disease occur [90, 103].
Canine elbow joint kinematics are more complex than flexion and extension of the joint and influenced by multiple factors like breed, limb length, gait, exercise and joint pathologies. The precise interaction of the three joint forming bones is essential for physiologic joint contact and intra articular force and pressure distribution. Based on the current literature an significantly increased humero-ulnar rotational movement as well as an reduced adjustment of the radio-ulnar joint during the regular locomotion of the dog seem to be two essential pathological factors influencing the development of MCD. This kind of movement is only measurable using laborious techniques like 3D fluoroscopic based kinematography. Nevertheless, further studies are needed to evaluate the complex kinematics of the healthy and the diseased canine elbow joint and to understand the effect of different kinematics onto kinetics.
The author declares no conflict of interest.
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\\n\\nBut, one thing we have in common is -- we are all scientists at heart!
\\n\\nSara Uhac, COO
\\n\\nSara Uhac was appointed Managing Director of IntechOpen at the beginning of 2014. She directs and controls the company’s operations. Sara joined IntechOpen in 2010 as Head of Journal Publishing, a new strategically underdeveloped department at that time. After obtaining a Master's degree in Media Management, she completed her Ph.D. at the University of Lugano, Switzerland. She holds a BA in Financial Market Management from the Bocconi University in Milan, Italy, where she started her career in the American publishing house Condé Nast and further collaborated with the UK-based publishing company Time Out. Sara was awarded a professional degree in Publishing from Yale University (2012). She is a member of the professional branch association of "Publishers, Designers and Graphic Artists" at the Croatian Chamber of Commerce.
\\n\\nAdrian Assad De Marco
\\n\\nAdrian Assad De Marco joined the company as a Director in 2017. With his extensive experience in management, acquired while working for regional and global leaders, he took over direction and control of all the company's publishing processes. Adrian holds a degree in Economy and Management from the University of Zagreb, School of Economics, Croatia. A former sportsman, he continually strives to develop his skills through professional courses and specializations such as NLP (Neuro-linguistic programming).
\\n\\nDr Alex Lazinica
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\n\nCo-founded by Alex Lazinica and Vedran Kordic: “We are passionate about the advancement of science. As Ph.D. researchers in Vienna, we found it difficult to access the scholarly research we needed. We created IntechOpen with the specific aim of putting the academic needs of the global research community before the business interests of publishers. Our Team is now a global one and includes highly-renowned scientists and publishers, as well as experts in disseminating your research.”
\n\nBut, one thing we have in common is -- we are all scientists at heart!
\n\nSara Uhac, COO
\n\nSara Uhac was appointed Managing Director of IntechOpen at the beginning of 2014. She directs and controls the company’s operations. Sara joined IntechOpen in 2010 as Head of Journal Publishing, a new strategically underdeveloped department at that time. After obtaining a Master's degree in Media Management, she completed her Ph.D. at the University of Lugano, Switzerland. She holds a BA in Financial Market Management from the Bocconi University in Milan, Italy, where she started her career in the American publishing house Condé Nast and further collaborated with the UK-based publishing company Time Out. Sara was awarded a professional degree in Publishing from Yale University (2012). She is a member of the professional branch association of "Publishers, Designers and Graphic Artists" at the Croatian Chamber of Commerce.
\n\nAdrian Assad De Marco
\n\nAdrian Assad De Marco joined the company as a Director in 2017. With his extensive experience in management, acquired while working for regional and global leaders, he took over direction and control of all the company's publishing processes. Adrian holds a degree in Economy and Management from the University of Zagreb, School of Economics, Croatia. A former sportsman, he continually strives to develop his skills through professional courses and specializations such as NLP (Neuro-linguistic programming).
\n\nDr Alex Lazinica
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The chapter concludes with remarks on the significance of the sources of error.",book:{id:"6540",slug:"multifunctional-operation-and-application-of-gps",title:"Multifunctional Operation and Application of GPS",fullTitle:"Multifunctional Operation and Application of GPS"},signatures:"Malek Karaim, Mohamed Elsheikh and Aboelmagd Noureldin",authors:[{id:"227711",title:"Mr.",name:"Malek",middleName:null,surname:"Karaim",slug:"malek-karaim",fullName:"Malek Karaim"},{id:"240292",title:"Prof.",name:"Aboelmagd",middleName:null,surname:"Noureldin",slug:"aboelmagd-noureldin",fullName:"Aboelmagd Noureldin"},{id:"243124",title:"Dr.",name:"Mohamed",middleName:null,surname:"Elsheikh",slug:"mohamed-elsheikh",fullName:"Mohamed Elsheikh"}]},{id:"57384",title:"A Review: Remote Sensing Sensors",slug:"a-review-remote-sensing-sensors",totalDownloads:3663,totalCrossrefCites:24,totalDimensionsCites:42,abstract:"The cost of launching satellites is getting lower and lower due to the reusability of rockets (NASA, 2015) and using single missions to launch multiple satellites (up to 37, Russia, 2014). In addition, low-orbit satellite constellations have been employed in recent years. These trends indicate that satellite remote sensing has a promising future in acquiring high-resolution data with a low cost and in integrating high-resolution satellite imagery with ground-based sensor data for new applications. These facts have motivated us to develop a comprehensive survey of remote sensing sensor development, including the characteristics of sensors with respect to electromagnetic spectrums (EMSs), imaging and non-imaging sensors, potential research areas, current practices, and the future development of remote sensors.",book:{id:"6334",slug:"multi-purposeful-application-of-geospatial-data",title:"Multi-purposeful Application of Geospatial Data",fullTitle:"Multi-purposeful Application of Geospatial Data"},signatures:"Lingli Zhu, Juha Suomalainen, Jingbin Liu, Juha Hyyppä, Harri\nKaartinen and Henrik Haggren",authors:[{id:"213512",title:"Dr.",name:"Lingli",middleName:null,surname:"Zhu",slug:"lingli-zhu",fullName:"Lingli Zhu"},{id:"213522",title:"Dr.",name:"Suomalainen",middleName:null,surname:"Juha",slug:"suomalainen-juha",fullName:"Suomalainen Juha"},{id:"213523",title:"Prof.",name:"Jingbin",middleName:null,surname:"Liu",slug:"jingbin-liu",fullName:"Jingbin Liu"},{id:"220941",title:"Prof.",name:"Juha",middleName:null,surname:"Hyyppä",slug:"juha-hyyppa",fullName:"Juha Hyyppä"},{id:"220942",title:"Prof.",name:"Harri",middleName:null,surname:"Kaartinen",slug:"harri-kaartinen",fullName:"Harri Kaartinen"},{id:"220943",title:"Prof.",name:"Henrik",middleName:null,surname:"Haggren",slug:"henrik-haggren",fullName:"Henrik Haggren"}]},{id:"59608",title:"GNSSs, Signals, and Receivers",slug:"gnsss-signals-and-receivers",totalDownloads:2089,totalCrossrefCites:3,totalDimensionsCites:3,abstract:"This chapter describes Global Navigation Satellite Systems (GNSSs) and their signal characteristics, beginning with an overview of Global Positioning System (GPS) architecture and describing its three primary segments: control, space, and user segments. After that, it addresses the GPS modernization program including the new civilian and military signals and their significance. It continues by outlining the GPS signal characteristics and the sources of GPS measurement error. GPS receivers as well are briefly described. Then, it gives an overview of the GLONASS and describes its modernization program. Additionally, it delves into many aspects the GLONASS, including GLONASS signal characteristics, the GLONASS radio frequency (RF) plan, pseudorandom (PR) ranging codes, and the intra-system interference navigation message. Finally, GPS and GLONASS are compared to highlight the advantages of combined GPS and GLONASS measurements over the GPS-only measurements.",book:{id:"6540",slug:"multifunctional-operation-and-application-of-gps",title:"Multifunctional Operation and Application of GPS",fullTitle:"Multifunctional Operation and Application of GPS"},signatures:"Mohamed Tamazin, Malek Karaim and Aboelmagd Noureldin",authors:[{id:"227711",title:"Mr.",name:"Malek",middleName:null,surname:"Karaim",slug:"malek-karaim",fullName:"Malek Karaim"},{id:"240292",title:"Prof.",name:"Aboelmagd",middleName:null,surname:"Noureldin",slug:"aboelmagd-noureldin",fullName:"Aboelmagd Noureldin"},{id:"227709",title:"Dr.",name:"Mohamed",middleName:null,surname:"Tamazin",slug:"mohamed-tamazin",fullName:"Mohamed Tamazin"}]},{id:"45989",title:"Exploring and Using the Magnetic Methods",slug:"exploring-and-using-the-magnetic-methods",totalDownloads:4835,totalCrossrefCites:4,totalDimensionsCites:6,abstract:null,book:{id:"3838",slug:"advanced-geoscience-remote-sensing",title:"Advanced Geoscience Remote Sensing",fullTitle:"Advanced Geoscience Remote Sensing"},signatures:"Othniel K. Likkason",authors:[{id:"72626",title:"Prof.",name:"Othniel",middleName:null,surname:"Likkason",slug:"othniel-likkason",fullName:"Othniel Likkason"}]}],onlineFirstChaptersFilter:{topicId:"653",limit:6,offset:0},onlineFirstChaptersCollection:[],onlineFirstChaptersTotal:0},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:8,limit:8,total:0},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:9,numberOfPublishedChapters:89,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:104,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:31,numberOfPublishedChapters:314,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:11,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:11,numberOfPublishedChapters:141,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:8,numberOfPublishedChapters:129,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!0},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:113,numberOfOpenTopics:3,numberOfUpcomingTopics:1,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:11,numberOfPublishedChapters:105,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2632-0517",doi:"10.5772/intechopen.73681",isOpenForSubmission:!0}],sshSeriesList:[{id:"22",title:"Business, Management and Economics",numberOfPublishedBooks:1,numberOfPublishedChapters:18,numberOfOpenTopics:2,numberOfUpcomingTopics:1,issn:"2753-894X",doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:5,numberOfOpenTopics:1,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!0},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:0,numberOfPublishedChapters:14,numberOfOpenTopics:5,numberOfUpcomingTopics:0,issn:null,doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{id:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. The whole process of submitting an article and editing of the submitted article goes extremely smooth and fast, the number of reads and downloads of chapters is high, and the contributions are also frequently cited.",author:{id:"55578",name:"Antonio",surname:"Jurado-Navas",institutionString:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRisIQAS/Profile_Picture_1626166543950",slug:"antonio-jurado-navas",institution:{id:"720",name:"University of Malaga",country:{id:null,name:"Spain"}}}},{id:"6",text:"It is great to work with the IntechOpen to produce a worthwhile collection of research that also becomes a great educational resource and guide for future research endeavors.",author:{id:"259298",name:"Edward",surname:"Narayan",institutionString:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259298/images/system/259298.jpeg",slug:"edward-narayan",institution:{id:"3",name:"University of Queensland",country:{id:null,name:"Australia"}}}}]},series:{item:{id:"11",title:"Biochemistry",doi:"10.5772/intechopen.72877",issn:"2632-0983",scope:"Biochemistry, the study of chemical transformations occurring within living organisms, impacts all areas of life sciences, from molecular crystallography and genetics to ecology, medicine, and population biology. Biochemistry examines macromolecules - proteins, nucleic acids, carbohydrates, and lipids – and their building blocks, structures, functions, and interactions. Much of biochemistry is devoted to enzymes, proteins that catalyze chemical reactions, enzyme structures, mechanisms of action and their roles within cells. Biochemistry also studies small signaling molecules, coenzymes, inhibitors, vitamins, and hormones, which play roles in life processes. Biochemical experimentation, besides coopting classical chemistry methods, e.g., chromatography, adopted new techniques, e.g., X-ray diffraction, electron microscopy, NMR, radioisotopes, and developed sophisticated microbial genetic tools, e.g., auxotroph mutants and their revertants, fermentation, etc. More recently, biochemistry embraced the ‘big data’ omics systems. Initial biochemical studies have been exclusively analytic: dissecting, purifying, and examining individual components of a biological system; in the apt words of Efraim Racker (1913 –1991), “Don’t waste clean thinking on dirty enzymes.” Today, however, biochemistry is becoming more agglomerative and comprehensive, setting out to integrate and describe entirely particular biological systems. The ‘big data’ metabolomics can define the complement of small molecules, e.g., in a soil or biofilm sample; proteomics can distinguish all the comprising proteins, e.g., serum; metagenomics can identify all the genes in a complex environment, e.g., the bovine rumen. This Biochemistry Series will address the current research on biomolecules and the emerging trends with great promise.",coverUrl:"https://cdn.intechopen.com/series/covers/11.jpg",latestPublicationDate:"June 24th, 2022",hasOnlineFirst:!0,numberOfPublishedBooks:31,editor:{id:"31610",title:"Dr.",name:"Miroslav",middleName:null,surname:"Blumenberg",slug:"miroslav-blumenberg",fullName:"Miroslav Blumenberg",profilePictureURL:"https://mts.intechopen.com/storage/users/31610/images/system/31610.jpg",biography:"Miroslav Blumenberg, Ph.D., was born in Subotica and received his BSc in Belgrade, Yugoslavia. He completed his Ph.D. at MIT in Organic Chemistry; he followed up his Ph.D. with two postdoctoral study periods at Stanford University. Since 1983, he has been a faculty member of the RO Perelman Department of Dermatology, NYU School of Medicine, where he is codirector of a training grant in cutaneous biology. Dr. Blumenberg’s research is focused on the epidermis, expression of keratin genes, transcription profiling, keratinocyte differentiation, inflammatory diseases and cancers, and most recently the effects of the microbiome on the skin. He has published more than 100 peer-reviewed research articles and graduated numerous Ph.D. and postdoctoral students.",institutionString:null,institution:{name:"New York University Langone Medical Center",institutionURL:null,country:{name:"United States of America"}}},editorTwo:null,editorThree:null},subseries:{paginationCount:4,paginationItems:[{id:"14",title:"Cell and Molecular Biology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/14.jpg",isOpenForSubmission:!0,editor:{id:"165627",title:"Dr.",name:"Rosa María",middleName:null,surname:"Martínez-Espinosa",slug:"rosa-maria-martinez-espinosa",fullName:"Rosa María Martínez-Espinosa",profilePictureURL:"https://mts.intechopen.com/storage/users/165627/images/system/165627.jpeg",biography:"Dr. Rosa María Martínez-Espinosa has been a Spanish Full Professor since 2020 (Biochemistry and Molecular Biology) and is currently Vice-President of International Relations and Cooperation development and leader of the research group 'Applied Biochemistry” (University of Alicante, Spain). Other positions she has held at the university include Vice-Dean of Master Programs, Vice-Dean of the Degree in Biology and Vice-Dean for Mobility and Enterprise and Engagement at the Faculty of Science (University of Alicante). She received her Bachelor in Biology in 1998 (University of Alicante) and her PhD in 2003 (Biochemistry, University of Alicante). She undertook post-doctoral research at the University of East Anglia (Norwich, U.K. 2004-2005; 2007-2008).\nHer multidisciplinary research focuses on investigating archaea and their potential applications in biotechnology. She has an H-index of 21. She has authored one patent and has published more than 70 indexed papers and around 60 book chapters.\nShe has contributed to more than 150 national and international meetings during the last 15 years. Her research interests include archaea metabolism, enzymes purification and characterization, gene regulation, carotenoids and bioplastics production, antioxidant\ncompounds, waste water treatments, and brines bioremediation.\nRosa María’s other roles include editorial board member for several journals related\nto biochemistry, reviewer for more than 60 journals (biochemistry, molecular biology, biotechnology, chemistry and microbiology) and president of several organizing committees in international meetings related to the N-cycle or respiratory processes.",institutionString:null,institution:{name:"University of Alicante",institutionURL:null,country:{name:"Spain"}}},editorTwo:null,editorThree:null},{id:"15",title:"Chemical Biology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/15.jpg",isOpenForSubmission:!0,editor:{id:"441442",title:"Dr.",name:"Şükrü",middleName:null,surname:"Beydemir",slug:"sukru-beydemir",fullName:"Şükrü Beydemir",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00003GsUoIQAV/Profile_Picture_1634557147521",biography:"Dr. Şükrü Beydemir obtained a BSc in Chemistry in 1995 from Yüzüncü Yıl University, MSc in Biochemistry in 1998, and PhD in Biochemistry in 2002 from Atatürk University, Turkey. He performed post-doctoral studies at Max-Planck Institute, Germany, and University of Florence, Italy in addition to making several scientific visits abroad. He currently works as a Full Professor of Biochemistry in the Faculty of Pharmacy, Anadolu University, Turkey. Dr. Beydemir has published over a hundred scientific papers spanning protein biochemistry, enzymology and medicinal chemistry, reviews, book chapters and presented several conferences to scientists worldwide. He has received numerous publication awards from various international scientific councils. He serves in the Editorial Board of several international journals. Dr. Beydemir is also Rector of Bilecik Şeyh Edebali University, Turkey.",institutionString:null,institution:{name:"Anadolu University",institutionURL:null,country:{name:"Turkey"}}},editorTwo:{id:"13652",title:"Prof.",name:"Deniz",middleName:null,surname:"Ekinci",slug:"deniz-ekinci",fullName:"Deniz Ekinci",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYLT1QAO/Profile_Picture_1634557223079",biography:"Dr. Deniz Ekinci obtained a BSc in Chemistry in 2004, MSc in Biochemistry in 2006, and PhD in Biochemistry in 2009 from Atatürk University, Turkey. He studied at Stetson University, USA, in 2007-2008 and at the Max Planck Institute of Molecular Cell Biology and Genetics, Germany, in 2009-2010. Dr. Ekinci currently works as a Full Professor of Biochemistry in the Faculty of Agriculture and is the Head of the Enzyme and Microbial Biotechnology Division, Ondokuz Mayıs University, Turkey. He is a member of the Turkish Biochemical Society, American Chemical Society, and German Genetics society. Dr. Ekinci published around ninety scientific papers, reviews and book chapters, and presented several conferences to scientists. He has received numerous publication awards from several scientific councils. Dr. Ekinci serves as the Editor in Chief of four international books and is involved in the Editorial Board of several international journals.",institutionString:null,institution:{name:"Ondokuz Mayıs University",institutionURL:null,country:{name:"Turkey"}}},editorThree:null},{id:"17",title:"Metabolism",coverUrl:"https://cdn.intechopen.com/series_topics/covers/17.jpg",isOpenForSubmission:!0,editor:{id:"138626",title:"Dr.",name:"Yannis",middleName:null,surname:"Karamanos",slug:"yannis-karamanos",fullName:"Yannis Karamanos",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002g6Jv2QAE/Profile_Picture_1629356660984",biography:"Yannis Karamanos, born in Greece in 1953, completed his pre-graduate studies at the Université Pierre et Marie Curie, Paris, then his Masters and Doctoral degree at the Université de Lille (1983). He was associate professor at the University of Limoges (1987) before becoming full professor of biochemistry at the Université d’Artois (1996). He worked on the structure-function relationships of glycoconjugates and his main project was the investigations on the biological roles of the de-N-glycosylation enzymes (Endo-N-acetyl-β-D-glucosaminidase and peptide-N4-(N-acetyl-β-glucosaminyl) asparagine amidase). From 2002 he contributes to the understanding of the Blood-brain barrier functioning using proteomics approaches. He has published more than 70 papers. His teaching areas are energy metabolism and regulation, integration and organ specialization and metabolic adaptation.",institutionString:null,institution:{name:"Artois University",institutionURL:null,country:{name:"France"}}},editorTwo:null,editorThree:null},{id:"18",title:"Proteomics",coverUrl:"https://cdn.intechopen.com/series_topics/covers/18.jpg",isOpenForSubmission:!0,editor:{id:"200689",title:"Prof.",name:"Paolo",middleName:null,surname:"Iadarola",slug:"paolo-iadarola",fullName:"Paolo Iadarola",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSCl8QAG/Profile_Picture_1623568118342",biography:"Paolo Iadarola graduated with a degree in Chemistry from the University of Pavia (Italy) in July 1972. He then worked as an Assistant Professor at the Faculty of Science of the same University until 1984. In 1985, Prof. Iadarola became Associate Professor at the Department of Biology and Biotechnologies of the University of Pavia and retired in October 2017. Since then, he has been working as an Adjunct Professor in the same Department at the University of Pavia. His research activity during the first years was primarily focused on the purification and structural characterization of enzymes from animal and plant sources. During this period, Prof. Iadarola familiarized himself with the conventional techniques used in column chromatography, spectrophotometry, manual Edman degradation, and electrophoresis). Since 1995, he has been working on: i) the determination in biological fluids (serum, urine, bronchoalveolar lavage, sputum) of proteolytic activities involved in the degradation processes of connective tissue matrix, and ii) on the identification of biological markers of lung diseases. In this context, he has developed and validated new methodologies (e.g., Capillary Electrophoresis coupled to Laser-Induced Fluorescence, CE-LIF) whose application enabled him to determine both the amounts of biochemical markers (Desmosines) in urine/serum of patients affected by Chronic Obstructive Pulmonary Disease (COPD) and the activity of proteolytic enzymes (Human Neutrophil Elastase, Cathepsin G, Pseudomonas aeruginosa elastase) in sputa of these patients. More recently, Prof. Iadarola was involved in developing techniques such as two-dimensional electrophoresis coupled to liquid chromatography/mass spectrometry (2DE-LC/MS) for the proteomic analysis of biological fluids aimed at the identification of potential biomarkers of different lung diseases. He is the author of about 150 publications (According to Scopus: H-Index: 23; Total citations: 1568- According to WOS: H-Index: 20; Total Citations: 1296) of peer-reviewed international journals. He is a Consultant Reviewer for several journals, including the Journal of Chromatography A, Journal of Chromatography B, Plos ONE, Proteomes, International Journal of Molecular Science, Biotech, Electrophoresis, and others. He is also Associate Editor of Biotech.",institutionString:null,institution:{name:"University of Pavia",institutionURL:null,country:{name:"Italy"}}},editorTwo:{id:"201414",title:"Dr.",name:"Simona",middleName:null,surname:"Viglio",slug:"simona-viglio",fullName:"Simona Viglio",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRKDHQA4/Profile_Picture_1630402531487",biography:"Simona Viglio is an Associate Professor of Biochemistry at the Department of Molecular Medicine at the University of Pavia. She has been working since 1995 on the determination of proteolytic enzymes involved in the degradation process of connective tissue matrix and on the identification of biological markers of lung diseases. She gained considerable experience in developing and validating new methodologies whose applications allowed her to determine both the amount of biomarkers (Desmosine and Isodesmosine) in the urine of patients affected by COPD, and the activity of proteolytic enzymes (HNE, Cathepsin G, Pseudomonas aeruginosa elastase) in the sputa of these patients. Simona Viglio was also involved in research dealing with the supplementation of amino acids in patients with brain injury and chronic heart failure. She is presently engaged in the development of 2-DE and LC-MS techniques for the study of proteomics in biological fluids. The aim of this research is the identification of potential biomarkers of lung diseases. She is an author of about 90 publications (According to Scopus: H-Index: 23; According to WOS: H-Index: 20) on peer-reviewed journals, a member of the “Società Italiana di Biochimica e Biologia Molecolare,“ and a Consultant Reviewer for International Journal of Molecular Science, Journal of Chromatography A, COPD, Plos ONE and Nutritional Neuroscience.",institutionString:null,institution:{name:"University of Pavia",institutionURL:null,country:{name:"Italy"}}},editorThree:null}]},overviewPageOFChapters:{paginationCount:43,paginationItems:[{id:"82374",title:"The Potential of the Purinergic System as a Therapeutic Target of Natural Compounds in Cutaneous Melanoma",doi:"10.5772/intechopen.105457",signatures:"Gilnei Bruno da Silva, Daiane Manica, Marcelo Moreno and Margarete Dulce Bagatini",slug:"the-potential-of-the-purinergic-system-as-a-therapeutic-target-of-natural-compounds-in-cutaneous-mel",totalDownloads:4,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Purinergic System",coverURL:"https://cdn.intechopen.com/books/images_new/10801.jpg",subseries:{id:"17",title:"Metabolism"}}},{id:"82103",title:"The Role of Endoplasmic Reticulum Stress and Its Regulation in the Progression of Neurological and Infectious Diseases",doi:"10.5772/intechopen.105543",signatures:"Mary Dover, Michael Kishek, Miranda Eddins, Naneeta Desar, Ketema Paul and Milan Fiala",slug:"the-role-of-endoplasmic-reticulum-stress-and-its-regulation-in-the-progression-of-neurological-and-i",totalDownloads:5,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Updates on Endoplasmic Reticulum",coverURL:"https://cdn.intechopen.com/books/images_new/11674.jpg",subseries:{id:"14",title:"Cell and Molecular Biology"}}},{id:"82212",title:"Protein Prenylation and Their Applications",doi:"10.5772/intechopen.104700",signatures:"Khemchand R. Surana, Ritesh B. Pawar, Ritesh A. Khairnar and Sunil K. Mahajan",slug:"protein-prenylation-and-their-applications",totalDownloads:9,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Modifications of Biomolecules",coverURL:"https://cdn.intechopen.com/books/images_new/11098.jpg",subseries:null}},{id:"80954",title:"Ion Channels and Neurodegenerative Disease Aging Related",doi:"10.5772/intechopen.103074",signatures:"Marika Cordaro, Salvatore Cuzzocrea and Rosanna Di Paola",slug:"ion-channels-and-neurodegenerative-disease-aging-related",totalDownloads:6,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Ion Channels - From Basic Properties to Medical Treatment",coverURL:"https://cdn.intechopen.com/books/images_new/10838.jpg",subseries:{id:"14",title:"Cell and Molecular Biology"}}}]},overviewPagePublishedBooks:{paginationCount:31,paginationItems:[{type:"book",id:"7006",title:"Biochemistry and Health Benefits of Fatty Acids",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/7006.jpg",slug:"biochemistry-and-health-benefits-of-fatty-acids",publishedDate:"December 19th 2018",editedByType:"Edited by",bookSignature:"Viduranga Waisundara",hash:"c93a00abd68b5eba67e5e719f67fd20b",volumeInSeries:1,fullTitle:"Biochemistry and Health Benefits of Fatty Acids",editors:[{id:"194281",title:"Dr.",name:"Viduranga Y.",middleName:null,surname:"Waisundara",slug:"viduranga-y.-waisundara",fullName:"Viduranga Y. Waisundara",profilePictureURL:"https://mts.intechopen.com/storage/users/194281/images/system/194281.jpg",biography:"Dr. Viduranga Waisundara obtained her Ph.D. in Food Science\nand Technology from the Department of Chemistry, National\nUniversity of Singapore, in 2010. She was a lecturer at Temasek Polytechnic, Singapore from July 2009 to March 2013.\nShe relocated to her motherland of Sri Lanka and spearheaded the Functional Food Product Development Project at the\nNational Institute of Fundamental Studies from April 2013 to\nOctober 2016. She was a senior lecturer on a temporary basis at the Department of\nFood Technology, Faculty of Technology, Rajarata University of Sri Lanka. She is\ncurrently Deputy Principal of the Australian College of Business and Technology –\nKandy Campus, Sri Lanka. She is also the Global Harmonization Initiative (GHI)",institutionString:"Australian College of Business & Technology",institution:null}]},{type:"book",id:"6820",title:"Keratin",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/6820.jpg",slug:"keratin",publishedDate:"December 19th 2018",editedByType:"Edited by",bookSignature:"Miroslav Blumenberg",hash:"6def75cd4b6b5324a02b6dc0359896d0",volumeInSeries:2,fullTitle:"Keratin",editors:[{id:"31610",title:"Dr.",name:"Miroslav",middleName:null,surname:"Blumenberg",slug:"miroslav-blumenberg",fullName:"Miroslav Blumenberg",profilePictureURL:"https://mts.intechopen.com/storage/users/31610/images/system/31610.jpg",biography:"Miroslav Blumenberg, Ph.D., was born in Subotica and received his BSc in Belgrade, Yugoslavia. He completed his Ph.D. at MIT in Organic Chemistry; he followed up his Ph.D. with two postdoctoral study periods at Stanford University. Since 1983, he has been a faculty member of the RO Perelman Department of Dermatology, NYU School of Medicine, where he is codirector of a training grant in cutaneous biology. Dr. Blumenberg’s research is focused on the epidermis, expression of keratin genes, transcription profiling, keratinocyte differentiation, inflammatory diseases and cancers, and most recently the effects of the microbiome on the skin. 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