Proof-of-principle gene-drive systems with and without antimalarial effectors in
\\n\\n
Released this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\\n\\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
\\n"}]',published:!0,mainMedia:{caption:"Highly Cited",originalUrl:"/media/original/117"}},components:[{type:"htmlEditorComponent",content:'IntechOpen is proud to announce that 191 of our authors have made the Clarivate™ Highly Cited Researchers List for 2020, ranking them among the top 1% most-cited.
\n\nThroughout the years, the list has named a total of 261 IntechOpen authors as Highly Cited. Of those researchers, 69 have been featured on the list multiple times.
\n\n\n\nReleased this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\n\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
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Use theory and possible practical application to drive the knowledge from human involvement in workplace activities to any possible risk of health and safety hazards of the job.
",isbn:"978-1-80356-651-1",printIsbn:"978-1-80356-650-4",pdfIsbn:"978-1-80356-652-8",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,isSalesforceBook:!1,isNomenclature:!1,hash:"769f942393275479acca64e4f4fea958",bookSignature:"Dr. Bankole Kolawole Fasanya and Dr. Sridhar Krishnamurti",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11518.jpg",keywords:"Frequency, Sound Power, Absorption, Noise, Soundproof, Reflection, Inverse Square, Perception, Signal, Background Noise, Building, Noise Barrier",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"March 18th 2022",dateEndSecondStepPublish:"May 26th 2022",dateEndThirdStepPublish:"July 25th 2022",dateEndFourthStepPublish:"October 13th 2022",dateEndFifthStepPublish:"December 12th 2022",dateConfirmationOfParticipation:null,remainingDaysToSecondStep:"3 months",secondStepPassed:!0,areRegistrationsClosed:!0,currentStepOfPublishingProcess:4,editedByType:null,kuFlag:!1,biosketch:"Dr. Fasanya is an Assistant Professor at Purdue University, USA. Prior to his current position, he has worked in different capacities with different institutions: Senior research associate (Auditory Protection and Prevention - US Army Aeromedical Research Laboratory, Adjunct Assistant Professor-NCAT, Facilities Engineer MVA, etc). Dr. Fasanya holds a Ph.D. in Industrial and systems engineering with a specialization in ergonomics and human factors.",coeditorOneBiosketch:"Dr. Sridhar Krishnamurti is a Professor and Program Director of Audiology at Auburn University. Sridhar has\r\nauthored a book, journal articles, and book chapters in Audiology and Hearing Conservation. He\r\nis a recipient of several Research grant awards, including the 1999 New Investigator Research\r\nAward from the American Academy of Audiology and the 2011 Auburn University Alumni\r\nUndergraduate Teaching Excellence and 2012 Auburn University Faculty Research Awards.",coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"214494",title:"Dr.",name:"Bankole",middleName:"Kolawole",surname:"Fasanya",slug:"bankole-fasanya",fullName:"Bankole Fasanya",profilePictureURL:"https://mts.intechopen.com/storage/users/214494/images/system/214494.jpg",biography:"Bankole K. Fasanya received a BSc in Mechanical Engineering in 1999 from The Polytechnic Ibadan, Nigeria, his Master’s degree in Industrial and Systems Engineering from Morgan State University, Maryland, USA and his doctorate degree in Industrial and Systems Engineering specialized in ergonomics and human factors from North Carolina Agricultural and Technical State University, USA. His research focuses on human and environmental safety, ergonomics and human factors, auditory prevention and protection and noise assessment and control at workplaces. Dr. Fasanya is currently an assistant professor at Purdue University Northwest in Indiana, USA. He currently serves as one of the executive members of the American Hearing Conservative Association (NHCA). He is an OSHA-Authorized general industry safety train the trainer and a certified occupational hearing conservationist (COHC).",institutionString:"Purdue University Northwest",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"2",totalChapterViews:"0",totalEditedBooks:"1",institution:{name:"Purdue University Northwest",institutionURL:null,country:{name:"United States of America"}}}],coeditorOne:{id:"466252",title:"Dr.",name:"Sridhar",middleName:null,surname:"Krishnamurti",slug:"sridhar-krishnamurti",fullName:"Sridhar Krishnamurti",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00003RKaOOQA1/Profile_Picture_2022-04-08T11:15:28.jpg",biography:"Dr. Sridhar Krishnamurti is a Professor and Program Director of Audiology at Auburn University.\r\nHe has served on the research grants review panel for several agencies and journals including\r\nAlzheimer’s Association, DOD Hearing Restoration Research, Ear and Hearing, American\r\nJournal of Public Health, and Journal of the American Academy of Audiology. Sridhar\r\nKrishnamurti has served as the past-continuing education administrator for Audiology Special\r\nInterest Divisions 6-9 and a Fellow of the American Academy of Audiology. Sridhar has\r\nauthored a book, journal articles, and book chapters in Audiology and Hearing Conservation. He\r\nis a recipient of several Research grant awards, including the 1999 New Investigator Research\r\nAward from the American Academy of Audiology and the 2011 Auburn University Alumni\r\nUndergraduate Teaching Excellence and 2012 Auburn University Faculty Research Awards.\r\nSridhar is currently President of the Council of Au.D Programs and an Executive Council member\r\nfor the National Hearing Conservation Association. His research has been funded by Oak Ridge\r\nAssociated Universities (ORISE) program and CDC-NIOSH.",institutionString:"Auburn University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"0",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"Auburn University",institutionURL:null,country:{name:"United States of America"}}},coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"11",title:"Engineering",slug:"engineering"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"429342",firstName:"Zrinka",lastName:"Tomicic",middleName:null,title:"Ms.",imageUrl:"https://mts.intechopen.com/storage/users/429342/images/20008_n.jpg",email:"zrinka@intechopen.com",biography:"As an Author Service Manager, my responsibilities include monitoring and facilitating all publishing activities for authors and editors. From chapter submission and review to approval and revision, copyediting and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully commit and concentrate on the chapters they are writing, editing, or reviewing. I assist authors in the preparation of their full chapter submissions and track important deadlines and ensure they are met. I help to coordinate internal processes such as linguistic review, and monitor the technical aspects of the process. As an ASM I am also involved in the acquisition of editors. Whether that be identifying an exceptional author and proposing an editorship collaboration, or contacting researchers who would like the opportunity to work with IntechOpen, I establish and help manage author and editor acquisition and contact."}},relatedBooks:[{type:"book",id:"7620",title:"Safety and Health for Workers",subtitle:"Research and Practical Perspective",isOpenForSubmission:!1,hash:"1233909d682e2cced428e1042fd40ad4",slug:"safety-and-health-for-workers-research-and-practical-perspective",bookSignature:"Bankole Fasanya",coverURL:"https://cdn.intechopen.com/books/images_new/7620.jpg",editedByType:"Edited by",editors:[{id:"214494",title:"Dr.",name:"Bankole",surname:"Fasanya",slug:"bankole-fasanya",fullName:"Bankole Fasanya"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10198",title:"Response Surface Methodology in Engineering Science",subtitle:null,isOpenForSubmission:!1,hash:"1942bec30d40572f519327ca7a6d7aae",slug:"response-surface-methodology-in-engineering-science",bookSignature:"Palanikumar Kayaroganam",coverURL:"https://cdn.intechopen.com/books/images_new/10198.jpg",editedByType:"Edited by",editors:[{id:"321730",title:"Prof.",name:"Palanikumar",surname:"Kayaroganam",slug:"palanikumar-kayaroganam",fullName:"Palanikumar Kayaroganam"}],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:"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. 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Biofilms can be defined as an accumulation of microorganisms and their extracellular products forming structured communities attached to a surface. Biofilms are able to build up under natural circumstances, for instance on the urothelium or prostate stones and they can also colonize the surfaces of implanted medical devices. Biofilm infections have a major role on temporary and permanent implants or devices placed in the human body. In the process of endourological development a great variety of foreign bodies have been invented besides urethral catheters like ureter, prostatic stents, percutan nephrostomy, penile, testicular implants and artificial urinary sphincters. Many biofilms are quite harmful but others can have a positive impact, namely lining healthy intestine and female genito-urinary tract. Biofilms have significant implications for clinical pharmacology, particularly related to antibiotic resistance, drug adsorption onto and off of devices, and minimum inhibitory concentrations of drugs required for effective therapy.
\n\t\tA biofilm is an aggregate of microorganisms in which cells adhere to each other and/or to a surface. These adherent cells are frequently embedded within a self-produced matrix of extracellular polymeric substance (EPS). Formation of a biofilm begins with the attachment of free-floating microorganisms to a surface. The first step of biofilm formation is always the deposition of a conditioning film produced by the host to the foreign body. It is followed by the attachment of microorganisms. The microbial adhesion and anchorage to the surface are made by exopolymer production. After this process their growth, multiplication and dissemination can be observed [1,2,3,4,5].
\n\t\t\tAfter insertion of the device into the body the material surface enters into contact with body fluids around the implant. In case of the urinary tract Tamm-Horsfall glycoprotein, various ions, polysaccharides and other components diffuse toward the implant surface from the urine within minutes [6]. Macromolecular components (serum albumin, fibrinogen, collagen, fibronectin) from these body fluids adsorb extremely fast onto the material surfaces to form a conditioning film, prior to the arrival of the first organisms [7]. The creation of a conditioning film alters the surface characteristics of implants. The role of the conditioning film is vital as many pathogens do not have mechanisms allowing them to adhere directly or strongly onto bare implant surfaces [8].
\n\t\t\tThe next step in the development of a biofilm is the approach and attachment of microorganisms. The ability of microorganisms to adhere to surfaces is influenced by electrostatic and hydrophobic interactions, ionic strength, osmolality and urinary pH [9,10].
\n\t\t\tIn order for bacteria to react to a surface or an interface like an air-water interface, these cells must be able to ’sense’ their proximity to these surfaces. The planktonic ’free-floating’ bacterial cells release both protons and signaling molecules as they move through the bulk fluid. These protons and signaling molecules must diffuse radially away from the floating cell, if not adjacent to any surface or interface. But a significantly higher concentration of either protons or signaling molecules can develop on the side of the bacterial cell close to any surface. This allows the cell to sense that it is near a surface because diffusion is limited on this side [4]. After the planktonic bacterial cell has sensed the surface, it may commit to the active process of adhesion and biofilm formation.
\n\t\t\tThere is no single process or theory, which can completely describe microbial adhesion. The initial adhesion is reversible and involves hydrophobic and electrostatic forces. It is followed by irreversible attachment provided by bacterial polysaccharides which anchor the organisms to the surface. Subsequently, colonization takes by species factors, such as slow migration and spreading, rolling, packing and adhesion of the progress. A developed biofilm consists of groups of microorganisms, sometimes in mushroom-like forms, separated by interstitial spaces that are filled with the surrounding fluid [11]. The growth rates of organisms on a surface as well as the strategies used by microorganisms to spread over a surface are important for colonization. These strategies are species specific which can influence the distribution of a biofilm on a surface [12].
\n\t\t\tThe final stage of microbial colonization of a surface is the formation of a biofilm structure. At this point, the microorganisms have created a microenvironment protective against many antimicrobial agents and host immune defense mechanisms. Biofilm has been described as having a heterogeneous structure with a rough surface [13]. The microcolony is actually the basic structural unit of the biofilm, similar to the tissue which is the basic unit of growth of more complex organisms. Depending on the species involved, the microcolony may be composed of 10-25% cells and 75-90% exopolysaccharide (EPS) matrix. The biofilm contains ‘water channels’ which allow transporting of essential nutrients and oxygen for the growth of the cells [14]. Microorganisms within the biofilm also secrete chemical signals that mediate population density-dependent gene expression, which has an important role in biofilm development [15]. In summary, the biofilm is usually built up of three layers [16]:
\n\t\t\tthe linking film which attaches to the surface of tissue or biomaterials
the base film of compact microorganisms
the surface film as an outer layer, where planktonic organisms can be released free-floating and spreading over the surface.
Infections caused as a result of biofilm formation are characterized by particularly strong antibiotic and immune resistance patterns. Bacteria within the biofilms differ in behaviour and in phenotypic form from the planktonic bacteria. Antimicrobial agents are effective against planktonic bacteria and appear to clear mucosal surfaces of adherent bacterial microcolonies but frequently fail to eradicate bacterial biofilms on urological devices. The use of antibiotics is currently one of the possibilities of the prevention of biofilm formation. However, even in the presence of antibiotics bacteria can adhere, colonize and survive on implanted medical devices as has been shown for urinary catheters and ureteral stent surfaces in vitro and in vivo [17,18,19]. The problem in conventional clinical microbiology is how to treat patients in the best way when choosing antibiotics is based on bacterial cultures derived from planktonic bacterial cells which differ very much from bacteria in the biofilm mode. This can stand behind the clinical failure rate of treating chronic bacterial infection.
\n\t\t\tThe failure of antimicrobial agents to treat biofilms has been associated with a variety of mechanisms (4) [18,19,20,21,22,23,24]. One mechanism of biofilm resistance to antimicrobial agents is the failure of an agent to penetrate the full depth of the biofilm (extrinsic resistance). The extracellular matrix for instance may block the penetration at the very beginning.
\n\t\t\tOne mechanism is the failure of an agent to penetrate the full depth of the biofilm (
The organisms growing at a slower rate within the biofilm are more resistant to the effects of antimicrobial agents, which require active growth.
Bacteria within biofilm are phenotypically so different from their planktonic counterparts that antimicrobial agents developed against the latter often fail to eradicate organisms in the biofilm. Bacteria within a biofilm activate many genes which alter the cell envelope, the molecular targets and the susceptibility to antimicrobial agents (intrinsic resistance). Current opinion is that phenotypic changes caused by a genetic switch, when approximately 65-80 proteins change, play a more important role in the protection from antimicrobial agents than the external resistance provided by the exopolysaccharide matrix.
Bacteria within a biofilm can sense the external environment, communicate with each other and transfer genetic information and plasmids within biofilm.
Bacteria in a biofilm can usually survive the presence of antimicrobial agents at a concentration 1000-1500 times higher than the concentration that kills planktonic cells of the same species.
According to in vitro and in vivo studies aminoglycosides and beta-lactam antibiotics can prevent the formation of ‘young’ biofilms, while fluoroquinolones are effective in case of both ‘young’ and ‘older’ biofilms because of their good penetrative qualities. They are present in biofilms even one or two weeks after the end of the antibiotic treatment [25-28].
\n\t\t\tMost researchers believe that antibiotics can only slow down the progress of biofilm formation by eliminating unprotected planktonic bacteria and reducing the metabolic activity of bacteria on the biofilm surface [23, 29-30]. However, during an acute febrile phase of a biofilm infection.
\n\t\tDue to the urinary catheter the development of bacteriuria and biofilm formation is inevitable. Urinary catheters are readily targets of biofilm development on their inner and outer surfaces once they are inserted. The long-term use of them leads to infection in most of the cases. The surface of a catheter (depending on its material) provides sufficient circumstances for bacteria to adhere and spread along in two ways. One route is when organisms ascend the catheter extraluminally by direct inoculation at the time of the catheter insertion or migrate in the mucous sheath that surrounds the external aspect of the catheter. Extraluminal organisms are primarily endogenous, originating from the gastrointestinal tract. These organisms colonize the patient’s perineum and ascend the urethra after catheter insertion [13,31,32,33,34] Approximately 70% of bacteriuria in catheterized women is believed to occur through the extraluminal entry.
\n\t\t\tBacteria can ascend the catheter also by an
An additional problem in use of medical biomaterials in the urinary tract environment is the development of encrustation and consecutive obstruction. When the drained urinary tract becomes infected by urease producing bacteria such as
In vitro and in vivo studies confirmed the difficulty in detecting biofilm formation by using conventional laboratory procedures [38, 39]. Reid at al found that 90% of indwelling silicone double J stents were colonized by adherent bacteria, however the incidence of urinary infection detected clinically was only 27% [38]. The difficulty in detecting biofilm formation by using conventional laboratory procedures was confirmed in a large study where 237 ureteral stents were tested. It was shown that 68% of stents were actually colonized but only 30% of patients were found to have bacteriuria [39]. Therefore, a negative urine culture does not rule out the possibility of stent colonization. The study testified correlation between the length of the indwelling time and the development of infection.
\n\t\tThe prosthesis-associated chronic pain due to subclinical infection is more common than clinically apparent infection (3). Staphylococcus species, especially Staphylococcus epidermidis are the most common pathogens found in penile prostheses infection (35-56%) [40], while Gram-negative enteric bacteria are liable for 20 % of infections [41,42]. S. epidermidis was cultured in 40% of penile prosthesis removed for malfunction with no clinical evidence of infection [43]. Staphylococcal species were also found to enhance biofilm formation. These cases can be ‘silent’ for many years before becoming clinically evident [44] in contrast to Gram-negative bacterial infection (
To reduce the risk of device associated infections many modifications have been developed such as antibiotic and hydrophilic coated devices.Hydrophilic penile prosthesis coating was has been shown to decrease bacterial adherence in vitro and in animal models [45]. Antibiotic prophylaxis is desirable for the above-mentioned facts. Since the most common pathogen is the Staphylococcus epidermidis, first-generation cephalosporins, broad-spectrum penicillin should be used [46]. In cases of chronic pain, long-term administration of quinolones eased 60% of symptoms. Lack of success involves the necessity of implant removal.
\n\t\tAround 3% of the AUS become infected and symptoms are mainly associated with the control pump device. Avoiding the risk factors as infected urine, prolonged urinary retention and large bladder residual can reduce this high occurrence [43,46]. Since the parts of the sphincter device form one continuous surface, the AUS is suggested to be removed entirely as the first step to eliminate the infection. The reimplantation must be preceded by the complete treatment of the infected area. This is not always achievable as many of these patients are paraplegic or have a neurogenic bladder with recurrent UTIs [43,46].
\n\t\tIn case of urease-producing bacteriuria the infection can be conjoined with the formation of struvite and calcium phosphate calculi as described above. The infected calculi grow rapidly and provide safe environment for the bacteria adhered to the biofilm [47]. The complete removal of all stone fragments during stone operation (PCNL, URS, ±combined with ESWL), prolonged administration of antibiotics (8-10 weeks for destroying urease-producing bacteria) and metaphylaxis are the features of the most effective treatment strategy.
\n\t\tAlthough the diagnosis and classification of chronic prostatitis have been standardized, the differentiation of chronic non-bacterial from bacterial inflammation is still challenging. Being out of the sweeping effect of streaming urine the prostatic ducts and acini provides safe circumstances to planktonic bacteria to multiply rapidly and induce a host response with infiltration of acute inflammatory cells into the ducts. The ducts become engorged with infiltrate composed of dead and living bacteria as well as living and dying acute inflammatory cells, desquamated epithelial cells and cellular debris. At this point it is relatively easy to eradicate all the offending organisms which are in a ‘planktonic state’ with appropriate antibiotic therapy. If the bacteria persist from either clinically acute or more likely, subacute inflammation, they can form sporadic bacterial microcolonies or biofilms adherent to the epithelium of the ductal system (2b) [48,49]. These bacteria also produce an exopolysaccharide slime or glycocalyx that envelops these adherent microcolonies. The bacteria persisting in the prostate gland within these focal biofilms can provoke persistent immunological stimulation and subsequent chronic inflammation [48]. The diagnosis of chronic bacterial prostatitis can be difficult as colonized bacteria will not get into the prostatic secretion or urine sample. Antimicrobial therapy eradicates the planktonic bacteria but not the adherent bacterial biofilms deep within the prostate gland. Another cause of unsuccessful treatment may be the fact that the bacteria within biofilms differ significantly from their planktonic counterparts in metabolic rate, molecular targets and expression of antimicrobial binding proteins [3,19]. There is a need in development of diagnostic tools which would be able to recognize small adherent bacterial biofilms which exist deep within the prostate gland in chronic bacterial prostatitis. New treatment regimens should be carried out in order to be able to deliver much higher antibiotic concentrations to the biofilm within the prostatic duct.
\n\t\tEntry of E. coli into the urinary tract is not well understood, although sexual intercourse is the most clearly defined predisposing factor. Presumably, a small number of E. coli from the vaginal or enteric flora are introduced into the bladder during an average incident, and it seems plausible that in most cases the innate defenses in the bladder would be able to prevent infection. However, sometimes Uropathogenic E.Coli (UPEC) clearly possess mechanisms to overcome these defenses and establish a foothold in the bladder. UPEC pathogenesis initiates with bacterial binding of superficial bladder epithelial cells. Initial colonization events activate inflammatory and apoptotic cascades in the epithelium, which is normally inert and only turns over every 6 to 12 months. Bladder epithelial cells respond to invading bacteria in part by recognizing bacterial lipopolysaccharide (LPS) via the Toll-like receptor pathway, which results in strong neutrophil influx into the bladder. In addition, interactions mediated by adhesin FimH at the tips of type 1 pili with the bladder epithelium stimulate exfoliation of superficial epithelial cells, causing many of the pathogens to be shed into the urine. Genetic programs are activated that lead to differentiation and proliferation of the underlying transitional cells in an effort to renew the exfoliated superficial epithelium. Despite the robust inflammatory response and epithelial exfoliation, UPEC are able to maintain high titers in the bladder for several days.
\n\t\t\tA bacterial mechanism of FimH-mediated invasion into the superficial cells apparently allows evasion of these innate defenses. Initially, bacteria replicate rapidly inside superficial cells as disorganized clusters. Subsequently, bacteria in the clusters divide without much growth in cell size, resulting in coccoid-shaped bacteria, presumably due to changes in genetic programs. Furthermore, the bacterial clusters became highly compact and organized into biofilm-like structures, termed intracellular bacterial communities (IBCs), inside bladder superficial cells [50]. The IBCs push the bladder superficial cell membranes outward to give a “pod” like appearance by scanning electron microscopy. Bacteria in the IBCs are held together by exopolymeric matrices, reminiscent of biofilm structures [51]. At some point during this IBC developmental process, bacteria on the edges of IBCs become elongated again, become motile and start to move away from IBCs. Bacteria can exit out of infected bladder cells, probably due to compromised membrane integrity. UPEC undergo such IBC cascade to increase in numbers, resulting in high bacterial titers in the bladder. In addition, bacteria in these intracellular niches can create a chronic quiescent reservoir in the bladder, which can persist undetected for several months without bacteria shedding in the urine [52,53,54]. Bacteria in IBCs are completely resistant to 3- and 10-day courses of antibiotics [55].
\n\t\tOnce bacteria reach the kidney either by ascending infection or vesicoureteral reflux they are able to adhere to the urothelium and papillae. Nickel et al showed that bacteria could adhere in thin biofilms to the urothelium before invading the renal tissue with resultant pyelonephritis [47]. These bacterial biofilms are more easily eradicated by antimicrobial agents, in contrast to the biofilms on catheter surfaces [51], which may be ascribed to the effective synergistic actions of antimicrobial agents and host defenses against the biofilms on urothelium [56].
\n\t\tBacterial vaginosis (BV) is the most common vaginal disorder in adult women [57]. Although it is a non-fatal disease, BV presents an increased risk for other more severe clinical outcomes, such as preterm birth and HIV infections [58,59]. As defined by Amsel clinical criteria, BV exhibits at least 3 of the following 4 clinical symptoms:
\n\t\t\televation of vaginal fluid pH to above 4.5;
detectable “fishy odor” of vaginal fluid upon addition of 10% potassium hydroxide;
presence of clue cells, vaginal epithelial cells covered with bacteria, in vaginal fluid; and
milky vaginal discharge.
The vaginal flora of healthy women consists predominantly of Gram-positive lactobacilli, especially
The attempts to demonstrate
Swidsinski and co-workers demonstrated the presence of bacterial biofilms on the vaginal epithelium of biopsies from women with BV [68]. These biofilm showed characteristics of dense surface bacterial biofilm and were comprised predominantly of
The harsh and potentially fatal consequences of microbial biofilm infections generated efforts to prevent their formation, particularly on indwelling medical devices using chemical and mechanical approaches. Catheters coated with hydrogel, silver salts, and antimicrobials have been evaluated; however, they provide minimal reduction in infection incidence (75).
\n\t\t\tAntibiotic (minocycline, rifampicin, nitrofurantoin) impregnated catheters lowered the rate of asymptomatic bacteriuria compared to catheters without impregnation at less than one week but difference was not statistically significant at greater than one week, and the authors concluded that the data were too few to draw conclusions about long-term catheterization. [76]
\n\t\t\tSilver alloy catheters significantly reduced the incidence of asymptomatic bacteriuria at less than one week of catheterization [76]. Beyond one week the estimated effect was smaller but the risk of asymptomatic bacteriuria was still less in the silver alloy group. There are no available clinical trials with appropriate setting about the effect of silver alloy coated catheters on bacteriuria or biofilm formation in case of long-term catheterisation.
\n\t\t\tDe Ridder et al found that fewer patients using hydrophilic-coated catheter (64%) for CIC experienced UTIs compared to the uncoated catheter group (82%)[77]. However, in a randomised controlled study the authors did not find significant difference between hydrophilic-coated and uncoated indwelling urethral catheters in place for 6 weeks with respect to symptomatic urinary tract infection and microbiological analysis of urine culture [78].
\n\t\t\tHeparin coated ureteral stents did not show any organic (biofilms) or anorganic (crystals) deposits after being in situ for up to 6 weeks whereas significant biofilms were demonstrated in 33% of uncoated stents [79].
\n\t\tBiofilm formation can be prevented- or delayed- by applying low intensity nanowaves along the surfaces of an indwelling catheter. This approach opens new options for pharmacological prevention of urinary tract infections (80,81).The concept of using low-energy SAW is based on the hypothesis that these acoustic waves are able to disrupt the formation of biofilms if transmitted directly to indwelling medical devices by inhibiting the adhesion of planktonic bacteria to their surface. Hazan et al. demonstrated the the effectiveness of Low-Energy Surface Acoustic Waves in the prevention of biofilm formation in an animal model in vivo. They found that SAW treatment reduced biofilm formation in vitro, leaving catheters virtually clean of adherent microorganisms, irrespective of the types of bacteria that were examined. In the animal model SAW treated catheters showed strong inhibition of bacterial biofilm compared to controls [82].
\n\t\t\tIn a double blind sham controlled randomized study related to short term catheterization, applying SAW releasing device to catheters prevented biofilm formation in all of the catheters whereas biofilm was present in 63% of the control group [83].
\n\t\t\tA workgroup of the authors of the present article performed a prospective parallel group comparative study on the efficacy of the SAW treatment in case of long-term catheterisation (8 weeks). SAW treatment lowered the rate of significant bacteriuria (33% vs. 81%) and the rate of biofilm formation was also significantly lower in the SAW group compared to the controls[84].
\n\t\tThe number of biomaterial devices used in urology has been increasing permanently. Biofilm infections have a major impact on implants or devices placed in the human body. The mechanism and the different bacterial and host factors taking part in the formation of biofilms have been extensively researched in the last decades, such ideal method has not been developed yet. Antimicrobial agents are effective against planktonic bacteria and appear to clear mucosal surfaces of adherent bacterial microcolonies but frequently fail to eradicate bacterial biofilms on urological devices. Several different approaches to disease prevention are being investigated and some promising results have been obtained.
\n\t\tMosquitoes in the genus
Interventions to control anophelines have been ongoing since Sir Ronald Ross’s discovery of the complete malaria transmission cycle in the late nineteenth century. The first large-scale vector control interventions in the early twentieth century relied on management and control of anopheline breeding habitats via manipulation of the environment (Figure 1) [2]. However, the discovery and subsequent development of dichloro-diphenyl-trichloroethane (DDT) in the early 1940s led to a new era of vector control after successes with the insecticide by the U.S. Army in World War II and various field trials proved its powerful ability to control malaria [3]. The initial successes with DDT were so great that malaria eradication began to appear feasible to some malariologists, and in 1955, the World Health Assembly launched the Global Malaria Eradication Programme (GMEP) with a goal to assist nations in eradicating malaria by providing technical advice and consolidating the resources needed for large-scale eradication campaigns. The World Health Organization (WHO) Expert Committee on Malaria was responsible for designing the eradication campaign schedule, which consisted of four distinct phases: preparatory, attack, consolidation, and maintenance. Completion of the eradication schedule was estimated to require 8–10 years [4]. Despite previous observations of insecticide resistance to DDT in Greece in 1951, the attack phase relied almost exclusively on the use of indoor residual spraying (IRS) of this insecticide to reduce adult mosquito populations supplemented by chloroquine to treat infections [5]. Large reductions in malaria case incidence, morbidity and mortality were observed worldwide because of the GMEP campaign and malaria was eliminated in many countries with temperate climates (Figure 2) [6, 7, 8, 9, 10]. However, progress began to falter by the mid 1960s and some countries participating in the GMEP reverted from the consolidation phase back to the attack phase. Countries such as Sri Lanka, which was an exemplary model for GMEP successes, began to experience epidemic resurgences of malaria [11]. Additionally, resistance to DDT became widespread throughout the participating countries. By the late 1960s, political and financial support for the GMEP had waned and the aim for eradication within a finite timeline was replaced by the aim of controlling malaria within an indefinite timeline.
Timeline of vector-control approaches and outcomes. Important events and timepoints of malaria vector control efforts and progress in the perspective of obstacles and downturns. Although great progress was made through the history of malaria vector control, many natural and artificial challenges have hindered the goal of malaria eradication.
Global estimated number of malaria deaths. Estimated malaria mortality declined significantly from 1920s to 1970s due to many malaria control efforts countrywide and internationally but slowed from 1970s to 2020. Sources [
Control of malaria after the dissolution of the GMEP devolved to a country-by-country basis. Some nations that had benefited from participation in the GMEP continued to make progress in reducing the burden of malaria. However, most African nations were never included in the GMEP, and without dedicated resources, financial support or personnel trained in vector control techniques, the continent continued to suffer greatly as population growth paralleled an increase in malaria morbidity and mortality. In 1975 the WHO estimated that over one million infants and children were dying annually due to malaria in sub-Saharan Africa [12]. A systemic analysis of global malaria mortality from 1980 to 2010 estimated a peak of malaria deaths occurred in 2004 with over 1.8 million deaths occurring globally [13]. By the beginning of the second millennium, the rapid expansion of disease burden due to the absence of a global strategy and lack of unified political will became soberingly evident in the global malaria mortality rates.
The combination of skyrocketing malaria mortality and philanthropic interests of the world’s ultra-wealthy led to a renewed interest and consolidation of financial and political will for advances in malaria control and elimination at the beginning of the second millennium. The formation of the Roll Back Malaria Partnership (RBM) and creation of the United Nations Millennium Development Goals helped to solidify a new global strategy. After years of disparate global malaria control without clearly-defined metrics to track progress, the renewed enthusiasm ushered in a return to specific targets and strategies reminiscent of what was attempted in the 1950s with the GMEP. The new global malaria programme (GMP) had the benefit of additional vector control tools such as a wider variety of insecticide products for IRS and insecticide-treated nets (ITN). The new program also benefited from the historical perspectives of renown malariologists on the causes leading to the failures of the original eradication effort. The UN development goals included Target 6.C with a stated aim “to have halted by 2015 and begun to reverse the incidence of malaria and other major diseases” (UN Millennium goals [14]) and the RBM created a Global Malaria Action Plan, which outlined an overarching strategy and system of support needed to achieve malaria eradication [15]. The enhanced frameworks for combating malaria also were accompanied by increased funding in the formation of the Global Fund to Fight AIDS, Tuberculosis and Malaria and the US President’s Malaria Initiative [16]. The renewed efforts and consolidation of strategies and finances in the early 2000s proved successful, and Target 6.C of the development goals was achieved. There was a 30% reduction in global incidence and 47% decline in mortality due to malaria from 2001 to 2015 [1]. Continuing the momentum of the progress made in the early millennium, WHO member states created and adopted a new global technical strategy (GTS) in 2015 and set an ambitious new target for a 90% reduction in global malaria burden by 2030 [17].
The WHO and RBM developed a new framework of strategies and guidelines to meet the ambitious 2030 targets. The first pillar of the WHO’s post-2015 GTS called for expansions of access. Firstly, it called for expanded access to vector control using either IRS or long-lasting insecticide treated nets (LLINs) and secondly, it called for expanded access to chemoprevention and treatment, especially in vulnerable groups such as children and pregnant women. The new guidelines also highlighted the importance of generating entomological and epidemiological surveillance data to guide vector control and disease-treatment efforts and advised that accumulation of these data should be considered an intervention in itself. While supporting elements of the post-2015 GTS encouraged advancements in research and new technology, these were secondary to the ramp-up of coverage using existing vector control and treatment technologies. Unfortunately, despite the restructured objectives and continual commitment to malaria elimination by global parties in 2015, progress in reducing malaria morbidity and mortality has slowed or stalled in many mid- to high-transmission countries. The post-2015 GTS set an interim goal of achieving 40% reductions in malaria case incidence and mortality by 2020, however, the case incidence at that time had only decreased by 3% and mortality decreased by 22% compared to 2015 levels [17].
Many factors contribute to the decreased rate of reducing malaria incidence and mortality rates. Population growth in malaria-endemic countries has substantially increased the at-risk population. Initial modeling efforts completed during the creation of the post-2015 GTS predicted that with the existing vector control tools and treatment options available, coverage would have to exceed 80% of high-risk populations to reduce the malaria burden [17]. However, growing populations combined with continuing instabilities of governments, natural disasters, conflicts, and epidemics have hampered the ability to reach this needed intervention coverage. As a result, there has been inadequate access to available vector control interventions. It is estimated that only 46% of the population at risk for malaria is protected by an insecticide-treated net and the percent of at-risk population covered by IRS is only 2.4%, a 2.9% decrease when compared to 2010 coverage [1].
In addition to problems of access, the existing vector control interventions face problems of reduced efficacy due to the widespread emergence of insecticide resistance in the major anopheline vectors. Resistance in the form of either target-site insensitivity or metabolomic changes has been observed for all classes of insecticides currently being used to treat bed nets or in IRS campaigns [18]. Cuticular or penetration resistance has also been observed [19], which also reduces the impact of bed nets and IRS campaigns. As of 2020, only eight of the 82 malaria-endemic countries reported no resistance to all classes of insecticides. Resistance to pyrethroids, the only insecticide approved to treat bed nets, is widespread and resistance was reported in just under 70% of the locations that performed WHO approved standardized testing [1]. The varied resistance mechanisms and wide geographical spread of resistance imposes a major threat to the objectives of the GTS, yet no vector control products based on a new class of insecticide have been introduced to global markets since pyrethroids were introduced in the 1970s however, several have been re-purposed for their use in bed-nets and IRS and new formulations are under development with the World Health Organization Pesticide Evaluation Scheme [20, 21]. An additional challenge to current vector control tactics is behavioral resistance of the mosquito vectors. The long-term use of ITN and IRS creates a selective pressure that has been shown to result in behavioral and population compositional changes of malaria-vectoring species over time [22]. Changes in
An increase in access to vector control interventions to above 80% coverage of at-risk populations will likely lead to a reduction in case incidence and mortality but may not result in the desired 90% reduction of malaria burdens due to the challenges presented by resistance. With no new classes of insecticide approved for the control of malaria, widespread insecticide resistance and evidence of behavioral changes perpetuating residual transmission, the limitations of the current GTS vector control initiatives are obvious. New tools and technologies are needed urgently to meet the 2030 targets of the GTS. Ideally, novel vector control strategies should be cost-effective and sustainable as well as implementable and maintainable in a variety of regions irrespective of changes in government stability, conflicts or catastrophes. Population modification using genetic techniques to confer parasite refractoriness in mosquitoes is one such novel strategy that could greatly aid in achieving the ambitious goals of the GMP.
Population modification is the concept of incorporating genes or genetic elements in vector species that increase their refractoriness to the pathogens they transmit thereby inhibiting transfer of the pathogens to host species (Figure 3). Population modification was first described in the contemporary literature using the term ‘population replacement’ by Christopher Curtis in 1968 [26]. Due to misinterpretations of population replacement and negative connotations of the term ‘modification’ related to cultural perspectives on genetically-modified organisms (GMOs), a third term, ‘population alteration’, also was proposed [27]. The early conceptions of population modification were made prior to the discovery and refinement of current gene-drive technologies, however, the original concept as proposed by Curtis suggested the need for a mechanism to elicit fixation of the favorable genes in a population. The advancements and development of genetic-engineering techniques to inhibit
Outcomes anticipated from genetic control approaches. Vector control strategy utilizes genetic-engineering technology with gene drive via two different approaches, population modification/alteration (top) or population suppression (bottom). In both approaches, the transgenic mosquitoes qualified for releases should carry at least three components: the gene drive system, the marker and the effector or suppression component aiming at reducing the vector competence or the vector population, respectively. The anticipated outcome for the population modification/alteration approach is that the treated population become refractory to pathogen as the effector genes spread into the population; whereas with the population suppression approach the anticipated outcome would be the reduction or elimination of whole population. In both cases, the goal is to break the parasite cycle in the mosquito stages.
AsMCRkh2 | Reckh2 | AgNosCd-1 | AgTP13 | ||
---|---|---|---|---|---|
Species | |||||
Drive system | |||||
Target locus | |||||
Effector | Cp-1C3, Vg-2A10 | None | None | Cp-1C3, Vg-2A10 | |
Drive efficiency | Male | ~99% | ~99% | ~99% | ~99% |
Female | 65–90% | ~56% | ~95% | ~85–96% | |
Maternal effect | Significant | Significant | Mild | Mild | |
Fitness | Male contribution | Comparable with WT male | Comparable with WT male | mild reduction | Moderate reduction |
Fertility and fecundity | Post Blood meal lethality in homozygotes | Comparable with WT females | Comparable with WT females | Comparable with WT females | |
Small cage trials | Cage trial ratios, gene drive: wild-type males | 1:1, 1:3, 1:10 | 1:1, 1:3, 1:10 | 1:1, 1:3, 1:10 | 1:1, 1:3 |
Full introduction result | No | >95% introduction for all ratios | Yes | Yes for 1:1 ratio |
Proof-of-principle gene-drive systems with and without antimalarial effectors in
Cp, carboxypeptidase gene promoter; Vg, vitellogenin gene promoter; 1C3, 2A10: single-chain antibodies; WT: wild-type.
Population suppression is an alternative strategy to population modification that utilizes genetic-engineering technologies to reduce vector number and therefore reduce pathogen transmission (Figure 3). This can be achieved by diminishing the fitness or distorting sex ratios so that the vector populations reduce in number and eventually go extinct locally. Similar to population modification, proof-of-principle concepts also exist for population suppression in
Population modification and population suppression vary in their strengths and weaknesses so a complementary approach that involves the sequential application of both technologies can be proposed (Figure 4). This strategy maximizes the benefits of both approaches and lowers their respective hurdles to long-lasting success. The complementary approach includes an initial field release of a population suppression strain that will act to quickly reduce the local population of vectors and their associated population of parasites. When the population structure of native vectors has been sufficiently disrupted by the suppression strategy, the low level of individuals becomes more susceptible to events that may inhibit its ability to persist long term. For example, a re-introduction of wild-type individuals can occur, and these may overwhelm any low levels of remaining drive individuals, or individuals with drive-resistant alleles may build up over time inhibiting future suppression [43]. At this point, when a suppression system has driven the population to levels near extinction, a modification line can be introduced for maximal effect. Allowing a population replacement mosquito line to form the new population of mosquitoes prevents any negative ecological effects that may have occurred due to an empty ecological niche. It also allows the population modification drives to become established in an environment with a minimized risk for resistance to the transgene introduction. The effector genes will be less prone to having pathogen-based resistance develop as the natural pathogen population will have been greatly diminished by the suppression system, and lower pathogen reproduction numbers lower the likelihood of randomly-generated resistance conferring mutations in the pathogens. In the absence of threats from resistance, the only further threat faced by the population modification strain is long-term stability of the effector elements. However, new effector elements can be developed carefully as the needed window for protection resulting from the complementary approach is likely to be much longer than either approach alone.
Vector control with population modification and population suppression complementary approach. Proposed strategy combining sequential releases of mosquitoes with population modification and population suppression drives. The combined approach initiated with releasing population suppression gene-drive mosquitoes, which theoretically reduce the whole mosquito population in the treated area. Follow up with releasing of population modification gene-drive mosquitoes, this strategy ensures avoidance of an empty niche or re-introducing of wild mosquitoes that are susceptible to the malaria parasite. Black: wild-type mosquito; yellow: transgenics mosquitoes with suppression drive; Green: Transgenic mosquitoes with population modification drive.
The malaria parasites go through a multi-staged life cycle within their mosquito vectors (Figure 5). After the female
Malaria developmental pathway and compartments for blocking parasite development. Gametes are ingested with the blood meal. They differentiate, fertile and form a zygote. The zygote develops into a motile form, the ookinete, that then invades the mosquito midgut epithelium. There it develops into an oocyst in which many sporozoites are generated. These burst into the hemolymph and migrate to the salivary glands. From there the sporozoites can be transmitted to a new host during the next blood meal. The midgut compartment allows access to the gametes, zygotes, ookinetes and oocysts. The hemolymph and salivary gland compartments allow access to the sporozoites (image adapted from Isaacs et al. [
A synthetic approach was used in our laboratory to develop the anti-parasite effector genes and introduce these desired traits into the target genomes to generate the genetically-engineered mosquitoes (GEMs) [37]. This approach has several advantages, for example, the components of a synthetic construct can be relatively small, their functions are more fully known and the site in the mosquito genome where they will be located can be characterized or determined prior to genome integration. A synthetic cassette for population modification has two main components: (1) promoters and (2) antimalarial effector genes.
Promoters are regulatory DNA sequences that will drive the expression of a transgene (a marker or an antimalarial effector) in mosquitoes. During its development in the mosquito, the malaria parasite occupies three main compartments: midgut lumen, hemocoel and salivary gland lumen (Figure 5). Expression of the anti-parasite genes in these compartments is crucial to block their transmission and several tissue-specific promoters have been identified and used in mosquito transgenesis. These include control sequences for a gene encoding a carboxypeptidase, a digestive enzyme, and AgAper1, a peritrophic matrix protein, which are activated in response to a blood meal [44, 45, 46]. The vitellogenin-encoding gene promoters drive strong expression in the fat body and hemocoel [47, 48]. A hemocyte-specific hemolectin (hml) gene promoter and three salivary gland-specific promoters, (
The effector molecules can be classified into four groups depending on their mode of action.
Parasite blocking: exogenous molecules that eliminate the parasites such as antimicrobial peptides from the immune system of other insects (gambicin, defensin, cecropin) or other arthropods (scorpine). Natural and synthetic lytic peptides such as angiotensin II, magainins, Shiva-1, Shiva-3 and gomesin have been used to generate refractory
Interaction with parasites: single-chain monoclonal antibodies (scFvs) that bind to ookinete or sporozoite surface or secreted proteins, such as m2A10 that targets the
Interaction with mosquito tissues: molecules that bind putative mosquito receptors in the midgut or salivary glands blocking the ookinete and sporozoite invasion (for example, SM1) and molecules that can modify the properties of the midgut epithelia (mPLA2- phospholipase A2) [64, 65].
Mosquito immune system: manipulation of mosquito immune-related genes can lead to decreased mosquito vectorial competence. Expression of Akt, a key signaling component in the insulin signaling pathway or overexpression of IMD pathway-mediated transcription factor Rel2 can result in refractoriness to the parasite [66, 67].
The identification and characterization of efficient anti-
Mobile genetic elements called transposons can spread rapidly through populations despite severe costs to the host [69, 70, 71, 72]. Their ability to mobilize (excise and insert) led to their being developed as powerful systems for introducing exogenous DNA into several organisms. The adaptation of the P transposable element for transgenesis of the vinegar fly,
Other tools and systems for introducing genes into mosquito genomes include site-specific recombinases. These require the presence of an endogenous nucleotide sequence in the genome that is identical to the recombinase target cleavage site, or a mechanism for introducing such a site (called a docking site; [86]) into that genome. This has been achieved using the previously-described transposons. Two recombinases have been used successfully to generate transgenic mosquitoes, the bacteriophage φC31 integrase and Cre/lox recombinase derived from yeast. Their dependence on a precise site for integration of the desired transgene limits their usefulness as the basis of gene-drive systems for spreading transgenes into populations [82, 87, 88, 89, 90].
The application of zinc-finger nuclease (ZFNs) and the transcription activator-like effector nucleases (TALENs) for engineering target-site recognition in mosquitoes introduced a major advance for genetic modification in mosquitoes. However, the high cost and low success rate limited their use [91, 92, 93]. The application of homing endonucleases nucleases genes (HEGs) for spreading genes into mosquito populations was proposed in 2003 [94] as useful basis for gene drives and in 2011 a successful HEG-based gene drive in
A major breakthrough for mosquito transgenesis and gene-drive systems was achieved following the discovery and adaptation of the RNA-guided Cas9 nuclease from the bacterial Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR/Cas9) adaptive immune system [96]. This powerful tool simplified the highly-specific genome editing processes and made possible useful gene-drive systems. The Cas9 endonuclease is directed to its genomic target by a single 20 base-pair guide RNA (gRNA) complementary to its DNA target. This gRNA can be designed to target virtually any locus in a chromosome. CRISPR/Cas9 exploits the natural mechanism of cell repair to precisely insert a synthetic construct through homology-directed repair (HDR), a DNA repair system initiated by a double-strand break made at the site of a target location by the Cas9 nuclease [96]. CRISPR/Cas9 has been shown to be an excellent candidate technology for developing gene drive-based strategies to introduce beneficial genes into mosquito populations [28, 29, 30]. The properties of the system bias the inheritance of a desired trait, allowing them to quickly increase in frequency and spread through a mosquito population. CRISPR/Cas9 gene drives can efficiently convert pre-meiotic diploid germline cells in hemizygous mosquitoes (carrying one copy of the drive) into homozygotes carrying two copies [28, 29, 30]. Recently, the CRISPR/Cas9 technology has been adapted for the development of gene drives in anopheline mosquitoes and shows great promise for rapid introduction of anti-parasite genes into mosquito populations [28, 29, 30, 32].
The recent adaptation of CRISPR/Cas9-based biology to generate gene drives has been proposed to provide a powerful, inexpensive, and easily-implemented solution for malaria control due to the rapid introduction of the antimalarial genes into mosquito populations [37]. To produce the desired epidemiological outcomes of reduced malaria transmission, the drive system and associated effector components must be introduced quickly and efficiently into wild populations. Rapid introduction requires population modification lines to have high rates of drive allele conversion in the germline so that maximally-biased inheritance is achieved. This will result in a remarkable increase in frequency of the gene-drive system in the following generations.
The first CRISPR/Cas9 gene drive for mosquito population modification was described in 2015 for the Indo-Pakistani vector,
A next-generation gene drive system for
The fitness load in population modification CRISPR/Cas9 drive lines have been assessed on male and female mosquitoes. An ideal CRISPR/Cas9 drive candidate for population modification would have little-to-no fitness effects resulting from the drive system and its corresponding locus, as it is predicted that the effector components are likely to have some effect on overall fitness [98, 99].
One notable example of a fitness cost was observed in the
In contrast, AgNosCd-1 individuals do not have reduced fitness in most of the fitness parameters evaluated (fertility, fecundity, longevity, larval and pupal development), but a mild reduction in male mating competitiveness was observed [29]. AgNosCd-1 males are slightly less likely to contribute to the next generation than wild-type males, ~2% less likely for hemizygote males and ~8% for homozygote males. Despite these observed reductions in fitness, the power of the drive system was sufficient to negate the effects in subsequent generations and the AgNosCd-1 line achieved fixation in all multi-generation cage trial experiments at different release ratios of homozygous AgNosCd-1 to wild type males [29]. However, the AgTP13 homozygous males were ~22% less likely to contribute to the next generation than wild-type males in competition experiments and have a significantly reduced median lifespan than the hemizygous AgTP13 or the wild-type males. Despite the increased fitness burden in AgTP13 males, there was no increased fitness load on AgTP13 females [31]. Theoretical modeling supports the conclusion that given an appropriate drive mechanism, a gene-drive system could have a significant fitness cost and still be driven through the population [102, 103].
Ideally, GEMs should have no or minimal fitness costs to avoid reducing the effectiveness of the genetic drive mechanism that is used to introduce the synthetic construct into field mosquito populations and to maximize the likelihood of successfully introducing refractory genes into a wild population [98]. Several factors can impact the fitness, including the possible negative effect of the transgene products, insertional position effects (chromatin rearrangement and/or new regulatory element interactions/pressure), inbreeding, and to “leaky (low level constitutive) promoter expression”. GEMS can have different degrees of fitness cost and estimates of transgene fitness costs are essential for modeling and planning release strategies. However, it is clear that a robust drive system can compensate for reduced fitness.
The efficacy of population modification mosquito drive lines may be reduced by the presence of naturally-occurring cleavage-resistant allelic variants of the target site in wild populations or by such alleles generated through NHEJ during the Cas9/gRNA targeting and DNA repair processes. The latter may result from double-stranded DNA breaks necessary for drive that are occasionally repaired through NHEJ resulting in insertions or deletions at the target site, making them refractory to the drive system. Both the naturally-occurring and induced allelic variants have been called resistance alleles [104, 105, 106, 107]. The latter may arise in the germline and be passed on to subsequent generations or may be generated in somatic cells where they give rise to mosaic phenotypes [28, 29, 30]. Resistance alleles in the form of naturally-occurring mutations at the target site can be avoided by careful choice of the gene-drive target locus. Resistance alleles occurring because of NHEJ due to undesired Cas9 activity can be controlled by careful choice of the promoter used to induce Cas9 transcription.
Extensive analysis of suitable target loci must be performed prior to the creation of each proof-of-principle modification drive system. Loci must be chosen, in part, based on the minimization of naturally-present single nucleotide polymorphisms (SNPs) and overall conservation of the target site. Several SNPs in the AgNosCd-1
The pathways and frequency of resistance allele formation via undesired activity of the drive system was analyzed extensively for the AgNosCd-1 and AsMCRkh2 lines [29, 97]. Exceptional phenotype individuals (mosaics and LOF phenotypes) have been correlated to undesired Cas9 activity and possess indel mutations that would cause LOF in AgNosCd-1 and AsMCRkh2 lines. However, in contrast to the AgNosCd-1 drive system, the mosaic and LOF phenotypes made up the majority of the offspring (>99%) from AsMCRkh2 mothers [28]. The presence of mosaic and LOF phenotypes from female drive parents has been hypothesized to occur due to a maternal effect. The maternal effect is proposed to result from the accumulation of Cas9/gRNA complexes in the cytoplasm of embryos derived from mothers carrying the drive system, which perform cleavage on the paternally-donated allele during embryonic development. The differences in mosaic and LOF phenotypes observed in the progeny from AgNosCd-1 and AsMCRkh2 hemizygote females supports this hypothesis and this affect is higher in females with two copies (homozygous) of the drive system than those with one (hemizygous) [28, 29, 97]. In addition, the frequencies of such events are higher in the AsMCRkh2 line when compared to AgNosCd-1. These differences may result from the difference in the gene promoters used to express the Cas9 nuclease for each drive system,
As described previously, females homozygous for the drive system had a higher rate of resistance allele formation via maternal effect (~57% with mosaic phenotype and ~6% of progeny with LOF phenotype) than hemizygous females (~20% with mosaic phenotype and ~1% of progeny with LOF phenotype) but mosaic individuals were able to bias inheritance of the drive allele and had similar rates of drive efficiency when compared to AgNosCd-1 hemizygotes with wild-type eye phenotypes suggesting that the indels were primary somatic [29].
Suppression gene drive systems are much less flexible to drive-resistant alleles than population modification gene drive systems. Population modification mosquito lines can tolerate higher rates of drive-resistant alleles than population suppression mosquitoes, however, the former are still susceptible to instability and inability to achieve fixation in a population due to resistance alleles, especially if the drive system and respective cargo are associated with a significant fitness load [109]. Recent work suggests that suppression drive systems that incur a 100% fitness cost (death of females) would require a very low frequency of drive resistant alleles <5 × 10−7 in order to provide a 4–5-year window of protection, as opposed to population modification systems, which would provide a 4–5-year window of protection at a resistance allele frequency of 1%, given that fitness costs of the population modification strain are below 15% [109].
Multiplexed gene drives using additional gRNA target sites are expected to substantially decrease the likelihood of gene-drive resistant allele formation [110]. Practical ways to multiplex Cas9-based gene drives have been demonstrated using post-transcriptional processing of several gRNAs expressed from a single promoter, but these have not yet been applied to mosquitoes [110, 111, 112, 113].
The utility of CRISPR/Cas9 gene-drive systems may be affected by sequence similarity among gRNAs target and off-target sites in the mosquito genomes. Potential off-target sites can be predicted
The discovery, development, and deployment of CRISPR/Cas9 technologies is challenging due to the lack of an accepted pathway to move them from the laboratory to the field. The WHO released in 2014 the Guidance Framework for testing genetically modified (GM) mosquitoes (WHO Guidance Framework) describing a phased testing pathway and best practices to evaluate GEMs proposed as public health tools [120]. The Framework proposes a pathway to move from physically-confined studies in the laboratory/insectary (Phase 1) to a small-scale confined field-testing (Phase 2) that will lead to a staged open release trial (Phase 3). After successful completion of Phase 3, the national authorities in a malaria-endemic country will be responsible for determining if the tested GEMs can be included as part of their malaria control program and further deployment of the technology (Phase 4) [120]. However, pathways for moving gene-drive population modification mosquitoes to the field will be defined simultaneously with the laboratory work progress. As more CRISPR/Cas9 population modification gene-drive systems and strains are developed, new knowledge is being generated about the impact of introduced anti-parasite genes on the mosquitoes that carry them. Insight into genetic loads and their effects on fitness, generation of drive-resistant individuals as well as selection of resistant parasites and long-term stability of the system will emerge from these studies. The new empirical data generated is critical in the development of a phased pathway for further development and deployment. In 2018, James et al. published a series of recommendations that attempt to envision the development pathway for gene drive mosquitoes (from discovery to deployment) and to inform decision-making by regulators and policymakers [121]. They recognized that it is important to examine both the benefits and risks of this approach. Risk assessment will provide guidance on decision-making and information for the regulatory applications as well as for the development of mitigation plans, while cost-benefit analyses will compare the projected or estimated costs and benefits associated to the intervention. It also was recommended that these analyses be done by external third-party organizations or institutions with no interests in the success of the product and the outcomes of these analyses be made publicly available.
Any decision made to release gene-drive mosquitoes must be made on a case-by-case basis following a comprehensive environmental risk assessment [122], moreover, gene-drive population modification mosquitoes must meet the established Target Product Profile (TPP) criteria of safety and efficacy. A comprehensive draft TPP for gene-drive population modification mosquitoes was published providing the basis for evaluation of whether gene-drive mosquitoes should be made available for use [37]. Population modification TPPs will need to meet the efficacy and safety standards as well as the demands of different regulatory and social contexts. In addition, viable models for the inclusion of end-user and stakeholder involvement and control are absolutely needed before any such system can be brought to the field. We have favored the relationship-based model (RBM), which gives stakeholders and community key roles at the center of the decision-making processes [123]. It is important that open dialog and relationships with the scientists developing the technologies be established and that appropriate capacity-building take place to empower the communities affected by malaria to make informed decisions about the risk and use of the new technologies.
Population modification genetic control focuses on targeting the mosquito vector to interrupt the malaria transmission by introducing effector genes into the mosquito genome with the purpose of generating parasite-refractory mosquitoes.
Advances in gene-editing technologies using CRISPR/Cas9 gene drives have made available new possibilities for an efficient introduction of the desired genetic traits into mosquito populations. Gene drives represent a powerful tool to achieve genome editing in a species-specific targeted way with minimal infrastructure, are predicted to be self-sustaining and able to spread anti-parasite effectors to fixation.
Gene-drive systems for population modification of anopheline vector species to prevent transmission of parasites may play a future role in the malaria eradication agenda. Future steps will need to consider how to evaluate gene drives at large scale and evaluate their efficacy and robustness under more realistic ecological settings.
Challenges to such technologies are being addressed by scientists and regulators by development of pathways for their deployment and establishing acceptable efficacy and safety criteria. Importantly, the knowledge transfer process is being addressed in new models for public engagement that will further development, testing and eventual deployment of gene drives for malaria control.
Funding was provided by the University of California Irvine Malaria Initiative and ‘anonymous donor’. AAJ is a Donald Bren Professor at the University of California, Irvine.
The authors declare no conflict of interest.
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Sarrico and Alberto Amaral",authors:[{id:"97785",title:"Prof.",name:"Alberto",middleName:null,surname:"Amaral",slug:"alberto-amaral",fullName:"Alberto Amaral"}]},{id:"33278",doi:"10.5772/33487",title:"Improving Quality Assurance in Automation Systems Development Projects",slug:"improving-quality-assurance-in-automation-systems-development-projects",totalDownloads:3289,totalCrossrefCites:19,totalDimensionsCites:20,abstract:null,book:{id:"1803",slug:"quality-assurance-and-management",title:"Quality Assurance and Management",fullTitle:"Quality Assurance and Management"},signatures:"Dietmar Winkler and Stefan Biffl",authors:[{id:"95798",title:"Dr.",name:"Dietmar",middleName:null,surname:"Winkler",slug:"dietmar-winkler",fullName:"Dietmar Winkler"},{id:"135962",title:"Prof.",name:"Stefan",middleName:null,surname:"Biffl",slug:"stefan-biffl",fullName:"Stefan Biffl"}]},{id:"38088",doi:"10.5772/46106",title:"Some Applicable Methods to Analyze and Optimize System Processes in Quality Management",slug:"some-applicable-methods-to-analyze-and-optimize-system-processes-in-quality-management",totalDownloads:3142,totalCrossrefCites:12,totalDimensionsCites:14,abstract:null,book:{id:"2164",slug:"total-quality-management-and-six-sigma",title:"Total Quality Management and Six Sigma",fullTitle:"Total Quality Management and Six Sigma"},signatures:"Andrey Kostogryzov, George Nistratov and Andrey Nistratov",authors:[{id:"148322",title:"Dr.",name:"Andrey",middleName:null,surname:"Kostogryzov",slug:"andrey-kostogryzov",fullName:"Andrey Kostogryzov"},{id:"156748",title:"Dr.",name:"Andrey",middleName:null,surname:"Nistratov",slug:"andrey-nistratov",fullName:"Andrey Nistratov"},{id:"156749",title:"Dr.",name:"George",middleName:null,surname:"Nistratov",slug:"george-nistratov",fullName:"George Nistratov"}]},{id:"37729",doi:"10.5772/51109",title:"QA: Fraud Control for Foods and Other Biomaterials by Product Fingerprinting",slug:"qa-fraud-control-for-foods-and-other-biomaterials-by-product-fingerprinting",totalDownloads:2756,totalCrossrefCites:2,totalDimensionsCites:14,abstract:null,book:{id:"3276",slug:"latest-research-into-quality-control",title:"Latest Research into Quality Control",fullTitle:"Latest Research into Quality Control"},signatures:"Edoardo Capuano and Saskia M. van Ruth",authors:[{id:"153179",title:"Dr.",name:"Saskia",middleName:null,surname:"Van Ruth",slug:"saskia-van-ruth",fullName:"Saskia Van Ruth"},{id:"153628",title:"Dr.",name:"Edoardo",middleName:null,surname:"Capuano",slug:"edoardo-capuano",fullName:"Edoardo Capuano"}]}],mostDownloadedChaptersLast30Days:[{id:"37593",title:"Standard Operating Procedures (What Are They Good For ?)",slug:"standard-operating-procedures-what-are-they-good-for-",totalDownloads:26573,totalCrossrefCites:7,totalDimensionsCites:9,abstract:null,book:{id:"3276",slug:"latest-research-into-quality-control",title:"Latest Research into Quality Control",fullTitle:"Latest Research into Quality Control"},signatures:"Isin Akyar",authors:[{id:"36323",title:"Dr.",name:"Isin",middleName:null,surname:"Akyar",slug:"isin-akyar",fullName:"Isin Akyar"}]},{id:"65419",title:"Determination of Impurities in Pharmaceuticals: Why and How?",slug:"determination-of-impurities-in-pharmaceuticals-why-and-how-",totalDownloads:4464,totalCrossrefCites:4,totalDimensionsCites:12,abstract:"The presence of impurities, particularly the API-related impurities, i.e., degradation-related impurities (DRIs) and interaction-related impurities (IRIs), may affect the quality, safety, and efficacy of drug products. Since the regulatory requirements and management strategies are required to be established and complied, sources of impurities shall be carefully classified prior to take subsequent steps such as development of analytical methods and acceptance criteria. Current international regulatory requirements for the management of impurities in pharmaceuticals were reviewed. Procedures for the identification of DPIs in pharmaceuticals, i.e., ethyl cysteinate dimer, (R)-N-methyl-3-(2-bromophenoxy)-3-phenylpropanamine, sestamibi, etc., using high-performance liquid chromatography tandem mass spectrometry (LC-MS/MS) were studied. Scheme for the establishment of analytical methods and acceptance criteria of process-related impurities (PRIs) and DRIs in accordance with the requirements of International Council for Harmonization (ICH) and algorithm to perform the identification of DPIs by using LC-MS/MS has been proposed. Practice of kinetic study to distinguish PRIs and DRIs, determination of the potential core fragments coupled with a predicted list of relevant transformations for conducting MS/MS scans, applications of stable isotope distribution patterns or natural abundances, practice of mass balance, etc., have been well demonstrated to justify the reliabilities of identification results.",book:{id:"7710",slug:"quality-management-and-quality-control-new-trends-and-developments",title:"Quality Management and Quality Control",fullTitle:"Quality Management and Quality Control - New Trends and Developments"},signatures:"Kung-Tien Liu and Chien-Hsin Chen",authors:[{id:"36122",title:"PhD.",name:"Kung-Tien",middleName:null,surname:"Liu",slug:"kung-tien-liu",fullName:"Kung-Tien Liu"},{id:"153497",title:"Dr.",name:"Chien-Hsin",middleName:null,surname:"Chen",slug:"chien-hsin-chen",fullName:"Chien-Hsin Chen"}]},{id:"58966",title:"Quality Management Systems for Laboratories and External Quality Assurance Programs",slug:"quality-management-systems-for-laboratories-and-external-quality-assurance-programs",totalDownloads:4673,totalCrossrefCites:2,totalDimensionsCites:5,abstract:"A quality management system (QMS) plans, controls, and improves the elements that impact on the achievement of the desired results by the laboratory and on the satisfaction of the users. There are different standards that establish requirements for the implementation of a quality management system for laboratories, and a cross comparison between them is shown. Additionally, external quality assurance or assessment (EQA) programs offer multiple benefits to laboratories: method validation, comparing of results with other laboratories, testing problem identification, accreditation requirement compliance, and credibility. In order to control the quality of the procedures, these programs are a tool to keep the laboratory procedures and every variable involved in (staff, equipment, and method) well controlled. In the frame of a quality management system, benefits from external quality assurance programs are discussed, and different available designs are reviewed. On the other hand, previous benefits will be real only if reported results for each program are analyzed in detail. Because additional advantages are achieved when the EQA results are integrated in the quality management system of the laboratory, a procedure is proposed. In addition, results from external quality assurance programs corroborate the usefulness of internal controls implemented by the laboratory as part of its quality management system.",book:{id:"6325",slug:"quality-control-in-laboratory",title:"Quality Control in Laboratory",fullTitle:"Quality Control in Laboratory"},signatures:"Verónica Valdivieso-Gómez and Rocío Aguilar-Quesada",authors:[{id:"217457",title:"Ph.D.",name:"Rocio",middleName:null,surname:"Aguilar-Quesada",slug:"rocio-aguilar-quesada",fullName:"Rocio Aguilar-Quesada"},{id:"217467",title:"Ms.",name:"Veronica",middleName:null,surname:"Valdivieso-Gomez",slug:"veronica-valdivieso-gomez",fullName:"Veronica Valdivieso-Gomez"}]},{id:"41063",title:"Cosmetics’ Quality Control",slug:"cosmetics-quality-control",totalDownloads:12724,totalCrossrefCites:2,totalDimensionsCites:12,abstract:null,book:{id:"3276",slug:"latest-research-into-quality-control",title:"Latest Research into Quality Control",fullTitle:"Latest Research into Quality Control"},signatures:"Bruna Galdorfini Chiari, Maria Gabriela José de Almeida, Marcos Antonio Corrêa and Vera Lucia Borges Isaac",authors:[{id:"35801",title:"Dr.",name:"Vera",middleName:null,surname:"Isaac",slug:"vera-isaac",fullName:"Vera Isaac"},{id:"56070",title:"MSc.",name:"Bruna",middleName:null,surname:"Chiari",slug:"bruna-chiari",fullName:"Bruna Chiari"},{id:"56072",title:"Dr.",name:"Marcos Antonio",middleName:null,surname:"Corręa",slug:"marcos-antonio-correa",fullName:"Marcos Antonio Corręa"},{id:"154324",title:"BSc.",name:"Maria Gabriela José De",middleName:null,surname:"Almeida",slug:"maria-gabriela-jose-de-almeida",fullName:"Maria Gabriela José De Almeida"}]},{id:"58071",title:"Systematic Error Detection in Laboratory Medicine",slug:"systematic-error-detection-in-laboratory-medicine",totalDownloads:1795,totalCrossrefCites:4,totalDimensionsCites:4,abstract:"Measurements in laboratory medicine have a degree of uncertainty; this uncertainty is often called “error” and refers to imprecisions and inaccuracies in measurement. This measurement error refers to the difference between the true value of the measured sample and the measured value. One of the types of error is systematic error, also called bias, because these errors errors are reproducible and skew the results consistently in the same direction. A common approach to identify systematic error is to use control samples with a method comparison approach. An alternative is use of statistical methods that analyze actual patient values either as an “Average of Normals” or a “Moving Patient Averages.” Fundamental questions should be decided before a quality control method is used: how are weights assigned to the results? Is preference given to more recent samples or to the older samples? How sensitive should the model be? In this chapter, we will expand the fundamental notion of systematic error and explain why it is difficult to identify and measure and current statistical methods that are used to detect systematic error or bias.",book:{id:"6325",slug:"quality-control-in-laboratory",title:"Quality Control in Laboratory",fullTitle:"Quality Control in Laboratory"},signatures:"Amir Momeni-Boroujeni and Matthew R. Pincus",authors:[{id:"213334",title:"Prof.",name:"Matthew",middleName:null,surname:"Pincus",slug:"matthew-pincus",fullName:"Matthew Pincus"},{id:"213335",title:"Dr.",name:"Amir",middleName:null,surname:"Momeni",slug:"amir-momeni",fullName:"Amir Momeni"}]}],onlineFirstChaptersFilter:{topicId:"78",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:90,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:107,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:33,numberOfPublishedChapters:330,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:14,numberOfPublishedChapters:145,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:9,numberOfPublishedChapters:139,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!0},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:122,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:11,numberOfPublishedChapters:112,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:21,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2753-894X",doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:10,numberOfOpenTopics:1,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!0},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:5,numberOfUpcomingTopics:0,issn:"2753-6580",doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{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"}}}},{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"}}}}]},series:{item:{id:"14",title:"Artificial Intelligence",doi:"10.5772/intechopen.79920",issn:"2633-1403",scope:"Artificial Intelligence (AI) is a rapidly developing multidisciplinary research area that aims to solve increasingly complex problems. In today's highly integrated world, AI promises to become a robust and powerful means for obtaining solutions to previously unsolvable problems. This Series is intended for researchers and students alike interested in this fascinating field and its many applications.",coverUrl:"https://cdn.intechopen.com/series/covers/14.jpg",latestPublicationDate:"July 5th, 2022",hasOnlineFirst:!0,numberOfPublishedBooks:9,editor:{id:"218714",title:"Prof.",name:"Andries",middleName:null,surname:"Engelbrecht",slug:"andries-engelbrecht",fullName:"Andries Engelbrecht",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRNR8QAO/Profile_Picture_1622640468300",biography:"Andries Engelbrecht received the Masters and PhD degrees in Computer Science from the University of Stellenbosch, South Africa, in 1994 and 1999 respectively. He is currently appointed as the Voigt Chair in Data Science in the Department of Industrial Engineering, with a joint appointment as Professor in the Computer Science Division, Stellenbosch University. Prior to his appointment at Stellenbosch University, he has been at the University of Pretoria, Department of Computer Science (1998-2018), where he was appointed as South Africa Research Chair in Artifical Intelligence (2007-2018), the head of the Department of Computer Science (2008-2017), and Director of the Institute for Big Data and Data Science (2017-2018). In addition to a number of research articles, he has written two books, Computational Intelligence: An Introduction and Fundamentals of Computational Swarm Intelligence.",institutionString:null,institution:{name:"Stellenbosch University",institutionURL:null,country:{name:"South Africa"}}},editorTwo:null,editorThree:null},subseries:{paginationCount:6,paginationItems:[{id:"22",title:"Applied Intelligence",coverUrl:"https://cdn.intechopen.com/series_topics/covers/22.jpg",isOpenForSubmission:!0,editor:{id:"27170",title:"Prof.",name:"Carlos",middleName:"M.",surname:"Travieso-Gonzalez",slug:"carlos-travieso-gonzalez",fullName:"Carlos Travieso-Gonzalez",profilePictureURL:"https://mts.intechopen.com/storage/users/27170/images/system/27170.jpeg",biography:"Carlos M. Travieso-González received his MSc degree in Telecommunication Engineering at Polytechnic University of Catalonia (UPC), Spain in 1997, and his Ph.D. degree in 2002 at the University of Las Palmas de Gran Canaria (ULPGC-Spain). He is a full professor of signal processing and pattern recognition and is head of the Signals and Communications Department at ULPGC, teaching from 2001 on subjects on signal processing and learning theory. His research lines are biometrics, biomedical signals and images, data mining, classification system, signal and image processing, machine learning, and environmental intelligence. He has researched in 52 international and Spanish research projects, some of them as head researcher. He is co-author of 4 books, co-editor of 27 proceedings books, guest editor for 8 JCR-ISI international journals, and up to 24 book chapters. He has over 450 papers published in international journals and conferences (81 of them indexed on JCR – ISI - Web of Science). He has published seven patents in the Spanish Patent and Trademark Office. He has been a supervisor on 8 Ph.D. theses (11 more are under supervision), and 130 master theses. He is the founder of The IEEE IWOBI conference series and the president of its Steering Committee, as well as the founder of both the InnoEducaTIC and APPIS conference series. He is an evaluator of project proposals for the European Union (H2020), Medical Research Council (MRC, UK), Spanish Government (ANECA, Spain), Research National Agency (ANR, France), DAAD (Germany), Argentinian Government, and the Colombian Institutions. He has been a reviewer in different indexed international journals (<70) and conferences (<250) since 2001. He has been a member of the IASTED Technical Committee on Image Processing from 2007 and a member of the IASTED Technical Committee on Artificial Intelligence and Expert Systems from 2011. \n\nHe has held the general chair position for the following: ACM-APPIS (2020, 2021), IEEE-IWOBI (2019, 2020 and 2020), A PPIS (2018, 2019), IEEE-IWOBI (2014, 2015, 2017, 2018), InnoEducaTIC (2014, 2017), IEEE-INES (2013), NoLISP (2011), JRBP (2012), and IEEE-ICCST (2005)\n\nHe is an associate editor of the Computational Intelligence and Neuroscience Journal (Hindawi – Q2 JCR-ISI). He was vice dean from 2004 to 2010 in the Higher Technical School of Telecommunication Engineers at ULPGC and the vice dean of Graduate and Postgraduate Studies from March 2013 to November 2017. He won the “Catedra Telefonica” Awards in Modality of Knowledge Transfer, 2017, 2018, and 2019 editions, and awards in Modality of COVID Research in 2020.\n\nPublic References:\nResearcher ID http://www.researcherid.com/rid/N-5967-2014\nORCID https://orcid.org/0000-0002-4621-2768 \nScopus Author ID https://www.scopus.com/authid/detail.uri?authorId=6602376272\nScholar Google https://scholar.google.es/citations?user=G1ks9nIAAAAJ&hl=en \nResearchGate https://www.researchgate.net/profile/Carlos_Travieso",institutionString:null,institution:{name:"University of Las Palmas de Gran Canaria",institutionURL:null,country:{name:"Spain"}}},editorTwo:null,editorThree:null},{id:"23",title:"Computational Neuroscience",coverUrl:"https://cdn.intechopen.com/series_topics/covers/23.jpg",isOpenForSubmission:!0,editor:{id:"14004",title:"Dr.",name:"Magnus",middleName:null,surname:"Johnsson",slug:"magnus-johnsson",fullName:"Magnus Johnsson",profilePictureURL:"https://mts.intechopen.com/storage/users/14004/images/system/14004.png",biography:"Dr Magnus Johnsson is a cross-disciplinary scientist, lecturer, scientific editor and AI/machine learning consultant from Sweden. \n\nHe is currently at Malmö University in Sweden, but also held positions at Lund University in Sweden and at Moscow Engineering Physics Institute. \nHe holds editorial positions at several international scientific journals and has served as a scientific editor for books and special journal issues. \nHis research interests are wide and include, but are not limited to, autonomous systems, computer modeling, artificial neural networks, artificial intelligence, cognitive neuroscience, cognitive robotics, cognitive architectures, cognitive aids and the philosophy of mind. \n\nDr. Johnsson has experience from working in the industry and he has a keen interest in the application of neural networks and artificial intelligence to fields like industry, finance, and medicine. \n\nWeb page: www.magnusjohnsson.se",institutionString:null,institution:{name:"Malmö University",institutionURL:null,country:{name:"Sweden"}}},editorTwo:null,editorThree:null},{id:"24",title:"Computer Vision",coverUrl:"https://cdn.intechopen.com/series_topics/covers/24.jpg",isOpenForSubmission:!0,editor:{id:"294154",title:"Prof.",name:"George",middleName:null,surname:"Papakostas",slug:"george-papakostas",fullName:"George Papakostas",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002hYaGbQAK/Profile_Picture_1624519712088",biography:"George A. Papakostas has received a diploma in Electrical and Computer Engineering in 1999 and the M.Sc. and Ph.D. degrees in Electrical and Computer Engineering in 2002 and 2007, respectively, from the Democritus University of Thrace (DUTH), Greece. Dr. Papakostas serves as a Tenured Full Professor at the Department of Computer Science, International Hellenic University, Greece. Dr. Papakostas has 10 years of experience in large-scale systems design as a senior software engineer and technical manager, and 20 years of research experience in the field of Artificial Intelligence. Currently, he is the Head of the “Visual Computing” division of HUman-MAchines INteraction Laboratory (HUMAIN-Lab) and the Director of the MPhil program “Advanced Technologies in Informatics and Computers” hosted by the Department of Computer Science, International Hellenic University. He has (co)authored more than 150 publications in indexed journals, international conferences and book chapters, 1 book (in Greek), 3 edited books, and 5 journal special issues. His publications have more than 2100 citations with h-index 27 (GoogleScholar). His research interests include computer/machine vision, machine learning, pattern recognition, computational intelligence. \nDr. Papakostas served as a reviewer in numerous journals, as a program\ncommittee member in international conferences and he is a member of the IAENG, MIR Labs, EUCogIII, INSTICC and the Technical Chamber of Greece (TEE).",institutionString:null,institution:{name:"International Hellenic University",institutionURL:null,country:{name:"Greece"}}},editorTwo:null,editorThree:null},{id:"25",title:"Evolutionary Computation",coverUrl:"https://cdn.intechopen.com/series_topics/covers/25.jpg",isOpenForSubmission:!0,editor:{id:"136112",title:"Dr.",name:"Sebastian",middleName:null,surname:"Ventura Soto",slug:"sebastian-ventura-soto",fullName:"Sebastian Ventura Soto",profilePictureURL:"https://mts.intechopen.com/storage/users/136112/images/system/136112.png",biography:"Sebastian Ventura is a Spanish researcher, a full professor with the Department of Computer Science and Numerical Analysis, University of Córdoba. Dr Ventura also holds the positions of Affiliated Professor at Virginia Commonwealth University (Richmond, USA) and Distinguished Adjunct Professor at King Abdulaziz University (Jeddah, Saudi Arabia). Additionally, he is deputy director of the Andalusian Research Institute in Data Science and Computational Intelligence (DaSCI) and heads the Knowledge Discovery and Intelligent Systems Research Laboratory. He has published more than ten books and over 300 articles in journals and scientific conferences. Currently, his work has received over 18,000 citations according to Google Scholar, including more than 2200 citations in 2020. In the last five years, he has published more than 60 papers in international journals indexed in the JCR (around 70% of them belonging to first quartile journals) and he has edited some Springer books “Supervised Descriptive Pattern Mining” (2018), “Multiple Instance Learning - Foundations and Algorithms” (2016), and “Pattern Mining with Evolutionary Algorithms” (2016). He has also been involved in more than 20 research projects supported by the Spanish and Andalusian governments and the European Union. He currently belongs to the editorial board of PeerJ Computer Science, Information Fusion and Engineering Applications of Artificial Intelligence journals, being also associate editor of Applied Computational Intelligence and Soft Computing and IEEE Transactions on Cybernetics. Finally, he is editor-in-chief of Progress in Artificial Intelligence. He is a Senior Member of the IEEE Computer, the IEEE Computational Intelligence, and the IEEE Systems, Man, and Cybernetics Societies, and the Association of Computing Machinery (ACM). Finally, his main research interests include data science, computational intelligence, and their applications.",institutionString:null,institution:{name:"University of Córdoba",institutionURL:null,country:{name:"Spain"}}},editorTwo:null,editorThree:null},{id:"26",title:"Machine Learning and Data Mining",coverUrl:"https://cdn.intechopen.com/series_topics/covers/26.jpg",isOpenForSubmission:!0,editor:{id:"24555",title:"Dr.",name:"Marco Antonio",middleName:null,surname:"Aceves Fernandez",slug:"marco-antonio-aceves-fernandez",fullName:"Marco Antonio Aceves Fernandez",profilePictureURL:"https://mts.intechopen.com/storage/users/24555/images/system/24555.jpg",biography:"Dr. Marco Antonio Aceves Fernandez obtained his B.Sc. (Eng.) in Telematics from the Universidad de Colima, Mexico. 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He is currently a principal researcher in data analytics and optimisation at TECNALIA (Spain), a visiting fellow at the Basque Center for Applied Mathematics (BCAM) and a part-time lecturer at the University of the Basque Country (UPV/EHU). His research interests gravitate on the use of descriptive, prescriptive and predictive algorithms for data mining and optimization in a diverse range of application fields such as Energy, Transport, Telecommunications, Health and Industry, among others. In these fields he has published more than 240 articles, co-supervised 8 Ph.D. theses, edited 6 books, coauthored 7 patents and participated/led more than 40 research projects. 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He is an academic staff member of the Department of Reproduction and Artificial Insemination, Selçuk University, Turkey. He manages several studies on sperms and embryos and is an editorial board member for several international journals. His studies include sperm cryobiology, in vitro fertilization, and embryo production in animals.",institutionString:"Selçuk University, Faculty of Veterinary Medicine",institution:null},{id:"90846",title:"Prof.",name:"Yusuf",middleName:null,surname:"Bozkurt",slug:"yusuf-bozkurt",fullName:"Yusuf Bozkurt",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/90846/images/system/90846.jpg",biography:"Yusuf Bozkurt has a BSc, MSc, and Ph.D. from Ankara University, Turkey. He is currently a Professor of Biotechnology of Reproduction in the field of Aquaculture, İskenderun Technical University, Turkey. His research interests include reproductive biology and biotechnology with an emphasis on cryo-conservation. He is on the editorial board of several international peer-reviewed journals and has published many papers. Additionally, he has participated in many international and national congresses, seminars, and workshops with oral and poster presentations. He is an active member of many local and international organizations.",institutionString:"İskenderun Technical University",institution:{name:"İskenderun Technical University",country:{name:"Turkey"}}},{id:"61139",title:"Dr.",name:"Sergey",middleName:null,surname:"Tkachev",slug:"sergey-tkachev",fullName:"Sergey Tkachev",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/61139/images/system/61139.png",biography:"Dr. Sergey Tkachev is a senior research scientist at the Institute of Fundamental Medicine and Biology, Kazan Federal University, Russia, and at the Institute of Chemical Biology and Fundamental Medicine SB RAS, Novosibirsk, Russia. He received his Ph.D. in Molecular Biology with his thesis “Genetic variability of the tick-borne encephalitis virus in natural foci of Novosibirsk city and its suburbs.” His primary field is molecular virology with research emphasis on vector-borne viruses, especially tick-borne encephalitis virus, Kemerovo virus and Omsk hemorrhagic fever virus, rabies virus, molecular genetics, biology, and epidemiology of virus pathogens.",institutionString:"Russian Academy of Sciences",institution:{name:"Russian Academy of Sciences",country:{name:"Russia"}}},{id:"310962",title:"Dr.",name:"Amlan",middleName:"Kumar",surname:"Patra",slug:"amlan-patra",fullName:"Amlan Patra",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/310962/images/system/310962.jpg",biography:"Amlan K. Patra, FRSB, obtained a Ph.D. in Animal Nutrition from Indian Veterinary Research Institute, India, in 2002. He is currently an associate professor at West Bengal University of Animal and Fishery Sciences. He has more than twenty years of research and teaching experience. He held previous positions at the American Institute for Goat Research, The Ohio State University, Columbus, USA, and Free University of Berlin, Germany. His research focuses on animal nutrition, particularly ruminants and poultry nutrition, gastrointestinal electrophysiology, meta-analysis and modeling in nutrition, and livestock–environment interaction. He has authored around 175 articles in journals, book chapters, and proceedings. Dr. Patra serves on the editorial boards of several reputed journals.",institutionString:null,institution:{name:"West Bengal University of Animal and Fishery Sciences",country:{name:"India"}}},{id:"53998",title:"Prof.",name:"László",middleName:null,surname:"Babinszky",slug:"laszlo-babinszky",fullName:"László Babinszky",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/53998/images/system/53998.png",biography:"László Babinszky is Professor Emeritus, Department of Animal Nutrition Physiology, University of Debrecen, Hungary. He has also worked in the Department of Animal Nutrition, University of Wageningen, Netherlands; the Institute for Livestock Feeding and Nutrition (IVVO), Lelystad, Netherlands; the Agricultural University of Vienna (BOKU); the Institute for Animal Breeding and Nutrition, Austria; and the Oscar Kellner Research Institute for Animal Nutrition, Rostock, Germany. In 1992, Dr. Babinszky obtained a Ph.D. in Animal Nutrition from the University of Wageningen. His main research areas are swine and poultry nutrition. He has authored more than 300 publications (papers, book chapters) and edited four books and fourteen international conference proceedings.",institutionString:"University of Debrecen",institution:{name:"University of Debrecen",country:{name:"Hungary"}}},{id:"201830",title:"Dr.",name:"Fernando",middleName:"Sanchez",surname:"Davila",slug:"fernando-davila",fullName:"Fernando Davila",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/201830/images/5017_n.jpg",biography:"I am a professor at UANL since 1988. My research lines are the development of reproductive techniques in small ruminants. We also conducted research on sexual and social behavior in males.\nI am Mexican and study my professional career as an engineer in agriculture and animal science at UANL. Then take a masters degree in science in Germany (Animal breeding). Take a doctorate in animal science at the UANL.",institutionString:null,institution:{name:"Universidad Autónoma de Nuevo León",country:{name:"Mexico"}}},{id:"309250",title:"Dr.",name:"Miguel",middleName:null,surname:"Quaresma",slug:"miguel-quaresma",fullName:"Miguel Quaresma",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/309250/images/9059_n.jpg",biography:"Miguel Nuno Pinheiro Quaresma was born on May 26, 1974 in Dili, Timor Island. He is married with two children: a boy and a girl, and he is a resident in Vila Real, Portugal. He graduated in Veterinary Medicine in August 1998 and obtained his Ph.D. degree in Veterinary Sciences -Clinical Area in February 2015, both from the University of Trás-os-Montes e Alto Douro. He is currently enrolled in the Alternative Residency of the European College of Animal Reproduction. He works as a Senior Clinician at the Veterinary Teaching Hospital of UTAD (HVUTAD) with a role in clinical activity in the area of livestock and equine species as well as to support teaching and research in related areas. He teaches as an Invited Professor in Reproduction Medicine I and II of the Master\\'s in Veterinary Medicine degree at UTAD. Currently, he holds the position of Chairman of the Portuguese Buiatrics Association. He is a member of the Consultive Group on Production Animals of the OMV. He has 19 publications in indexed international journals (ISIS), as well as over 60 publications and oral presentations in both Portuguese and international journals and congresses.",institutionString:"University of Trás-os-Montes and Alto Douro",institution:{name:"University of Trás-os-Montes and Alto Douro",country:{name:"Portugal"}}},{id:"38652",title:"Prof.",name:"Rita",middleName:null,surname:"Payan-Carreira",slug:"rita-payan-carreira",fullName:"Rita Payan-Carreira",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRiFPQA0/Profile_Picture_1614601496313",biography:"Rita Payan Carreira earned her Veterinary Degree from the Faculty of Veterinary Medicine in Lisbon, Portugal, in 1985. She obtained her Ph.D. in Veterinary Sciences from the University of Trás-os-Montes e Alto Douro, Portugal. After almost 32 years of teaching at the University of Trás-os-Montes and Alto Douro, she recently moved to the University of Évora, Department of Veterinary Medicine, where she teaches in the field of Animal Reproduction and Clinics. Her primary research areas include the molecular markers of the endometrial cycle and the embryo–maternal interaction, including oxidative stress and the reproductive physiology and disorders of sexual development, besides the molecular determinants of male and female fertility. She often supervises students preparing their master's or doctoral theses. She is also a frequent referee for various journals.",institutionString:null,institution:{name:"University of Évora",country:{name:"Portugal"}}},{id:"283019",title:"Dr.",name:"Oudessa",middleName:null,surname:"Kerro Dego",slug:"oudessa-kerro-dego",fullName:"Oudessa Kerro Dego",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/283019/images/system/283019.png",biography:"Dr. Kerro Dego is a veterinary microbiologist with training in veterinary medicine, microbiology, and anatomic pathology. Dr. Kerro Dego is an assistant professor of dairy health in the department of animal science, the University of Tennessee, Institute of Agriculture, Knoxville, Tennessee. He received his D.V.M. (1997), M.S. (2002), and Ph.D. (2008) degrees in Veterinary Medicine, Animal Pathology and Veterinary Microbiology from College of Veterinary Medicine, Addis Ababa University, Ethiopia; College of Veterinary Medicine, Utrecht University, the Netherlands and Western College of Veterinary Medicine, University of Saskatchewan, Canada respectively. He did his Postdoctoral training in microbial pathogenesis (2009 - 2015) in the Department of Animal Science, the University of Tennessee, Institute of Agriculture, Knoxville, Tennessee. Dr. Kerro Dego’s research focuses on the prevention and control of infectious diseases of farm animals, particularly mastitis, improving dairy food safety, and mitigation of antimicrobial resistance. Dr. Kerro Dego has extensive experience in studying the pathogenesis of bacterial infections, identification of virulence factors, and vaccine development and efficacy testing against major bacterial mastitis pathogens. Dr. Kerro Dego conducted numerous controlled experimental and field vaccine efficacy studies, vaccination, and evaluation of immunological responses in several species of animals, including rodents (mice) and large animals (bovine and ovine).",institutionString:"University of Tennessee at Knoxville",institution:{name:"University of Tennessee at Knoxville",country:{name:"United States of America"}}},{id:"251314",title:"Dr.",name:"Juan Carlos",middleName:null,surname:"Gardón Poggi",slug:"juan-carlos-gardon-poggi",fullName:"Juan Carlos Gardón Poggi",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/251314/images/system/251314.jpeg",biography:"Juan Carlos Gardón Poggi received University degree from the Faculty of Agrarian Science in Argentina, in 1983. Also he received Masters Degree and PhD from Córdoba University, Spain. He is currently a Professor at the Catholic University of Valencia San Vicente Mártir, at the Department of Medicine and Animal Surgery. He teaches diverse courses in the field of Animal Reproduction and he is the Director of the Veterinary Farm. He also participates in academic postgraduate activities at the Veterinary Faculty of Murcia University, Spain. His research areas include animal physiology, physiology and biotechnology of reproduction either in males or females, the study of gametes under in vitro conditions and the use of ultrasound as a complement to physiological studies and development of applied biotechnologies. Routinely, he supervises students preparing their doctoral, master thesis or final degree projects.",institutionString:null,institution:{name:"Valencia Catholic University Saint Vincent Martyr",country:{name:"Spain"}}},{id:"309529",title:"Dr.",name:"Albert",middleName:null,surname:"Rizvanov",slug:"albert-rizvanov",fullName:"Albert Rizvanov",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/309529/images/9189_n.jpg",biography:'Albert A. Rizvanov is a Professor and Director of the Center for Precision and Regenerative Medicine at the Institute of Fundamental Medicine and Biology, Kazan Federal University (KFU), Russia. He is the Head of the Center of Excellence “Regenerative Medicine” and Vice-Director of Strategic Academic Unit \\"Translational 7P Medicine\\". Albert completed his Ph.D. at the University of Nevada, Reno, USA and Dr.Sci. at KFU. He is a corresponding member of the Tatarstan Academy of Sciences, Russian Federation. Albert is an author of more than 300 peer-reviewed journal articles and 22 patents. He has supervised 11 Ph.D. and 2 Dr.Sci. dissertations. Albert is the Head of the Dissertation Committee on Biochemistry, Microbiology, and Genetics at KFU.\nORCID https://orcid.org/0000-0002-9427-5739\nWebsite https://kpfu.ru/Albert.Rizvanov?p_lang=2',institutionString:"Kazan Federal University",institution:{name:"Kazan Federal University",country:{name:"Russia"}}},{id:"210551",title:"Dr.",name:"Arbab",middleName:null,surname:"Sikandar",slug:"arbab-sikandar",fullName:"Arbab Sikandar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/210551/images/system/210551.jpg",biography:"Dr. Arbab Sikandar, PhD, M. Phil, DVM was born on April 05, 1981. He is currently working at the College of Veterinary & Animal Sciences as an Assistant Professor. He previously worked as a lecturer at the same University. \nHe is a Member/Secretory of Ethics committee (No. CVAS-9377 dated 18-04-18), Member of the QEC committee CVAS, Jhang (Regr/Gen/69/873, dated 26-10-2017), Member, Board of studies of Department of Basic Sciences (No. CVAS. 2851 Dated. 12-04-13, and No. CVAS, 9024 dated 20/11/17), Member of Academic Committee, CVAS, Jhang (No. CVAS/2004, Dated, 25-08-12), Member of the technical committee (No. CVAS/ 4085, dated 20,03, 2010 till 2016).\n\nDr. Arbab Sikandar contributed in five days hands-on-training on Histopathology at the Department of Pathology, UVAS from 12-16 June 2017. He received a Certificate of appreciation for contributions for Popularization of Science and Technology in the Society on 17-11-15. He was the resource person in the lecture series- ‘scientific writing’ at the Department of Anatomy and Histology, UVAS, Lahore on 29th October 2015. He won a full fellowship as a principal candidate for the year 2015 in the field of Agriculture, EICA, Egypt with ref. to the Notification No. 12(11) ACS/Egypt/2014 from 10 July 2015 to 25th September 2015.; he received a grant of Rs. 55000/- as research incentives from Director, Advanced Studies and Research, UVAS, Lahore upon publications of research papers in IF Journals (DR/215, dated 19-5-2014.. He obtained his PhD by winning a HEC Pakistan indigenous Scholarship, ‘Ph.D. fellowship for 5000 scholars – Phase II’ (2av1-147), 17-6/HEC/HRD/IS-II/12, November 15, 2012. \n\nDr. Sikandar is a member of numerous societies: Registered Veterinary Medical Practitioner (life member) and Registered Veterinary Medical Faculty of Pakistan Veterinary Medical Council. The Registration code of PVMC is RVMP/4298 and RVMF/ 0102.; Life member of the University of Veterinary and Animal Sciences, Lahore, Alumni Association with S# 664, dated: 6-4-12. ; Member 'Vets Care Organization Pakistan” with Reference No. VCO-605-149, dated 05-04-06. :Member 'Vet Crescent” (Society of Animal Health and Production), UVAS, Lahore.",institutionString:"University of Veterinary & Animal Science",institution:{name:"University of Veterinary and Animal Sciences",country:{name:"Pakistan"}}},{id:"311663",title:"Dr.",name:"Prasanna",middleName:null,surname:"Pal",slug:"prasanna-pal",fullName:"Prasanna Pal",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/311663/images/13261_n.jpg",biography:null,institutionString:null,institution:{name:"National Dairy Research Institute",country:{name:"India"}}},{id:"202192",title:"Dr.",name:"Catrin",middleName:null,surname:"Rutland",slug:"catrin-rutland",fullName:"Catrin Rutland",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/202192/images/system/202192.png",biography:"Catrin Rutland is an Associate Professor of Anatomy and Developmental Genetics at the University of Nottingham, UK. She obtained a BSc from the University of Derby, England, a master’s degree from Technische Universität München, Germany, and a Ph.D. from the University of Nottingham. She undertook a post-doctoral research fellowship in the School of Medicine before accepting tenure in Veterinary Medicine and Science. Dr. Rutland also obtained an MMedSci (Medical Education) and a Postgraduate Certificate in Higher Education (PGCHE). She is the author of more than sixty peer-reviewed journal articles, twelve books/book chapters, and more than 100 research abstracts in cardiovascular biology and oncology. She is a board member of the European Association of Veterinary Anatomists, Fellow of the Anatomical Society, and Senior Fellow of the Higher Education Academy. 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Samir worked as a member of different local projects on E-learning and he is a board member of the African Association of Veterinary Anatomists and of anatomy societies and as an associated author at local and international journals. Orcid: https://orcid.org/0000-0002-6180-389X",institutionString:null,institution:{name:"Alexandria University",country:{name:"Egypt"}}},{id:"246149",title:"Dr.",name:"Valentina",middleName:null,surname:"Kubale",slug:"valentina-kubale",fullName:"Valentina Kubale",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/246149/images/system/246149.jpg",biography:"Valentina Kubale is Associate Professor of Veterinary Medicine at the Veterinary Faculty, University of Ljubljana, Slovenia. Since graduating from the Veterinary faculty she obtained her PhD in 2007, performed collaboration with the Department of Pharmacology, University of Copenhagen, Denmark. She continued as a post-doctoral fellow at the University of Copenhagen with a Lundbeck foundation fellowship. She is the editor of three books and author/coauthor of 23 articles in peer-reviewed scientific journals, 16 book chapters, and 68 communications at scientific congresses. Since 2008 she has been the Editor Assistant for the Slovenian Veterinary Research journal. She is a member of Slovenian Biochemical Society, The Endocrine Society, European Association of Veterinary Anatomists and Society for Laboratory Animals, where she is board member.",institutionString:"University of Ljubljana",institution:{name:"University of Ljubljana",country:{name:"Slovenia"}}},{id:"258334",title:"Dr.",name:"Carlos Eduardo",middleName:null,surname:"Fonseca-Alves",slug:"carlos-eduardo-fonseca-alves",fullName:"Carlos Eduardo Fonseca-Alves",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/258334/images/system/258334.jpg",biography:"Dr. Fonseca-Alves earned his DVM from Federal University of Goias – UFG in 2008. He completed an internship in small animal internal medicine at UPIS university in 2011, earned his MSc in 2013 and PhD in 2015 both in Veterinary Medicine at Sao Paulo State University – UNESP. Dr. Fonseca-Alves currently serves as an Assistant Professor at Paulista University – UNIP teaching small animal internal medicine.",institutionString:null,institution:{name:"Universidade Paulista",country:{name:"Brazil"}}},{id:"245306",title:"Dr.",name:"María Luz",middleName:null,surname:"Garcia Pardo",slug:"maria-luz-garcia-pardo",fullName:"María Luz Garcia Pardo",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/245306/images/system/245306.png",biography:"María de la Luz García Pardo is an agricultural engineer from Universitat Politècnica de València, Spain. She has a Ph.D. in Animal Genetics. Currently, she is a lecturer at the Agrofood Technology Department of Miguel Hernández University, Spain. Her research is focused on genetics and reproduction in rabbits. The major goal of her research is the genetics of litter size through novel methods such as selection by the environmental sensibility of litter size, with forays into the field of animal welfare by analysing the impact on the susceptibility to diseases and stress of the does. Details of her publications can be found at https://orcid.org/0000-0001-9504-8290.",institutionString:null,institution:{name:"Miguel Hernandez University",country:{name:"Spain"}}},{id:"350704",title:"M.Sc.",name:"Camila",middleName:"Silva Costa",surname:"Ferreira",slug:"camila-ferreira",fullName:"Camila Ferreira",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/350704/images/17280_n.jpg",biography:"Graduated in Veterinary Medicine at the Fluminense Federal University, specialist in Equine Reproduction at the Brazilian Veterinary Institute (IBVET) and Master in Clinical Veterinary Medicine and Animal Reproduction at the Fluminense Federal University. She has experience in analyzing zootechnical indices in dairy cattle and organizing events related to Veterinary Medicine through extension grants. I have experience in the field of diagnostic imaging and animal reproduction in veterinary medicine through monitoring and scientific initiation scholarships. I worked at the Equus Central Reproduction Equine located in Santo Antônio de Jesus – BA in the 2016/2017 breeding season. I am currently a doctoral student with a scholarship from CAPES of the Postgraduate Program in Veterinary Medicine (Pathology and Clinical Sciences) at the Federal Rural University of Rio de Janeiro (UFRRJ) with a research project with an emphasis on equine endometritis.",institutionString:null,institution:null},{id:"41319",title:"Prof.",name:"Lung-Kwang",middleName:null,surname:"Pan",slug:"lung-kwang-pan",fullName:"Lung-Kwang Pan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/41319/images/84_n.jpg",biography:null,institutionString:null,institution:null},{id:"125292",title:"Dr.",name:"Katy",middleName:null,surname:"Satué Ambrojo",slug:"katy-satue-ambrojo",fullName:"Katy Satué Ambrojo",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/125292/images/system/125292.jpeg",biography:"Katy Satué Ambrojo received her Veterinary Medicine degree, Master degree in Equine Technology and doctorate in Veterinary Medicine from the Faculty of Veterinary, CEU-Cardenal Herrera University in Valencia, Spain.Dr. Satué is accredited as a Private University Doctor Professor, Doctor Assistant, and Contracted Doctor by AVAP (Agència Valenciana d'Avaluació i Prospectiva) and currently, as a full professor by ANECA (since January 2022). To date, Katy has taught 22 years in the Department of Animal Medicine and Surgery at the CEU-Cardenal Herrera University in undergraduate courses in Veterinary Medicine (General Pathology, integrated into the Applied Basis of Veterinary Medicine module of the 2nd year, Clinical Equine I of 3rd year, and Equine Clinic II of 4th year). Dr. Satué research activity is in the field of Endocrinology, Hematology, Biochemistry, and Immunology in the Spanish Purebred mare. She has directed 5 Doctoral Theses and 5 Diplomas of Advanced Studies, and participated in 11 research projects as a collaborating researcher. She has written 2 books and 14 book chapters in international publishers related to the area, and 68 scientific publications in international journals. Dr. Satué has attended 63 congresses, participating with 132 communications in international congresses and 19 in national congresses related to the area. Dr. Satué is a scientific reviewer for various prestigious international journals such as Animals, American Journal of Obstetrics and Gynecology, Veterinary Clinical Pathology, Journal of Equine Veterinary Science, Reproduction in Domestic Animals, Research Veterinary Science, Brazilian Journal of Medical and Biological Research, Livestock Production Science and Theriogenology, among others. Since 2014 she has been responsible for the Clinical Analysis Laboratory of the CEU-Cardenal Herrera University Veterinary Clinical Hospital.",institutionString:null,institution:null},{id:"201721",title:"Dr.",name:"Beatrice",middleName:null,surname:"Funiciello",slug:"beatrice-funiciello",fullName:"Beatrice Funiciello",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/201721/images/11089_n.jpg",biography:"Graduated from the University of Milan in 2011, my post-graduate education included CertAVP modules mainly on equines (dermatology and internal medicine) and a few on small animal (dermatology and anaesthesia) at the University of Liverpool. After a general CertAVP (2015) I gained the designated Certificate in Veterinary Dermatology (2017) after taking the synoptic examination and then applied for the RCVS ADvanced Practitioner status. After that, I completed the Postgraduate Diploma in Veterinary Professional Studies at the University of Liverpool (2018). My main area of work is cross-species veterinary dermatology.",institutionString:null,institution:null},{id:"291226",title:"Dr.",name:"Monica",middleName:null,surname:"Cassel",slug:"monica-cassel",fullName:"Monica Cassel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/291226/images/8232_n.jpg",biography:'Degree in Biological Sciences at the Federal University of Mato Grosso with scholarship for Scientific Initiation by FAPEMAT (2008/1) and CNPq (2008/2-2009/2): Project \\"Histological evidence of reproductive activity in lizards of the Manso region, Chapada dos Guimarães, Mato Grosso, Brazil\\". Master\\\'s degree in Ecology and Biodiversity Conservation at Federal University of Mato Grosso with a scholarship by CAPES/REUNI program: Project \\"Reproductive biology of Melanorivulus punctatus\\". PhD\\\'s degree in Science (Cell and Tissue Biology Area) \n at University of Sao Paulo with scholarship granted by FAPESP; Project \\"Development of morphofunctional changes in ovary of Astyanax altiparanae Garutti & Britski, 2000 (Teleostei, Characidae)\\". She has experience in Reproduction of vertebrates and Morphology, with emphasis in Cellular Biology and Histology. She is currently a teacher in the medium / technical level courses at IFMT-Alta Floresta, as well as in the Bachelor\\\'s degree in Animal Science and in the Bachelor\\\'s degree in Business.',institutionString:null,institution:null},{id:"442807",title:"Dr.",name:"Busani",middleName:null,surname:"Moyo",slug:"busani-moyo",fullName:"Busani Moyo",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Gwanda State University",country:{name:"Zimbabwe"}}},{id:"439435",title:"Dr.",name:"Feda S.",middleName:null,surname:"Aljaser",slug:"feda-s.-aljaser",fullName:"Feda S. 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The applications of this research cover many related fields, such as biotechnology and medicine, where, for example, Bioinformatics contributes to faster drug design, DNA analysis in forensics, and DNA sequence analysis in the field of personalized medicine. Personalized medicine is a type of medical care in which treatment is customized individually for each patient. Personalized medicine enables more effective therapy, reduces the costs of therapy and clinical trials, and also minimizes the risk of side effects. Nevertheless, advances in personalized medicine would not have been possible without bioinformatics, which can analyze the human genome and other vast amounts of biomedical data, especially in genetics. The rapid growth of information technology enabled the development of new tools to decode human genomes, large-scale studies of genetic variations and medical informatics. The considerable development of technology, including the computing power of computers, is also conducive to the development of bioinformatics, including personalized medicine. In an era of rapidly growing data volumes and ever lower costs of generating, storing and computing data, personalized medicine holds great promises. Modern computational methods used as bioinformatics tools can integrate multi-scale, multi-modal and longitudinal patient data to create even more effective and safer therapy and disease prevention methods. Main aspects of the topic are: Applying bioinformatics in drug discovery and development; Bioinformatics in clinical diagnostics (genetic variants that act as markers for a condition or a disease); Blockchain and Artificial Intelligence/Machine Learning in personalized medicine; Customize disease-prevention strategies in personalized medicine; Big data analysis in personalized medicine; Translating stratification algorithms into clinical practice of personalized medicine.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/7.jpg",hasOnlineFirst:!0,hasPublishedBooks:!0,annualVolume:11403,editor:{id:"351533",title:"Dr.",name:"Slawomir",middleName:null,surname:"Wilczynski",slug:"slawomir-wilczynski",fullName:"Slawomir Wilczynski",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000035U1loQAC/Profile_Picture_1630074514792",biography:"Professor Sławomir Wilczyński, Head of the Chair of Department of Basic Biomedical Sciences, Faculty of Pharmaceutical Sciences, Medical University of Silesia in Katowice, Poland. 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