Illegally distributed peptides and proteins that have been analyzed by MALDI-ToF-MS and DICZE. The monoisotopic mass (Mmass) of the analytes and the employed analytical methodology is indicated.
\r\n\t
",isbn:"978-1-83968-760-0",printIsbn:"978-1-83968-759-4",pdfIsbn:"978-1-83968-761-7",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,hash:"cc49d6034d85f8f2e2890c6acc3cc629",bookSignature:"Dr. Abhijit Biswas",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/10285.jpg",keywords:"Mott Insulators, Semi Metals, Polycrystals, Single Crystals, Electronic Properties, Magnetic Properties, PLD, MBE, Topological Insulators, Topological Hall Effect, Devices Applications, Catalysis",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"September 9th 2020",dateEndSecondStepPublish:"October 7th 2020",dateEndThirdStepPublish:"December 6th 2020",dateEndFourthStepPublish:"February 24th 2021",dateEndFifthStepPublish:"April 25th 2021",remainingDaysToSecondStep:"4 months",secondStepPassed:!0,currentStepOfPublishingProcess:4,editedByType:null,kuFlag:!1,biosketch:"A pioneering researcher in the field of tailoring metal oxide crystal surfaces and growth as well as engineering of thin films for various emergent phenomena and energy applications. Dr. Biswas received his Ph.D. from POSTECH, South Korea.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"194151",title:"Dr.",name:"Abhijit",middleName:null,surname:"Biswas",slug:"abhijit-biswas",fullName:"Abhijit Biswas",profilePictureURL:"https://mts.intechopen.com/storage/users/194151/images/system/194151.png",biography:"Dr. Abhijit Biswas is a research associate at the Indian Institute of Science Education and Research (IISER) Pune, in India. His research goal is to design and synthesize highest quality epitaxial heterostructures and superlattices, to play with their internal degrees of freedom to exploit the structure–property relationships, in order to find the next-generation multi-functional materials, in view of applications and of fundamental interest. His current research interest ranges from growth of novel perovskite oxides to non-oxides epitaxial films, down to its ultra-thin limit, to observe unforeseeable phenomena. He is also engaged in the growth of high quality epitaxial layered carbides and two-dimensional non-oxide thin films, to exploit the strain, dimension, and quantum confinement effect. His recent work also includes the metal-insulator transitions and magneto-transport phenomena in strong spin-orbit coupled epitaxial perovskite oxide thin films by reducing dimensionality as well as strain engineering. He is also extremely interested in the various energy related environment friendly future technological applications of thin films. In his early research career, he had also extensively worked on the tailoring of metal oxide crystal surfaces to obtain the atomic flatness with single terminating layer. Currently, he is also serving as a reviewer of several reputed peer-review journals.\nDr. Biswas received his B.Sc. in Physics from Kalyani University, followed by M.Sc in Physics (specialization in experimental condensed matter physics) from Indian Institute of Technology (IIT), Bombay. His Ph.D., also in experimental condensed matter physics, was awarded by POSTECH, South Korea for his work on the transport phenomena in perovskite oxide thin films. Before moving back to India as a national post-doctoral fellow, he was a post-doc at POSTECH working in the field of growth and characterizations of strong spin-orbit coupled metal oxide thin films.",institutionString:"Indian Institute of Science Education and Research Pune",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"2",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"Indian Institute of Science Education and Research Pune",institutionURL:null,country:{name:"India"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"20",title:"Physics",slug:"physics"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"205697",firstName:"Kristina",lastName:"Kardum Cvitan",middleName:null,title:"Ms.",imageUrl:"https://mts.intechopen.com/storage/users/205697/images/5186_n.jpg",email:"kristina.k@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:"8356",title:"Metastable, Spintronics Materials and Mechanics of Deformable Bodies",subtitle:"Recent Progress",isOpenForSubmission:!1,hash:"1550f1986ce9bcc0db87d407a8b47078",slug:"solid-state-physics-metastable-spintronics-materials-and-mechanics-of-deformable-bodies-recent-progress",bookSignature:"Subbarayan Sivasankaran, Pramoda Kumar Nayak and Ezgi Günay",coverURL:"https://cdn.intechopen.com/books/images_new/8356.jpg",editedByType:"Edited by",editors:[{id:"190989",title:"Dr.",name:"Subbarayan",surname:"Sivasankaran",slug:"subbarayan-sivasankaran",fullName:"Subbarayan Sivasankaran"}],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:"Theophanides",surname:"Theophile",slug:"theophanides-theophile",fullName:"Theophanides Theophile"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3092",title:"Anopheles mosquitoes",subtitle:"New insights into malaria vectors",isOpenForSubmission:!1,hash:"c9e622485316d5e296288bf24d2b0d64",slug:"anopheles-mosquitoes-new-insights-into-malaria-vectors",bookSignature:"Sylvie Manguin",coverURL:"https://cdn.intechopen.com/books/images_new/3092.jpg",editedByType:"Edited by",editors:[{id:"50017",title:"Prof.",name:"Sylvie",surname:"Manguin",slug:"sylvie-manguin",fullName:"Sylvie Manguin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"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:"72",title:"Ionic Liquids",subtitle:"Theory, Properties, New Approaches",isOpenForSubmission:!1,hash:"d94ffa3cfa10505e3b1d676d46fcd3f5",slug:"ionic-liquids-theory-properties-new-approaches",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/72.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1373",title:"Ionic Liquids",subtitle:"Applications and Perspectives",isOpenForSubmission:!1,hash:"5e9ae5ae9167cde4b344e499a792c41c",slug:"ionic-liquids-applications-and-perspectives",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/1373.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"57",title:"Physics and Applications of Graphene",subtitle:"Experiments",isOpenForSubmission:!1,hash:"0e6622a71cf4f02f45bfdd5691e1189a",slug:"physics-and-applications-of-graphene-experiments",bookSignature:"Sergey Mikhailov",coverURL:"https://cdn.intechopen.com/books/images_new/57.jpg",editedByType:"Edited by",editors:[{id:"16042",title:"Dr.",name:"Sergey",surname:"Mikhailov",slug:"sergey-mikhailov",fullName:"Sergey Mikhailov"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"371",title:"Abiotic Stress in Plants",subtitle:"Mechanisms and Adaptations",isOpenForSubmission:!1,hash:"588466f487e307619849d72389178a74",slug:"abiotic-stress-in-plants-mechanisms-and-adaptations",bookSignature:"Arun Shanker and B. Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"878",title:"Phytochemicals",subtitle:"A Global Perspective of Their Role in Nutrition and Health",isOpenForSubmission:!1,hash:"ec77671f63975ef2d16192897deb6835",slug:"phytochemicals-a-global-perspective-of-their-role-in-nutrition-and-health",bookSignature:"Venketeshwer Rao",coverURL:"https://cdn.intechopen.com/books/images_new/878.jpg",editedByType:"Edited by",editors:[{id:"82663",title:"Dr.",name:"Venketeshwer",surname:"Rao",slug:"venketeshwer-rao",fullName:"Venketeshwer Rao"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"4816",title:"Face Recognition",subtitle:null,isOpenForSubmission:!1,hash:"146063b5359146b7718ea86bad47c8eb",slug:"face_recognition",bookSignature:"Kresimir Delac and Mislav Grgic",coverURL:"https://cdn.intechopen.com/books/images_new/4816.jpg",editedByType:"Edited by",editors:[{id:"528",title:"Dr.",name:"Kresimir",surname:"Delac",slug:"kresimir-delac",fullName:"Kresimir Delac"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"65589",title:"Human Papillomavirus (HPV) Infection in Males: A Need for More Awareness",doi:"10.5772/intechopen.84303",slug:"human-papillomavirus-hpv-infection-in-males-a-need-for-more-awareness",body:'The concern on male HPV infection stems from both the disease burden and the potential risk of its transmission from males to females [1]. To date, prevalence and incidence of HPV infection in males is much less established compared to females [2]. In males, infection with high-risk HPVs is associated with penile intraepithelial neoplasia (PIN) in addition to others such as anal and oropharyngeal cancers [3, 4]. The incidence of HPV-related anal and oral cancers is generally on the increase but especially among individuals who are immunocompromised [1, 5]. In some developed nations, the prevalence of oropharyngeal/anal squamous cell carcinoma (SCC) among both men and women was reported to be on the increase [4]. The range of HPV prevalence among males is between 1.3 and 72.9% and is minimally affected by age as against the observed trend in females. Females tend to have a higher probability of acquiring high-risk genotypes compared to males whose risk for acquiring both high- and low-risk types appear to be similar [6].
Based on successes recorded in females, HPV vaccination among males was introduced and had shown much promises so far [6]. However, acceptability/uptake and awareness of HPV vaccines among different male populations have continued to face challenges even in some developed countries despite the successes in female programs [7, 8, 9, 10, 11, 12]. This is worst in developing nations where even female immunization programs are almost nonexistent [13, 14, 15].
Over a century ago, an increased risk for the development of cervical cancer was observed among prostitutes as against nuns. Subsequently in the early 1980s, the suspected linkage between sexual behavior and the development of cervical neoplasia was confirmed to be due to genital infection with HPV [16]. In 1983 and 1984, HPV 16 and 18 were isolated from cervical cancer specimens [17].
Currently, there are more than 300 human and animal papillomaviruses which constitute the Papillomaviridae family out of which over 200 have been described and organized into 5 phylogenetic genera named alpha, beta, gamma, mu, and nu [17, 18]. However, even as at 1970, it was assumed that there was only one HPV which was thought to be the cause of various warty lesions that infected different tissue sites in humans. Initial perceptions about HPV were mainly as the etiology of transient and trivial/unsightly excrescences. This assertion was changed with the advent of recombinant DNA technology which revealed the presence and effect of multiple HPV types with tropism for different mucosal/cutaneous squamous surfaces and associated development of warts. It further became obvious that some of the HPV genotypes infecting the anogenital tract were oncogenic and causally associated with cancer of the uterine cervix [19].
Evolution of papillomaviruses have been closely linked with their relevant animal hosts over millions of years. The life cycle of HPV genotypes also reflects the differentiation of its respective epithelial target including different parts of the skin and oropharyngeal mucosa [20]. In view of the assertion that humans evolved from nonhuman primates in Africa, origin of HPV types was also linked to Africa phylogenetically. Additionally, the phylogeny of HPV variants (three lineages: European, Asian American, and African) reflects the migration patterns of Homo sapiens. The spectrum of diseases associated with HPV infections (anogenital malignancies and warty lesions) have also accompanied humans throughout evolution [21].
HPVs belongs to Papillomaviridae family which comprises a diverse family of non-enveloped, small circular double-stranded DNA viruses of about 55 nm in size and consists of about 72 capsomeres [22, 23, 24]. The HPV genome is made up of 8000 base pairs. They are relatively stable and could maintain infectivity over a long period in moist environment [25].
It has three functional coding regions: E, a gene coding early viral function; L, a gene coding late viral function; and LCR, a long control region (also referred to as noncoding regulatory region “NCR” or “upstream regulatory region” (URR)) which lies between E and L [24, 26]. Genes are designated as “early” or “late” on the basis of their functional action timing [16].
The genome is organized into eight open reading frames: a long local control region, six early proteins (E1, E2, and E4–E7) and two late proteins (L1 and L2). E1, E2, E5, E6, and E7 are expressed early in the differentiation, E4 is expressed throughout, and L1 and L2 are expressed during the final stages of differentiation [20]. The early genes are involved in DNA replication, transcriptional regulation, and cellular transformation, whereas late genes encode the viral capsid proteins (the capsomeres) which accounts for 80% of the viral particle [3, 16, 25, 27].
Two of the viral proteins, E6 and E7, are consistently expressed in HPV-positive cervical cancers. The high-risk HPV E6/E7 expression is rate limiting for cervical cancer development. These oncoproteins contribute to tumor initiation and also play important roles in malignant progression through the induction of genomic instability and other mechanisms [26]. E1 and E2 play direct roles in viral replication [3]. The viral gene expression also correlates with the differentiation stages of the epithelium [16]. The viral genome is maintained at the basal layer of the epithelium, where HPV infection is established [20]. The virally infected cells differentiate as they move upward from the basal layer toward the surface of the epithelium with associated induction of high-level viral replication and gene expression followed by virion assembly/release [18].
The phylogeny of HPV variants revealed three lineages: European, Asian American, and African. The evolutionary process stemmed from greater adaptability of certain intra-type HPV variants to specific human population groups. They remained stable viruses over time and have neither changed host species nor reorganized themselves. HPVs have maintained their basic genomic organization for a period exceeding 100-million-year period [21].
More than 200 types of HPV have been identified by DNA sequence data, and 85 HPV genotypes have been well characterized to date [25]. Classified under the Alpha papillomavirus genus are about 40 HPV genotypes that commonly infect the genital tract and are subdivided in to low- and high-risk types [28]. The high-risk types include HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 59. Others which include HPV 6, 11, 40, 42, 43, 44, 54, 61, 70, 72, 81, 89, and CP6108 are the low-risk group and are frequently detected in benign lesions such as condylomata acuminata [22, 23, 29]. HPV types 26, 53, 66, 68, 73, and 82 are considered as probably carcinogenic [29, 30]. However, HPV types 68, 73, and 82 were occasionally grouped under the high-risk types, while HPVs 34, 57, and 83 are of undetermined risk [30]. Another approach to classification of HPVs on the basis of different oncogenic potentials grouped them in to high-risk (HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, and 82), intermediate-risk (HPV 26, 53, and 66) and low-risk (HPV 6, 11, 40, 42, 43, 44, 54, 61, 70, 72, and 81) types [31].
The distinction between high- and low-risk HPV genotypes is constantly being revised as greater details about the virus become clearer. It therefore follows that classification based on oncogenicity of some HPV types could change over time, with consequent implications on diagnosis and management of HPV-related infections [32].
Oncogenic human viruses generally infect, but without killing their host cells. They have the tendency to establish long-term persistent infections. Malignant progression of hrHPV-associated lesions usually occurs in the presence of other risk factors, such as decreased immune function and/or after a long latency period after other genomic alterations in the host cell DNA has occurred [17].
In biological evolution, HPVs are successful infectious agents which induce persistent infections without frequent and serious complications for the host and shed virions for transmission to other naive individuals. They avoid the host’s defense systems through several processes which include lack of viral-induced cytolysis or necrosis and absence of inflammation, lack of blood-borne or viremic phase, poor access to vascular and lymphatic channels and to lymph nodes where immune responses are initiated, and having mechanisms for inhibiting interferon synthesis and receptor signaling [21].
Series of phases including the G0, G1, S, G2, and M constitute normal cell cycle which are modulated by cell cycle regulatory genes. These phases are under strict control during transition and are also well coordinated during progression with different cell signals. Cyclin-dependent kinases (CDKs), CDK inhibitors, p53, p27, and p21, and the retinoblastoma gene product (Rb) are the main regulators of cell progression with p53 and Rb as the two most important tumor suppressor genes in the human body. Minor mutations could alter the concentration of p53 with resultant arrest of mitosis and failure of DNA repair, while major damage is associated with apoptosis [16].
The life cycle of HPV follows the differentiation of keratinocytes and begins with expression of E6 and E7 oncoproteins by the virus in the affected epithelium. In the acute phase, viral DNA which is usually present as an episome within the affected host cell is cleared by IFN-β. However, cells with integrated HPV DNA are resistant to this antiviral effect, and the virus completes its life cycle and produces new infectious viral particles, using the host’s DNA and RNA polymerase [16, 19]. This mechanism of viral reproduction which is tightly controlled by E2 and regulated by E6 and E7 does not cause cancer [16]. But in high-risk HPVs, T-cell responses to E2 and E6 are lost or reduced, and E7 proteins bind to pRB more efficiently than in low-risk HPV. The E2 oncoprotein usually functions as a transcriptional repressor of the promoter that drives expression of both the E6 and E7 genes. With abrogation of E2 expression, there is dysregulation in E6/E7 expression due to loss of the transcriptional control and resultant suppression of the killer defense response and loss of p53-induced apoptosis increasing chromosomal instability and cancer development [3, 19, 26].
HPVs remain a serious global public health problem due to their association with anogenital/oral cancers and warts [22]. Approximately 630 million individuals are infected with HPV worldwide, while 30 million genital HPV infections are diagnosed each year. It is estimated that in the United States alone, there are 20 million people infected with HPV, and 6.2 million individuals become newly infected each year. Over half of sexually active men and women are infected at some point during their lives [26, 30]. The overall HPV transmission rate was estimated to be 58.8 per 100 person-years from penis-to-cervix and 208.8 per 100 person-years from cervix-to-penis [2]. The estimated total cost for the clinical management of HPV-related diseases in the United States is greater than $3 billion per year; the majority of this sum is spent on the management and treatment of premalignant lesions [26].
The widespread presence and acceptability of many risk factors (including early/polygamous marriages, high parity, and poverty) have made HPV infection to be endemic in Africa. This is due to both increase in acquisition and promotion of the oncogenic effect of the virus [33].
About 15 HPV types have been classified as oncogenic. Among the oncogenic viruses, HPV 16 and HPV 18 are the most prevalent [20]. HPV types tend to be transmitted together, resulting in a high proportion (20–30%) of concurrent infections with different types [20]. HPV 16 is the most prevalent type worldwide. HPV 18, 45, 31, and 33 are the next most prevalent types [23].
HPVs have both pronounced tropism for certain epithelial cells in addition to being specie specific and have been detected in a wide range of animal species [3]. The hrHPVs are causally related to anogenital cancers including cervix, vulva, and anus in women and penis and anus in men [19, 34]. Low-risk HPV types 6 and 11 are most commonly detected in genital and anal warts, representing 90% of these cases [22].
Although the predominant mode of viral transmission occurs through sexual contact, HPV also has been found in individuals prior to first coitus suggesting the possibility of vertical transmission from mother to child [35]. However, the viral mode transmission in children is still being elucidated [36].
Several studies [37, 38, 39, 40, 41] have reported different factors significantly associated with HPV infections which include current and past sexual behavior (including lifetime number of female sex partners (FSPs)), MSM, female partner with positive cervical HPV infection, early sexual debut, absence of circumcision, lack of condom use, immunosuppression, history of other sexually transmitted infections, race/ethnicity, educational level, and smoking cigarettes.
Different studies have reported varying prevalence rates from different countries. In the United States, prevalence was found to be 65.4% for any HPV, 29.2% for oncogenic HPV, and 36.3% for non-oncogenic HPV among males [37]. Another study revealed a prevalence of 49% of any type of HPV and 35% of hrHPV [38]. Overall prevalence in Europe was found to be 12.4–28.5% in general population and 30.9% in high-risk population [42]. Approximately 90% of anal cancers are associated with HPVs out of which 90% are due to types 16 and 18. This is in contrast to cervical cancers in which about 70% are due to these predominant high-risk genotypes [43]. Although women have higher rates of anal cancer than men in the general population, the greatest risk is seen among HIV-infected men who have sex with men (MSM) who also have higher prevalence of anal HPV [43, 44, 45].
Variation in prevalence has also been observed based on differences in the infected sites. In a Greek population, it was highest at anal sites (33%) compared with 23% at penile sites and 4% at oral sites [39]. In another study, the prevalence of HPV infection was 73% at anal site, 26% at penile site, and 16% at oral site [46]. MSM had higher prevalence (84 vs. 42%) at anal site and a lower clearance rate than heterosexuals [46]. Globally, HPV DNA was detected in 33.1% of penile cancers [47]. Prevalence of HPV-related malignancies have been found to be 22.4, 4.4, and 3.5% for oropharynx, oral cavity, and laryngeal cancers, respectively [48].
In Africa, the prevalence of anal HPV was 69.1% in Central Africa and 40.6% in Nigeria [49, 50]. Up to 82.7% of hrHPV was reported in Central Africa out of which 52.0% were multiple infections and more prevalent among HIV-positive MSM [49]. The prevalence of anal hrHPV among HIV-positive MSM was 91.1% in Nigeria [50]. In South Africa, HPV genotypes were detected in 72.8, 11.5, and 15.3% of anal, oropharyngeal, and urine specimens, respectively [51].
Neoplasias associated with HPV in men include genital warts, penile, anal, and oropharyngeal and other head and neck cancers [43]. Although there were studies suggesting possible association between HPV and prostate cancer in males, none have reached universal acceptability [52, 53]. Recently, a causal association between hrHPV and HPV-related multiphenotypic sinonasal carcinoma (HMSC) has been described [54, 55, 56, 57]. Other malignancies associated with HPV include SCC of the skin/nose tip and skin appendages [58, 59, 60, 61, 62]. Association between HPV and bladder cancer even though without uniform conclusions has also been reported in several studies [63, 64, 65, 66, 67, 68, 69].
Specimens for detecting HPV in males could be collected from any or all of the following parts of the genital tract, glans, coronal, penile shaft, scrotum, and anal region [43]. Other specimens could be based on the part of the body affected.
The diagnosis of human papillomavirus (HPV) can be inferred from morphologic, serologic, and clinical findings. HPVs cannot be cultured, and the detection of virus relies on a variety of techniques used in immunology, serology, and molecular biology [70].
Men do not develop adequate immune responses to maintain protection. Studies have shown that at all ages, antibody levels are lower in men than women [43]. Natural history studies of HPV in men show that HPV clears quite rapidly compared to females [43].
Despite HPV’s ability to evade the host’s immune system and to downregulate innate immunity, a primary HPV infection is cleared naturally in approximately 90% of cases within 2 years mainly because of cell-mediated immune responses directed against the early HPV proteins particularly E2 and E6. Seroconversion only occurs in about 60% of women, and men are much less likely to have HPV antibodies detected. CD4+ T-helper cells are crucial in avoiding persistent HPV infection, as well as inducing wart regression [2, 19, 21].
The host’s immune response to HPV infection (humoral immunity, mainly IgG) is usually slow, weak, wane over time, and varied considerably with many women not seroconverting [17, 19]. Generally, close to half of the individuals seroconvert to L1 protein of HPV 16, 18, or 6 within 18 months. Other HPV antigens [E1, E2, E6, and L2] do not evoke any antibody responses in patients with acute or persistent HPV infection [21]. Natural infection-elicited antibodies may not provide complete protection to HPV over time. A recent WHO position paper stated that host antibodies, mostly directed against the viral L1 protein, do not necessarily protect against subsequent infection by the same HPV genotype [21].
The evidence from animal papillomavirus infections, including some of the earliest published works, showed very clearly that neutralizing antibodies were protective. The experiments showed that if rabbits were infected systemically with the cottontail rabbit papillomavirus (CRPV) by direct injection of virus; papillomas did not arise on the skin of the challenged animals, and neutralizing antibodies were generated. The animals were completely resistant to subsequent viral challenge by abrasion of the epithelium [19]. Immunization also facilitates the regression of existing lesions [25].
Technological advancement leading to production of virus-like particles (VLPs) is the prelude to development of effective HPV vaccine. Highly immunogenic VLPs capable of mimicking natural infection and eliciting high titers of long-lasting virus-neutralizing antibodies (significantly more than natural infection) could be generated using recombinant DNA. This is because the antigenic dose in VLPs is much higher than what obtains in natural infection as the capsids are directly exposed to systemic immune responses. This leads to better quality and the quantity of the immune response generated by vaccines compared to natural infection. The intramuscular administration of HPV vaccines leads to rapid access to the local lymph nodes with subsequent evasion of immune avoidance strategies of the virus [19, 21].
A rapid, potent, and sustained immunologic response due to the administration of both quadrivalent vaccine (targeting HPV 6, 11, 16, and 18) and a bivalent vaccine (targeting HPV 16 and 18) has been reported. These vaccines can elicit an immunological response against the two most common oncogenic types (16 and 18) but not against all the high-risk types except for cross-neutralizing antibodies in some individuals [19, 21]. The duration of protection afforded by the vaccines revealed greater than 98% protection over a 5- to 6.4-year period against HPV 16, 18, 6, and 11 [19].
Strategies for the control and treatment of genital HPV infections are a matter of high priority typically because of their relationship with anogenital and other malignancies. Traditionally, vaccines have remained a cost-effective means of preventing many viral diseases including HPV in recent times [19]. Sexually naïve adolescents are routinely being vaccinated in many countries as recommended by the World Health Organization (WHO). The effectiveness of these vaccines is most pronounced in unexposed as against previously infected individuals [24]. This is because the current vaccines are not therapeutic against existing infections or lesions, and cross-protection against other HPV types is partial or nonexistent. Therefore, the greatest public health benefit of the current HPV vaccines is when given at an age before sexual debut [20].
Recommendation for routine vaccination of adolescents at ages 11 or 12 years has been in place.
Since 2006 for females and since 2011 for males [71]. The United States was the first country to adopt a gender-neutral routine HPV immunization policy in the year 2011 for both males and females [72]. The time of commencement of vaccine administration determines the minimum number of doses recommended based on the age of recipient. Two doses are recommended for those who initiate between ages 9 and 14 years, while three doses are for those initiating at ages 15 through 26 years and for immunocompromised individuals [71]. A three-dose regimen could be for all the three vaccines at time intervals of 0, 1, or 2 and 6 months [71]. The effect of all vaccine types is higher for HPV 16-/18-associated lesions than for others. It is also greater in those who are high-risk HPV negative at initiation compared to those with unknown HPV status [73]. The effect of HPV vaccination in males is also moderate against persistent anogenital infection and high-grade anal intraepithelial lesions if given to HPV infected males as against those without the infection. This supports a recommendation for vaccination of boys also before sexual debut so as to ensure maximum protection [74].
Although global attention has been more toward HPV infection in females, it is equally important in males due to increasing prevalence especially among the high-risk populations. Many developed countries have commenced routine immunization of males for HPV but virtually no low-income country followed the same pathway. There is need for more awareness especially in developing countries where the burden of HPV is highest.
The current trend suggests a relatively low level of awareness on HPV-associated diseases in males and acceptability of vaccination against the virus in most countries but worst in developing nations [75, 76, 77, 78, 79]. There are efforts from varying perspectives by different groups to improve the current situation based on findings from some studies [80, 81]. Technological advancements will see the use of various means such as mobile computer applications to influence the knowledge about HPV and acceptability/uptake of the vaccines [82]. There might be a need for changes in policies even in developed countries to accommodate more challenges as they unfold [83]. Culture and beliefs may be explored to further strengthen the level of awareness and acceptability of HPV vaccines in different populations [84]. Design and development of more potent and user-friendly vaccines for both preventive and therapeutic purposes will continue with resultant wider acceptability/improved safety [31]. With the successes observed in countries who have implemented structured programs for HPV vaccination, more nations may embrace similar/improved approaches for better outcomes [85]. cervical intraepithelial neoplasia cyclin-dependent kinases cottontail rabbit papillomavirus deoxyribonucleic acid female sex partners human immunodeficiency virus human papillomavirus high risk long control region low risk men having sex with men noncoding regulatory region penile intraepithelial neoplasia squamous cell carcinoma sexually transmitted infections upstream regulatory region virus-like particles World Health OrganizationAbbreviations
A broad range of proteins and peptides, for various purposes of enhancement, such as human growth hormone (hGH), i.e., somatropin, can be obtained from the illicit market. These products are mainly marketed as lyophilized formulations in small glass containers often without labelling. The customers are exposed to a range of potential harms, besides from the active components, including bacterial and fungal or viral infections which may arise from the fact that they are administered parenterally.
Figure 1A illustrates the total number of injection vials containing white lyophilized product cake being seized by the Swedish Customs during nine years in the past, i.e., 2010–2018. A large proportion of these samples, i.e., 64%, contained human growth hormone or melanotan II. About a third of the seized vials, i.e., 27%, did not contain any active peptide or protein, while the remaining 9% of the vials contained other compounds, Figure 1B.
Schematic illustration of the number of seized illicit products during 2010–2018 in Sweden (A), as well as the active peptides/proteins that have been identified in theses samples (B).
The concept of a proteolytic peptide pattern, i.e., protein peptide mapping (PPM), being characteristic of a protein was first demonstrated by SDS-PAGE [1]. In 1989, peptide sequencing by automated Edman degradation had a cycle-time of nearly one hour per amino acid residue. Samples of interest often contained complex mixtures of proteins, which usually required separation by SDS-PAGE followed by electroblotting onto a polyvinylidene fluoride (PVDF) membrane [2]. However, a more rapid approach to peptide sequencing is “peptide mass fingerprinting” (PMF). By PMF, proteins are enzymatically cleaved in a predictable manner and the sizes of the generated peptide fragments are specific for different proteins. Subsequent analysis of the obtained peptides by mass spectrometry (MS) generates mass-to-charge ratio (m/z) values in the mass spectrum which in turn give rise to a characteristic “peptide mass fingerprint” of the protein [3, 4]. The fingerprint serves to identify the protein by comparison with in silico digests, i.e., search engines attempt to match peptides from in silico digested proteins to those measured by the mass spectrometer [5, 6, 7, 8, 9]. Peptide mass fingerprinting with MS, which was first demonstrated with fast atom bombardment ionization in 1981, provides the possibility of identifying a protein at nanogram-level [5, 10, 11, 12]. Trypsin is a commonly used proteolytic enzyme for PMF, since it is relatively cheap, highly selective, and generates peptides with an average size of about 8–10 amino acids which are ideally suited for analysis by MS. It cleaves principally on the C-terminal side of arginine and lysine with the exception of Arg-Pro and Lys-Pro [2]. Limitations to protein identification by PMF include; I) The protein sequence must be present in a database for a successful protein identification. II) Proteins with extensive post-translational modifications may fail to yield good matches [13]. III) Different isoforms of a protein or alternatively spliced proteins may not be distinguished if the unique sequence regions are not observed in the peptide map. IV) Incomplete proteolytic digestion and differences in peptide ionization provide an incomplete mass fingerprint of the protein. Therefore, a complementary approach to PMF for protein identification is the use of tandem mass spectrometry (MS/MS), whereby tryptic peptide ions from the first stage of MS are dissociated along the backbone and then separated and detected in a second stage of MS to identify primary amino acid sequences [14, 15, 16]. Tandem mass spectrometry in conjunction with PMF provides even more specificity, thereby facilitating the identification [17, 18].
Since the innovation of sensitive commercial instrumentation based on MALDI-TOF MS in 1992, the technique has been widely used for protein identification due to its high sensitivity and mass accuracy, speed, extremely low material consumption, absence of multiple charge mass signals and relatively high tolerance toward additives and contaminants such as salts, matrix components and excipients [19, 20, 21, 22, 23, 24, 25, 26]. Furthermore, MALDI is a micro-destructive analytical technique and the remaining material on the MALDI target plate can be archived for later analysis. The high sensitivity of MALDI implies that only a small aliquot of the digested protein is required for mass analysis, and the remainder can be used for alternative measurements. MALDI provides additional information regarding the primary structure of the protein by sequencing of selected tryptic peptide ions in post source decay (PSD) mode [27, 28, 29, 30, 31, 32, 33, 34]. MALDI in-source decay (ISD) is another attractive method which generates partial sequence information of intact proteins with up to 20–50 amino acid residues [35], Figure 2.
MALDI in source decay analysis of a suspected illegal somatropin sample. The blue marked amino acid asp (D) is the deamidated form of Asn (N).
The sequence information from MALDI-PSD or MALDI-ISD analyses can be used to validate protein identification. The singly charged ions generated by MALDI-TOF-MS are a mixture of b-, y- and a-ions accompanied by ions resulting from neutral loss of ammonia or water [36, 37, 38, 39].
PMF-based protein identification is accomplished by searching a protein sequence database using different search engines such as ProFound [40], Mascot [41], or SEQUEST [15]. A value-based scoring system has been developed that facilitates the identification without accompanying amino acid data [42, 43]. Parameters which are considered to be important for the identification include; molecular mass, protein sequence coverage and the number of matching peptides [42]. However, presence of a signature peptide, being unique for a protein, facilitates the PMF-based identifications [44]. Prior reports suggest that a minimum of four matching peptides and a sequence coverage of at least 20% is necessary for positive PMF-based protein identification [45, 46]. The other alternative strategy for protein identification is the top down approach, where intact molecule ions are subjected to gas-phase fragmentation [47].
Proteins with posttranslational modifications, such as glycosylation, present additional challenges since the masses of the modified peptides are different and thus do not contribute to the identification. In such cases, the protein can be analyzed by capillary electrophoresis (CE), in order to explore the heterogeneity of the protein followed by comparison of its electropherogram with that of the corresponding reference standard [13, 48].
MALDI-TOF-MS is very tolerant to salts and sample matrices, hence it is seldom necessary to desalt the sample. However, sometimes it is necessary to use a C18 micro-column in order to fractionate a complex sample or enhance the target analyte concentration.
The sample to be analyzed is mixed with a matrix solution (1:1, v:v), e.g. sinapinic acid (SA) or alpha-cyano-4-hydroxycinnamic acid (ACHCA). One μl of the mixture is deposited on the MALDI target plate and allowed to air-dry (i.e., the dried-droplet method) before being placed in the mass spectrometer [19, 49].
The analyte to be digested is dissolved in ammonium bicarbonate (50 mM, pH 7.9). The intact sample is directly analyzed by MALDI in order to determine the molecular mass of the analyte. Then, 200 μl of the solution is digested by addition of 2–10 μl trypsin (200 μg/ml in 10 mM HCl). The reaction is carried out at room temperature or at 37°C for 30 minutes up to 24 hours, depending on peptide or protein in question. It has been found that 30 minutes digestion of somatropin at room temperature generated enough tryptic fragments for the MALDI analyses [50]. For more complex proteins, such as human chorionic gonadotropin, the required time period for proteolysis is found to be 24 hours at 37°C. Insulin porcine is digested at 37°C for 12 hours, while other peptides are digested at 37°C for 4 hours. In order to enable alkylation of the cysteine residues in a protein or peptide, it is reduced by using DTT or 2-mercaptoethanol (ME) followed by labelling of the free thiol groups with 2-iodoacetamide. The alkylation is carried out through the following procedure:
2.5 μl 100 mM ME is added to 10 μl of the protein solution.
The protein is then incubated at 50°C for 15 minutes to reduce the S-S linkages.
2.5 μl 2-iodoacetamide (100 mM) is added into the mixture to interact with free sulfide groups of the cysteine residues at +4°C for 15 to 60 minutes in darkness.
2.5 μl (10 μg/mL) trypsin is added to the mixture for the digestion. The reaction is performed at room temperature or at 37°C [13, 50].
MALDI-TOF analyses are performed using either an Autoflex or an Autoflex Max (Bruker Daltonics, Bremen, Germany) reflector type time-of-flight mass spectrometer, equipped with a pulsed nitrogen laser working at 337 nm and a smartbeam II laser working at 355 nm, respectively. The Autoflex instrument is operated in the positive ion mode with delayed extraction at an accelerating voltage of 20 kV and a variable voltage reflectron. The parameter settings are optimized to analyze peptides in reflectron mode. Before analysis, the instrument is externally calibrated with Bruker Daltonics standard peptide or protein mixtures. Peptide mass peaks occurring due to autolysis of trypsin (porcine) such as 842.51 and 2211.10 Da are also used for internal calibration. Mass spectra are obtained by averaging 250 laser shots (5× 50 shots) at different positions on the sample surface. All samples being used for post source decay (PSD) analysis are analyzed in the reflectron mode. The autoflex Max instrument TOF/TOF (2 kHz MS and 200 Hz MS/MS) operates in the positive ion mode. Metastable fragmentation is induced by laser (355 nm) without the further use of collision gas. The lyophilized samples are dissolved in 300 μL ammonium bicarbonate buffer (50 mM, pH 7.5). The liquid samples are diluted with same buffer. The wells of MALDI plate are spotted with 1 μl sample/matrix solution (1:1, v:v) and allowed to air dry before being placed in the mass spectrometer. ACHCA is used for analysis of peptides. About 20 mg of ACHCA is mixed in 1 ml of ethanol: acetonitrile (ACN) (1: 1 v/v) and 0.1% trifluoroacetic acid (TFA). SA is used for protein analysis. Two different solutions of SA in water and ethanol are made as follows: 1 - Saturated solution of SA in ethanol and 0.1% TFA; 2 - Saturated solution of SA in 50% acetonitrile (ACN) and 0.1% TFA. Solution 1 is first applied on the MALDI plate on which the sample mixed with SA in 50% ACN and 0.1% TFA (1: 1) is then applied.
Illegally distributed lyophilized or liquid products being suspected to contain pharmacologically active peptides were seized by the Swedish customs. The analyte to be identified is analyzed in both reflectron and linear modes in order to determine its molecular mass, Figure 3. Large peptides and proteins are then exposed to trypsin digestion in order to obtain peptide-mass map upon MALDI analysis in reflectron mode. Small peptides are, on the other hand, analyzed in reflectron mode and/or PSD mode directly. This strategy was applied to the identification of the following peptides and proteins, Figure 4 and Table 1.
The sample to be identified is analyzed in both reflectron and linear modes in order to determine the molecular mass of the analyte. Depending on the size of the molecule it will be exposed to enzymatic digestion in order to be identified through PMF. Small peptides used to be identified by de novo sequencing in PSD mode.
The primary structure of the analyzed peptides. (A) Somatoliberin, (B) AOD, (C) GHRP-2, (D) glycine-GHRP-2, (E) GHRP-6, (F) glycine-GHRP-2, (G) Ipamorelin, (H) MGF, (I) long-R3-IGF (disulfide bridges: C6-C48; C47-C52 and C18-C61; asp at position 3 is replaced by Arg), (J) insulin Aspart, (K) insulin porcine, (L) DSIP, (M) Thymosine β4, (N) Melanotan II, (O) Bremelanotide, (P) Dermorphin and (Q) BPC 157. For molecular structures of somatropin and hCG see references [13] and [50].
Recombinant hGH or somatropin consists of 191 amino acids with two disulfide bridges (Cys53-Cys165 and Cys182-Cys189) and promotes proteinogenesis as well as fat mobilization and oxidation [51, 52, 53]. Recombinant hGH is used as a prescription drug to treat children’s growth disorders and adult growth hormone deficiency. In the belief that the beneficial impact of somatropin on the growth can be extrapolated to healthy individuals, it is abused by bodybuilders and athletes [54]. However, many users are unaware of the correct dosage and how to prepare the solution for giving an injection. It has been demonstrated that supra-physiological dosages can have fatal consequences [55]. Apart from the undesired consequences following the abuse of somatropin, our investigations have shown that the illegally marketed products contained high levels of impurities such as endotoxins [50]. Endotoxins are associated with Gram-negative bacteria which can cause severe immune response and diseases in humans [56, 57]. Somatropin was identified through PMF and MALDI-ISD, see Figure 2 [48, 58, 59]. The availability of a compendial reference standard has made it possible to apply double injection capillary zone electrophoresis (DICZE) for both identification and impurity determination of somatropin products [50, 58, 59]. The DICZE-method provided complementary information on the native protein, providing a side by side comparison between the electrophoretic patterns of the reference standard and the analyte to be identified [50].
Human somatoliberin, growth hormone-releasing hormone (GHRH), constitutes of 44 amino acids without any post-translational modification or disulfide bridge. Somatoliberin was first isolated from two pancreatic islet cell tumors, and subsequently from normal human hypothalamus [60, 61, 62]. The MALDI results from determination of the molecular mass, PMF and amino acid sequence revealed that the Asn8 (N), Gly15 (G) and Met27 (M) residues have, respectively, been replaced by Gln8 (Q), Ala15 (A) and Leu27 (L) during the synthesis, see Figures 4 and 5. The peptide was successfully identified by PMF and de-novo sequencing of three of the tryptic peptides.
MALDI-PMF (A) and MALDI-PSD (B) analysis of somatoliberin.
The AOD peptide is a fragment of the C-terminus of human growth hormone (fragment 177–191) where a tyrosine is added at the N-terminus. It is a cyclic peptide consisting of 16 amino acids with a disulfide bridge between cysteine residues at positions 7 and 14 in the peptide chain [63], Figure 4 and Table 1. The fragment is the minimum length of the hGH sequence that retains the lipolytic and antilipogenic properties of hGH [63, 64, 65]. The molecular peptide masses of its tryptic peptides complied with the peptide map of hGH fragment 177–191. The existence of the disulfide bridge between C7 and C14 was confirmed upon analysis of the non-reduced tryptic sample, Figure 6. This peptide has also been employed as a signature peptide for the identification of hGH [48, 50]. The amino acid sequences of three selected tryptic peptides were also confirmed.
MALDI-PSD analysis of AOD.
GHRP, including GHRP-2, GHRP-6, Gly-GHRP-2, Gly-GHRP-6 and ipamorelin, as an agonist of the gut peptide ghrelin is an endogenous ligand for the growth hormone secretagogue receptor [66, 67]. Ghrelin strongly stimulates food intake and GH release in humans [68, 69, 70]. These peptides were identified through de-novo sequencing. The amino acid sequence of GHRP-6 differs slightly from that of GHRP-2, i.e., the amino acid residues dA and Naphthyl alanine (NalA) in GHRP2 are replaced by H and dW in GHRP-6, Figure 4 and Table 1 [70].
Ipamorelin is a penta-peptide, being derived from GHRP-1 [71]. Ipamorelin like the other GHR-peptides, stimulates production of growth hormone [72]. Incorporation of aminoisobutyric acid (Aib) in the peptide chain increases the stability of the peptide, Figure 4 [73].
MGF is a unique, spliced variant of IGF-1. MGF induces muscle cell proliferation in response to muscle stress and injury [74]. MGF and Long-R3-IGF1 were identified in several confiscated samples. Long-R3-IGF-1, an analogue of IGF-1, has 13 additional amino acids at its N-terminus, Figure 4 and Table 1. IGF-1 mediates the anabolic and mitogenic activity of GH [75, 76, 77]. MGF and Long-R3-IGF1 were identified by sequence coverages of 100% and 43%, respectively, Table 2 and Figure 7.
Peptide | Mmass | PMFa | PSDb | ISDc | DICZEd | NMR | LC/MS |
---|---|---|---|---|---|---|---|
Somatropin | 22115.07 22128.68e | X | — | X | X | X | X |
Human Somatoliberin | 3366.866 | X | X | — | — | — | — |
AOD (Anti Obesity Drug) HGH fragment 177–191 | 1813.850 | X | X | — | — | — | — |
GHRP-2 | 817.397 | — | X | — | — | — | — |
Gly-GHRP-2 | 874.419 | — | X | — | — | — | — |
GHRP-6 | 872.433 | — | X | — | — | — | — |
Gly-GHRP-6 | 929.455 | — | X | — | — | — | — |
Ipamorelin | 711.385 | — | X | — | — | — | — |
MGF | 2866.469 | X | X | — | — | — | — |
Long-R3-IGF | 9105.385 9111.576e | X | X | — | — | — | — |
Insulin Porcine | 5772.766 | X | X | — | X | X | X |
Insulin Aspart | 5821.611 | X | X | — | X | X | X |
DSIP | 848.318 | — | X | — | — | — | — |
Thymosin-β4 | 4960.474 | X | X | — | — | — | — |
hCG α - Chain β - Chain α + β | 13,431e 23,114e 36,341e | X | X | — | X | — | — |
Melanotan-II | 1023.502 | — | X | — | — | X | — |
Bremelanotide | 1024.510 | — | X | — | — | X | — |
Dermorphin | 802.337 | — | X | — | — | X | X |
BPC-157 | 1418.692 | — | X | — | — | X | X |
Albumin bovinef | > 66,000e | X | — | — | — | — | — |
Illegally distributed peptides and proteins that have been analyzed by MALDI-ToF-MS and DICZE. The monoisotopic mass (Mmass) of the analytes and the employed analytical methodology is indicated.
Identification by peptide mass fingerprinting using enzymatic degradation as well as other modifications.
De novo sequencing by MALDI- post source decay.
Protein sequencing by MALDI- in source decay.
Identification and/or impurity profiling by double injection capillary zone electrophoresis.
Average molecular mass.
Bovin albumin was detected in some of the samples.
Peptide fragments | Theoretical m/z [M + H]+ | Determined m/z [M + H]+ |
---|---|---|
YQPPSTNKNTKSQRRKGSTFEERK | 2869.169 | 2869.422 |
Glu-C digestion of the peptidea: | ||
YQPPSTNKNTKSQRRKGSTFEE | 2584.809 | 2584.816 |
Trypsin digestion of the peptide: | ||
GSTFEERKb | 953.458 | 953.574 |
YQPPSTNKb | 934.453 | 934.525 |
GSTFEERb | 825.363 | 825.469 |
SQRb | 390.199 | 390.186 |
NTKb | 362.193 | 362.302 |
MALDI peptide mass fingerprinting-data from analysis of mechano growth factor.
Glu-C cleaves at the C-terminus of either aspartic or glutamic acid residues.
The amino acid sequence of the peptide was determined.
MALDI analysis of intact long-R3-IGF and MALDI-PSD analysis of two tryptic peptides, i.e., m/z 1667.771 and m/z 1763.887.
Insulin regulates the cellular uptake, utilization, and storage of glucose, amino acids, and fatty acids and inhibits the breakdown of glycogen, protein, and fat. Since more than one decade ago the illegal use of insulin has been noticed [78]. However, the misuse and wrong administration of insulin could cause the, so called, dead in the bed syndrome [79]. In bodybuilding, insulin works such as testosterone or hGH to consolidate muscle tissue. Insulin also prevents breakdown of muscles and vanishes rapidly from the body, since it has a very short half-time (t1/2) [80].
Several illegal products containing insulin porcine or aspart have been analyzed. Insulin is composed of two peptide chains, i.e., A and B, which are joined by two inter-chain disulfide bonds. The A chain also contains an intra-chain disulfide bond, Figure 4. The results summarized in Table 3, demonstrate the applied strategy for the identification of porcine and insulin aspart. The insulin molecules were reduced using a potent reducing agent, i.e., 2-mercaptoethanol (ME). MS-analysis of the reduced samples resulted in a mass spectrum consisting of several signals from both reduced A and B chains. The A and B chains generated three and four signals, respectively, corresponding to the ME-modified peptide as described in Table 3. It is to be noted that the amino acid residues P and A at positions 28 and 30 in the B-chain, respectively, have been replaced by D and T in insulin aspart. Therefore, these insulin molecules are distinguished upon these differences. The tryptic digestion of the B chain yielded three peptide fragments of different sizes, Figure 8 and Table 3. The molecular masses of these peptides were determined accurately, and the amino acid sequence of the tryptic peptides were determined in PSD-mode.
Insulin | Theoretical m/z [M + H]+ | Determined m/z [M + H]+ |
---|---|---|
Porcine (intact) | 5774.635 | 5774.632 |
Aspart (intact) | 5822.612 | 5822.618 |
Peptide chains from Insulin porcine: | ||
[A-chain + Na]+ | 2404.990 | 2404.758 |
[A-chain +1ME + Na]+a | 2480.988 | 2480.769 |
[B-chain + H]+ | 3398.682 | 3398.460 |
[B-chain +1ME + H]+a | 3474.680 | 3474.486 |
Peptide chain from Insulin aspart:b | ||
[B-chain + H]+ | 3446.667 | 3446.434 |
[B-chain + Na]+ | 3468.648 | 3468.487 |
[B-chain +1ME + H]+a | 3522.665 | 3522.422 |
[B-chain - (GFFYTDKT) + H]+c | 2487.228 | 2487.030 |
[B-chain - (GFFYTDKT) + 1ME + H]+a, c | 2563.226 | 2563.302 |
Tryptic peptides from Insulin aspart: | ||
[GFFYTDK + H]+ | 877.399 | 877.317 |
[GFFYTDKT + H]+ | 978.457 | 978.446 |
[B-chain - (GFFYTDKT) + H]+c, d | 2487.217 | 2487.030 |
Tryptic peptides from Insulin porcine: | ||
[GFFYTPK + H]+ | 859.425 | 859.345 |
[GFFYTPKA + H]+ | 930.462 | 930.337 |
[B-chain - (GFFYTPKA) + H]+c | 2487.228 | 2487.234 |
[B-chain-(GFFYTPKA) + 1ME + H]+ a, c | 2563.226 | 2563.129 |
MALDI-TOF-MS analysis of insulin porcine and aspart.
Beta mercaptoethanol (ME) was used as reducing agent.
The A-chains of insulin aspart and Insulin porcine are identical.
Trypsinated B-chain.
These peptides originate from insulin aspart, see Figure 8.
MALDI analysis of insulin aspart; analysis of reduced B-chain (A), MALDI-PSD analysis of tryptic B-chain (B), see Table 3.
Double-injection capillary electrophoresis has also been applied for the identification of insulin molecules [81].
The nonapeptide delta DSIP was first isolated from the cerebral venous blood of rabbits in an induced state of sleep during the mid-70s [82]. It was primarily believed to be involved in sleep regulation due to its apparent ability to induce slow-wave sleep in rabbits. However, it has been demonstrated that short-term treatment of chronic insomnia with DSIP is not likely to be of major therapeutic benefit [83]. The peptide is marketed illegally presumably for the treatment of insomnia. The peptide was directly exposed to the PSD analysis in order to confirm its molecular mass and amino acid sequence, Figure 4 and Table 1.
Synthetic thymosin is a peptide consisting of 43 amino acids with artificial acetylation of the N-terminus, see Figure 4 and Table 1. Thymosin has the potential of playing a significant role in tissue development, maintenance, repair, pathology and other important biological activities [84]. Some important biological activities of thymosin are related to the peptide sequence L17KKTET22 [85]. Illegally distributed thymosin products are claimed to promote a variety of beneficial biological functions, such as muscle building. The peptide was identified through PMF and de-novo sequencing of the tryptic peptides, Table 4.
Peptide fragments | Theoretical m/z [M + H]+ | Determined m/z [M + H]+ |
---|---|---|
Ac-SDKPDMAEIEKFDKSKLKKTETQEKNPLPSKETI EQE-KQAGES | 4961.484 | 4960.987 |
KTETQEKNPLPSKETIEQEKQAGES | 2829.401 | 2829.219 |
Ac-SDKPDMAEIEKFDKSKLK | 2151.090 | 2151.124 |
Ac-SDKPDMAEIEKFDKSK | 1909.911 | 1909.698 |
Ac-SDKPDMAEIEKFDKa | 1694.784 | 1694.765 |
NPLPSKETIEQEK | 1512.780 | 1512.768 |
SKLKKTETQEK | 1319.743 | 1319.729 |
Ac-SDKPDMAEIEK | 1304.594 | 1304.498 |
ETIEQEK | 876.421 | 876.356 |
TETQEKa | 735.342 | 735.356 |
NPLPSKa | 655.367 | 655.354 |
FDKSK | 624.325 | N.D.b |
QAGES | 491.199 | N.D.b |
SKLK | 475.314 | N.D.b |
FDKa | 409.198 | 409.196 |
LKKa | 388.282 | 388.286 |
LKa | 260.187 | 260.168 |
SKa | 234.135 | 234.151 |
MALDI peptide mass fingerprinting data from analysis of thymosin β4.
The amino acid sequence of the peptide was determined in the PSD mode.
N.D. = Not detected.
Human chorionic gonadotropin (hCG) is a glycoprotein hormone consisting of α (92 amino acids) and β-subunits (145 amino acids) being noncovalently associated [86]. These subunits are, however, highly cross-linked internally through disulfide bridges, i.e., the α-subunit has five disulfide bridges [87], while the β-subunit has six [87, 88]. The protein is heavily glycosylated where oligosaccharides are attached to the protein backbone through asparagine and serine residues and constitute approximately 30% of the molecular mass [89]. The protein has been identified using MALDI-TOF-MS and DICZE [13, 50]. Approximately 40% of the amino acid sequence of hCG was confirmed upon PMF, Table 5 [13].
Peptide fragments | Peptide position in the peptide chain | Theoretical m/z [M + H]+ | Determined m/z [M + H]+ |
---|---|---|---|
AYPTPLR | α-hCG; 36–42 | 817.446 | 817.482 |
TMLVQK | α-hCG; 46–51 | 719.402 | 719.414 |
STNR | α-hCG; 64–67 | 477.231 | 477.165 |
VTVMGGFK | α-hCG; 68–75 | 838.439 | 838.471 |
SK | β-hCG; 1–2 | 234.135 | 243.142 |
PR | β-hCG; 7–8 | 272.161 | 271.996 |
EPLR | β-hCG; 3–6 | 514.288 | 514.291 |
EPLRPR | β-hCG; 3–8 | 767.442 | 767.469 |
DVR | β-hCG; 61–63 | 389.204 | 389.228 |
FESIR | β-hCG; 64–68 | 651.336 | 651.359 |
MALDI-PMF and MALDI-PSD analysis of human chorionic gonadotropin. The identified peptides from the α and β subunits are presented in the table below.
The identification was confirmed by DICZE analysis of illegal samples together with the corresponding reference standard [13, 50].
Melanotan, a melanocortin receptor agonist, is a cyclic-lactam bridge heptapeptide which induces melanogenesis (i.e., tanning of the skin), by activation of the MC1 receptor, being an analogue to alpha melanocyte hormone (α-MSH) [90]. The cyclic, lactam bridged structure of MII induces increased lipophilicity, Figure 4 [91].
Skin-tanning products that claim to contain MII are being advertised and sold on the illicit drug market. Injection of MII can result in systemic toxicity and rhabdomyolysis [90]. Bremelanotide (formerly PT-141) is an active metabolite of MII, Table 1.
These peptides were identified through the top-down approach by MALDI in PSD mode as illustrated in Figure 9.
MALDI-PSD analysis of melanotan II.
Dermorphin is a μ-opioid receptor-binding peptide that causes both central and peripheral effects [92], Figure 4 and Table 1. This peptide, being originally isolated from the skin of the south American tree frog Phyllomedusa sauvagii, is classified as one of the strongest mammalian endogenous analgesic opioids [93, 94]. Dried frog skin containing dermorphin, has been used as a therapeutic agent by the Matses tribes of the upper Amazonian basin, to treat cuts during hunting expeditions [95]. The analgetic effects of dermorphin has been demonstrated in rat, horse, dog and white sea cod [92, 94]. It has been used illegally in horse racing as a pain killing agent, allowing horses to run even if injured.
This peptide, which was detected in several samples, was identified by MALDI in the PSD mode, Figure 10. The molecular structure was confirmed by NMR spectroscopy.
MALDI-PSD analysis of dermorphin.
BPC 157 being a partial sequence of body protecting compound (BPC) (Mmass = 40 kDa) is a synthetic peptide, which is composed of fifteen amino acids, Figure 4 and Table 1. BPC was discovered and isolated from mouse gastric juice in response to stress stimuli in the gut mucosa [96]. BPC 157 is also known as Bepcin and PL. 14,736 or PL 10 [97]. This peptide fragment was speculated to be responsible for the BPC’s physiological and protective effects [96]. However, it is unclear whether this peptide is endogenous to humans. BPC 157 is suggested to aid in tendon, ligament and muscle healing, and therefore its use as a quick injury healing in the sporting world is appealing. However, no proper clinical trials in human subjects have yet been performed to investigate the healing capability and the harmful effects of this compound [97].
BPC 157 was recently identified in several confiscated vials for injection. The identification was carried out by MALDI in both PSD and reflectron modes, Figure 11. The amino acid sequence of the peptide was confirmed by NMR spectroscopy and LC-QTOF-MS.
MALDI-PSD analysis of BPC 157.
The proposed methods, based on PMF by MALDI-TOF-MS as well as analysis with DICZE, provided an efficient procedure for the identification of peptides and proteins in illegally distributed samples. The use of trypsin as a proteolytic enzyme generated peptide fragments which covered 40 to 80% of the amino acid sequences of the analyzed proteins. The presence of a signature peptide in the peptide map facilitated the analyte identification considerably. MALDI-TOF-MS was also applied in the PSD mode for the amino acid sequencing of selected tryptic peptides as well as small peptides, such as ipamorelin.
The double-injection CE method provided complementary information on the native protein in the presence of a reference standard. This provided the possibility of performing a comparison between the electrophoretic patterns of the reference standard and the analyte to be identified. In addition, the double-injection based identifications were carried out by comparing the corrected migration time of the analyte and the observed migration time of the reference standard.
ACHCA | α-cyano-4-hydroxycinnamic acid |
ACN | Acetonitrile |
Aib | Aminobutyric acid |
BPC | Body protecting compound |
DICZE | Double-injection capillary electrophoresis |
DSIP | Delta sleep-inducing peptide |
GH | Growth hormone |
GHRP | Growth hormone releasing peptide |
GHRH | Growth hormone releasing hormone (somatoliberin) |
hCG | Human chorionic gonadotropin |
hGH | Human growth hormone |
IGF-1 | Insulin like growth factor 1 |
ISD | In source decay |
Nle | Norleucine |
PMF | Protein mass fingerprinting |
PSD | Post source decay |
SA | Sinapinic acid |
TFA | Trifluoroacetic acid |
IntechOpen aims to ensure that original material is published while at the same time giving significant freedom to our Authors. To that end we maintain a flexible Copyright Policy guaranteeing that there is no transfer of copyright to the publisher and Authors retain exclusive copyright to their Work.
',metaTitle:"Publication Agreement - Chapters",metaDescription:"IN TECH aims to guarantee that original material is published while at the same time giving significant freedom to our authors. For that matter, we uphold a flexible copyright policy meaning that there is no transfer of copyright to the publisher and authors retain exclusive copyright to their work.\n\nWhen submitting a manuscript the Corresponding Author is required to accept the terms and conditions set forth in our Publication Agreement as follows:",metaKeywords:null,canonicalURL:"/page/publication-agreement-chapters",contentRaw:'[{"type":"htmlEditorComponent","content":"The Corresponding Author (acting on behalf of all Authors) and INTECHOPEN LIMITED, incorporated and registered in England and Wales with company number 11086078 and a registered office at 5 Princes Gate Court, London, United Kingdom, SW7 2QJ conclude the following Agreement regarding the publication of a Book Chapter:
\\n\\n1. DEFINITIONS
\\n\\nCorresponding Author: The Author of the Chapter who serves as a Signatory to this Agreement. The Corresponding Author acts on behalf of any other Co-Author.
\\n\\nCo-Author: All other Authors of the Chapter besides the Corresponding Author.
\\n\\nIntechOpen: IntechOpen Ltd., the Publisher of the Book.
\\n\\nBook: The publication as a collection of chapters compiled by IntechOpen including the Chapter. Chapter: The original literary work created by Corresponding Author and any Co-Author that is the subject of this Agreement.
\\n\\n2. CORRESPONDING AUTHOR'S GRANT OF RIGHTS
\\n\\n2.1 Subject to the following Article, the Corresponding Author grants and shall ensure that each Co-Author grants, to IntechOpen, during the full term of copyright and any extensions or renewals of that term the following:
\\n\\nThe aforementioned licenses shall survive the expiry or termination of this Agreement for any reason.
\\n\\n2.2 The Corresponding Author (on their own behalf and on behalf of any Co-Author) reserves the following rights to the Chapter but agrees not to exercise them in such a way as to adversely affect IntechOpen's ability to utilize the full benefit of this Publication Agreement: (i) reprographic rights worldwide, other than those which subsist in the typographical arrangement of the Chapter as published by IntechOpen; and (ii) public lending rights arising under the Public Lending Right Act 1979, as amended from time to time, and any similar rights arising in any part of the world.
\\n\\nThe Corresponding Author confirms that they (and any Co-Author) are and will remain a member of any applicable licensing and collecting society and any successor to that body responsible for administering royalties for the reprographic reproduction of copyright works.
\\n\\nSubject to the license granted above, copyright in the Chapter and all versions of it created during IntechOpen's editing process (including the published version) is retained by the Corresponding Author and any Co-Author.
\\n\\nSubject to the license granted above, the Corresponding Author and any Co-Author retains patent, trademark and other intellectual property rights to the Chapter.
\\n\\n2.3 All rights granted to IntechOpen in this Article are assignable, sublicensable or otherwise transferrable to third parties without the Corresponding Author's or any Co-Author’s specific approval.
\\n\\n2.4 The Corresponding Author (on their own behalf and on behalf of each Co-Author) will not assert any rights under the Copyright, Designs and Patents Act 1988 to object to derogatory treatment of the Chapter as a consequence of IntechOpen's changes to the Chapter arising from translation of it, corrections and edits for house style, removal of problematic material and other reasonable edits.
\\n\\n3. CORRESPONDING AUTHOR'S DUTIES
\\n\\n3.1 When distributing or re-publishing the Chapter, the Corresponding Author agrees to credit the Book in which the Chapter has been published as the source of first publication, as well as IntechOpen. The Corresponding Author warrants that each Co-Author will also credit the Book in which the Chapter has been published as the source of first publication, as well as IntechOpen, when they are distributing or re-publishing the Chapter.
\\n\\n3.2 When submitting the Chapter, the Corresponding Author agrees to:
\\n\\nThe Corresponding Author will be held responsible for the payment of the Open Access Publishing Fees.
\\n\\nAll payments shall be due 30 days from the date of the issued invoice. The Corresponding Author or the payer on the Corresponding Author's and Co-Authors' behalf will bear all banking and similar charges incurred.
\\n\\n3.3 The Corresponding Author shall obtain in writing all consents necessary for the reproduction of any material in which a third-party right exists, including quotations, photographs and illustrations, in all editions of the Chapter worldwide for the full term of the above licenses, and shall provide to IntechOpen upon request the original copies of such consents for inspection (at IntechOpen's option) or photocopies of such consents.
\\n\\nThe Corresponding Author shall obtain written informed consent for publication from people who might recognize themselves or be identified by others (e.g. from case reports or photographs).
\\n\\n3.4 The Corresponding Author and any Co-Author shall respect confidentiality rights during and after the termination of this Agreement. The information contained in all correspondence and documents as part of the publishing activity between IntechOpen and the Corresponding Author and any Co-Author are confidential and are intended only for the recipient. The contents may not be disclosed publicly and are not intended for unauthorized use or distribution. Any use, disclosure, copying, or distribution is prohibited and may be unlawful.
\\n\\n4. CORRESPONDING AUTHOR'S WARRANTY
\\n\\n4.1 The Corresponding Author represents and warrants that the Chapter does not and will not breach any applicable law or the rights of any third party and, specifically, that the Chapter contains no matter that is defamatory or that infringes any literary or proprietary rights, intellectual property rights, or any rights of privacy. The Corresponding Author warrants and represents that: (i) the Chapter is the original work of themselves and any Co-Author and is not copied wholly or substantially from any other work or material or any other source; (ii) the Chapter has not been formally published in any other peer-reviewed journal or in a book or edited collection, and is not under consideration for any such publication; (iii) they themselves and any Co-Author are qualifying persons under section 154 of the Copyright, Designs and Patents Act 1988; (iv) they themselves and any Co-Author have not assigned and will not during the term of this Publication Agreement purport to assign any of the rights granted to IntechOpen under this Publication Agreement; and (v) the rights granted by this Publication Agreement are free from any security interest, option, mortgage, charge or lien.
\\n\\nThe Corresponding Author also warrants and represents that: (i) they have the full power to enter into this Publication Agreement on their own behalf and on behalf of each Co-Author; and (ii) they have the necessary rights and/or title in and to the Chapter to grant IntechOpen, on behalf of themselves and any Co-Author, the rights and licenses expressed to be granted in this Publication Agreement. If the Chapter was prepared jointly by the Corresponding Author and any Co-Author, the Corresponding Author warrants and represents that: (i) each Co-Author agrees to the submission, license and publication of the Chapter on the terms of this Publication Agreement; and (ii) they have the authority to enter into this Publication Agreement on behalf of and bind each Co-Author. The Corresponding Author shall: (i) ensure each Co-Author complies with all relevant provisions of this Publication Agreement, including those relating to confidentiality, performance and standards, as if a party to this Publication Agreement; and (ii) remain primarily liable for all acts and/or omissions of each such Co-Author.
\\n\\nThe Corresponding Author agrees to indemnify and hold IntechOpen harmless against all liabilities, costs, expenses, damages and losses and all reasonable legal costs and expenses suffered or incurred by IntechOpen arising out of or in connection with any breach of the aforementioned representations and warranties. This indemnity shall not cover IntechOpen to the extent that a claim under it results from IntechOpen's negligence or willful misconduct.
\\n\\n4.2 Nothing in this Publication Agreement shall have the effect of excluding or limiting any liability for death or personal injury caused by negligence or any other liability that cannot be excluded or limited by applicable law.
\\n\\n5. TERMINATION
\\n\\n5.1 IntechOpen has a right to terminate this Publication Agreement for quality, program, technical or other reasons with immediate effect, including without limitation (i) if the Corresponding Author or any Co-Author commits a material breach of this Publication Agreement; (ii) if the Corresponding Author or any Co-Author (being an individual) is the subject of a bankruptcy petition, application or order; or (iii) if the Corresponding Author or any Co-Author (being a company) commences negotiations with all or any class of its creditors with a view to rescheduling any of its debts, or makes a proposal for or enters into any compromise or arrangement with any of its creditors.
\\n\\nIn case of termination, IntechOpen will notify the Corresponding Author, in writing, of the decision.
\\n\\n6. INTECHOPEN’S DUTIES AND RIGHTS
\\n\\n6.1 Unless prevented from doing so by events outside its reasonable control, IntechOpen, in its discretion, agrees to publish the Chapter attributing it to the Corresponding Author and any Co-Author.
\\n\\n6.2 IntechOpen has the right to use the Corresponding Author’s and any Co-Author’s names and likeness in connection with scientific dissemination, retrieval, archiving, web hosting and promotion and marketing of the Chapter and has the right to contact the Corresponding Author and any Co-Author until the Chapter is publicly available on any platform owned and/or operated by IntechOpen.
\\n\\n6.3 IntechOpen is granted the authority to enforce the rights from this Publication Agreement, on behalf of the Corresponding Author and any Co-Author, against third parties (for example in cases of plagiarism or copyright infringements). In respect of any such infringement or suspected infringement of the copyright in the Chapter, IntechOpen shall have absolute discretion in addressing any such infringement which is likely to affect IntechOpen's rights under this Publication Agreement, including issuing and conducting proceedings against the suspected infringer.
\\n\\n7. MISCELLANEOUS
\\n\\n7.1 Further Assurance: The Corresponding Author shall and will ensure that any relevant third party (including any Co-Author) shall, execute and deliver whatever further documents or deeds and perform such acts as IntechOpen reasonably requires from time to time for the purpose of giving IntechOpen the full benefit of the provisions of this Publication Agreement.
\\n\\n7.2 Third Party Rights: A person who is not a party to this Publication Agreement may not enforce any of its provisions under the Contracts (Rights of Third Parties) Act 1999.
\\n\\n7.3 Entire Agreement: This Publication Agreement constitutes the entire agreement between the parties in relation to its subject matter. It replaces and extinguishes all prior agreements, draft agreements, arrangements, collateral warranties, collateral contracts, statements, assurances, representations and undertakings of any nature made by or on behalf of the parties, whether oral or written, in relation to that subject matter. Each party acknowledges that in entering into this Publication Agreement it has not relied upon any oral or written statements, collateral or other warranties, assurances, representations or undertakings which were made by or on behalf of the other party in relation to the subject matter of this Publication Agreement at any time before its signature (together "Pre-Contractual Statements"), other than those which are set out in this Publication Agreement. Each party hereby waives all rights and remedies which might otherwise be available to it in relation to such Pre-Contractual Statements. Nothing in this clause shall exclude or restrict the liability of either party arising out of its pre-contract fraudulent misrepresentation or fraudulent concealment.
\\n\\n7.4 Waiver: No failure or delay by a party to exercise any right or remedy provided under this Publication Agreement or by law shall constitute a waiver of that or any other right or remedy, nor shall it preclude or restrict the further exercise of that or any other right or remedy. No single or partial exercise of such right or remedy shall preclude or restrict the further exercise of that or any other right or remedy.
\\n\\n7.5 Variation: No variation of this Publication Agreement shall be effective unless it is in writing and signed by the parties (or their duly authorized representatives).
\\n\\n7.6 Severance: If any provision or part-provision of this Publication Agreement is or becomes invalid, illegal or unenforceable, it shall be deemed modified to the minimum extent necessary to make it valid, legal and enforceable. If such modification is not possible, the relevant provision or part-provision shall be deemed deleted.
\\n\\nAny modification to or deletion of a provision or part-provision under this clause shall not affect the validity and enforceability of the rest of this Publication Agreement.
\\n\\n7.7 No partnership: Nothing in this Publication Agreement is intended to, or shall be deemed to, establish or create any partnership or joint venture or the relationship of principal and agent or employer and employee between IntechOpen and the Corresponding Author or any Co-Author, nor authorize any party to make or enter into any commitments for or on behalf of any other party.
\\n\\n7.8 Governing law: This Publication Agreement and any dispute or claim (including non-contractual disputes or claims) arising out of or in connection with it or its subject matter or formation shall be governed by and construed in accordance with the law of England and Wales. The parties submit to the exclusive jurisdiction of the English courts to settle any dispute or claim arising out of or in connection with this Publication Agreement (including any non-contractual disputes or claims).
\\n\\nLast updated: 2020-11-27
\\n\\n\\n\\n
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The Corresponding Author (acting on behalf of all Authors) and INTECHOPEN LIMITED, incorporated and registered in England and Wales with company number 11086078 and a registered office at 5 Princes Gate Court, London, United Kingdom, SW7 2QJ conclude the following Agreement regarding the publication of a Book Chapter:
\n\n1. DEFINITIONS
\n\nCorresponding Author: The Author of the Chapter who serves as a Signatory to this Agreement. The Corresponding Author acts on behalf of any other Co-Author.
\n\nCo-Author: All other Authors of the Chapter besides the Corresponding Author.
\n\nIntechOpen: IntechOpen Ltd., the Publisher of the Book.
\n\nBook: The publication as a collection of chapters compiled by IntechOpen including the Chapter. Chapter: The original literary work created by Corresponding Author and any Co-Author that is the subject of this Agreement.
\n\n2. CORRESPONDING AUTHOR'S GRANT OF RIGHTS
\n\n2.1 Subject to the following Article, the Corresponding Author grants and shall ensure that each Co-Author grants, to IntechOpen, during the full term of copyright and any extensions or renewals of that term the following:
\n\nThe aforementioned licenses shall survive the expiry or termination of this Agreement for any reason.
\n\n2.2 The Corresponding Author (on their own behalf and on behalf of any Co-Author) reserves the following rights to the Chapter but agrees not to exercise them in such a way as to adversely affect IntechOpen's ability to utilize the full benefit of this Publication Agreement: (i) reprographic rights worldwide, other than those which subsist in the typographical arrangement of the Chapter as published by IntechOpen; and (ii) public lending rights arising under the Public Lending Right Act 1979, as amended from time to time, and any similar rights arising in any part of the world.
\n\nThe Corresponding Author confirms that they (and any Co-Author) are and will remain a member of any applicable licensing and collecting society and any successor to that body responsible for administering royalties for the reprographic reproduction of copyright works.
\n\nSubject to the license granted above, copyright in the Chapter and all versions of it created during IntechOpen's editing process (including the published version) is retained by the Corresponding Author and any Co-Author.
\n\nSubject to the license granted above, the Corresponding Author and any Co-Author retains patent, trademark and other intellectual property rights to the Chapter.
\n\n2.3 All rights granted to IntechOpen in this Article are assignable, sublicensable or otherwise transferrable to third parties without the Corresponding Author's or any Co-Author’s specific approval.
\n\n2.4 The Corresponding Author (on their own behalf and on behalf of each Co-Author) will not assert any rights under the Copyright, Designs and Patents Act 1988 to object to derogatory treatment of the Chapter as a consequence of IntechOpen's changes to the Chapter arising from translation of it, corrections and edits for house style, removal of problematic material and other reasonable edits.
\n\n3. CORRESPONDING AUTHOR'S DUTIES
\n\n3.1 When distributing or re-publishing the Chapter, the Corresponding Author agrees to credit the Book in which the Chapter has been published as the source of first publication, as well as IntechOpen. The Corresponding Author warrants that each Co-Author will also credit the Book in which the Chapter has been published as the source of first publication, as well as IntechOpen, when they are distributing or re-publishing the Chapter.
\n\n3.2 When submitting the Chapter, the Corresponding Author agrees to:
\n\nThe Corresponding Author will be held responsible for the payment of the Open Access Publishing Fees.
\n\nAll payments shall be due 30 days from the date of the issued invoice. The Corresponding Author or the payer on the Corresponding Author's and Co-Authors' behalf will bear all banking and similar charges incurred.
\n\n3.3 The Corresponding Author shall obtain in writing all consents necessary for the reproduction of any material in which a third-party right exists, including quotations, photographs and illustrations, in all editions of the Chapter worldwide for the full term of the above licenses, and shall provide to IntechOpen upon request the original copies of such consents for inspection (at IntechOpen's option) or photocopies of such consents.
\n\nThe Corresponding Author shall obtain written informed consent for publication from people who might recognize themselves or be identified by others (e.g. from case reports or photographs).
\n\n3.4 The Corresponding Author and any Co-Author shall respect confidentiality rights during and after the termination of this Agreement. The information contained in all correspondence and documents as part of the publishing activity between IntechOpen and the Corresponding Author and any Co-Author are confidential and are intended only for the recipient. The contents may not be disclosed publicly and are not intended for unauthorized use or distribution. Any use, disclosure, copying, or distribution is prohibited and may be unlawful.
\n\n4. CORRESPONDING AUTHOR'S WARRANTY
\n\n4.1 The Corresponding Author represents and warrants that the Chapter does not and will not breach any applicable law or the rights of any third party and, specifically, that the Chapter contains no matter that is defamatory or that infringes any literary or proprietary rights, intellectual property rights, or any rights of privacy. The Corresponding Author warrants and represents that: (i) the Chapter is the original work of themselves and any Co-Author and is not copied wholly or substantially from any other work or material or any other source; (ii) the Chapter has not been formally published in any other peer-reviewed journal or in a book or edited collection, and is not under consideration for any such publication; (iii) they themselves and any Co-Author are qualifying persons under section 154 of the Copyright, Designs and Patents Act 1988; (iv) they themselves and any Co-Author have not assigned and will not during the term of this Publication Agreement purport to assign any of the rights granted to IntechOpen under this Publication Agreement; and (v) the rights granted by this Publication Agreement are free from any security interest, option, mortgage, charge or lien.
\n\nThe Corresponding Author also warrants and represents that: (i) they have the full power to enter into this Publication Agreement on their own behalf and on behalf of each Co-Author; and (ii) they have the necessary rights and/or title in and to the Chapter to grant IntechOpen, on behalf of themselves and any Co-Author, the rights and licenses expressed to be granted in this Publication Agreement. If the Chapter was prepared jointly by the Corresponding Author and any Co-Author, the Corresponding Author warrants and represents that: (i) each Co-Author agrees to the submission, license and publication of the Chapter on the terms of this Publication Agreement; and (ii) they have the authority to enter into this Publication Agreement on behalf of and bind each Co-Author. The Corresponding Author shall: (i) ensure each Co-Author complies with all relevant provisions of this Publication Agreement, including those relating to confidentiality, performance and standards, as if a party to this Publication Agreement; and (ii) remain primarily liable for all acts and/or omissions of each such Co-Author.
\n\nThe Corresponding Author agrees to indemnify and hold IntechOpen harmless against all liabilities, costs, expenses, damages and losses and all reasonable legal costs and expenses suffered or incurred by IntechOpen arising out of or in connection with any breach of the aforementioned representations and warranties. This indemnity shall not cover IntechOpen to the extent that a claim under it results from IntechOpen's negligence or willful misconduct.
\n\n4.2 Nothing in this Publication Agreement shall have the effect of excluding or limiting any liability for death or personal injury caused by negligence or any other liability that cannot be excluded or limited by applicable law.
\n\n5. TERMINATION
\n\n5.1 IntechOpen has a right to terminate this Publication Agreement for quality, program, technical or other reasons with immediate effect, including without limitation (i) if the Corresponding Author or any Co-Author commits a material breach of this Publication Agreement; (ii) if the Corresponding Author or any Co-Author (being an individual) is the subject of a bankruptcy petition, application or order; or (iii) if the Corresponding Author or any Co-Author (being a company) commences negotiations with all or any class of its creditors with a view to rescheduling any of its debts, or makes a proposal for or enters into any compromise or arrangement with any of its creditors.
\n\nIn case of termination, IntechOpen will notify the Corresponding Author, in writing, of the decision.
\n\n6. INTECHOPEN’S DUTIES AND RIGHTS
\n\n6.1 Unless prevented from doing so by events outside its reasonable control, IntechOpen, in its discretion, agrees to publish the Chapter attributing it to the Corresponding Author and any Co-Author.
\n\n6.2 IntechOpen has the right to use the Corresponding Author’s and any Co-Author’s names and likeness in connection with scientific dissemination, retrieval, archiving, web hosting and promotion and marketing of the Chapter and has the right to contact the Corresponding Author and any Co-Author until the Chapter is publicly available on any platform owned and/or operated by IntechOpen.
\n\n6.3 IntechOpen is granted the authority to enforce the rights from this Publication Agreement, on behalf of the Corresponding Author and any Co-Author, against third parties (for example in cases of plagiarism or copyright infringements). In respect of any such infringement or suspected infringement of the copyright in the Chapter, IntechOpen shall have absolute discretion in addressing any such infringement which is likely to affect IntechOpen's rights under this Publication Agreement, including issuing and conducting proceedings against the suspected infringer.
\n\n7. MISCELLANEOUS
\n\n7.1 Further Assurance: The Corresponding Author shall and will ensure that any relevant third party (including any Co-Author) shall, execute and deliver whatever further documents or deeds and perform such acts as IntechOpen reasonably requires from time to time for the purpose of giving IntechOpen the full benefit of the provisions of this Publication Agreement.
\n\n7.2 Third Party Rights: A person who is not a party to this Publication Agreement may not enforce any of its provisions under the Contracts (Rights of Third Parties) Act 1999.
\n\n7.3 Entire Agreement: This Publication Agreement constitutes the entire agreement between the parties in relation to its subject matter. It replaces and extinguishes all prior agreements, draft agreements, arrangements, collateral warranties, collateral contracts, statements, assurances, representations and undertakings of any nature made by or on behalf of the parties, whether oral or written, in relation to that subject matter. Each party acknowledges that in entering into this Publication Agreement it has not relied upon any oral or written statements, collateral or other warranties, assurances, representations or undertakings which were made by or on behalf of the other party in relation to the subject matter of this Publication Agreement at any time before its signature (together "Pre-Contractual Statements"), other than those which are set out in this Publication Agreement. Each party hereby waives all rights and remedies which might otherwise be available to it in relation to such Pre-Contractual Statements. Nothing in this clause shall exclude or restrict the liability of either party arising out of its pre-contract fraudulent misrepresentation or fraudulent concealment.
\n\n7.4 Waiver: No failure or delay by a party to exercise any right or remedy provided under this Publication Agreement or by law shall constitute a waiver of that or any other right or remedy, nor shall it preclude or restrict the further exercise of that or any other right or remedy. No single or partial exercise of such right or remedy shall preclude or restrict the further exercise of that or any other right or remedy.
\n\n7.5 Variation: No variation of this Publication Agreement shall be effective unless it is in writing and signed by the parties (or their duly authorized representatives).
\n\n7.6 Severance: If any provision or part-provision of this Publication Agreement is or becomes invalid, illegal or unenforceable, it shall be deemed modified to the minimum extent necessary to make it valid, legal and enforceable. If such modification is not possible, the relevant provision or part-provision shall be deemed deleted.
\n\nAny modification to or deletion of a provision or part-provision under this clause shall not affect the validity and enforceability of the rest of this Publication Agreement.
\n\n7.7 No partnership: Nothing in this Publication Agreement is intended to, or shall be deemed to, establish or create any partnership or joint venture or the relationship of principal and agent or employer and employee between IntechOpen and the Corresponding Author or any Co-Author, nor authorize any party to make or enter into any commitments for or on behalf of any other party.
\n\n7.8 Governing law: This Publication Agreement and any dispute or claim (including non-contractual disputes or claims) arising out of or in connection with it or its subject matter or formation shall be governed by and construed in accordance with the law of England and Wales. The parties submit to the exclusive jurisdiction of the English courts to settle any dispute or claim arising out of or in connection with this Publication Agreement (including any non-contractual disputes or claims).
\n\nLast updated: 2020-11-27
\n\n\n\n
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I am also a member of the team in charge for the supervision of Ph.D. students in the fields of development of silicon based planar waveguide sensor devices, study of inelastic electron tunnelling in planar tunnelling nanostructures for sensing applications and development of organotellurium(IV) compounds for semiconductor applications. I am a specialist in data analysis techniques and nanosurface structure. I have served as the editor for many books, been a member of the editorial board in science journals, have published many papers and hold many patents.",institutionString:null,institution:{name:"Sheffield Hallam University",country:{name:"United Kingdom"}}},{id:"54525",title:"Prof.",name:"Abdul Latif",middleName:null,surname:"Ahmad",slug:"abdul-latif-ahmad",fullName:"Abdul Latif Ahmad",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"20567",title:"Prof.",name:"Ado",middleName:null,surname:"Jorio",slug:"ado-jorio",fullName:"Ado Jorio",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Universidade Federal de Minas Gerais",country:{name:"Brazil"}}},{id:"47940",title:"Dr.",name:"Alberto",middleName:null,surname:"Mantovani",slug:"alberto-mantovani",fullName:"Alberto Mantovani",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"12392",title:"Mr.",name:"Alex",middleName:null,surname:"Lazinica",slug:"alex-lazinica",fullName:"Alex Lazinica",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/12392/images/7282_n.png",biography:"Alex Lazinica is the founder and CEO of IntechOpen. 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