Deregulation of typical SOX genes and their clinical relevance in cancers.
\r\n\tThe aim of this book will be to describe the most common forms of dermatitis putting emphasis on the pathophysiology, clinical appearance and diagnostic of each disease. We also will aim to describe the therapeutic management and new therapeutic approaches of each condition that are currently being studied and are supposed to be used in the near future.
",isbn:null,printIsbn:"979-953-307-X-X",pdfIsbn:null,doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,hash:"278931ae110500350d8b64805c70f193",bookSignature:"Dr. Eleni Papakonstantinou",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/7934.jpg",keywords:"Atopic eczema, Interleukin, Topical corticosteroids, Hand eczema, Blisters, Pruritus, Irritant contact dermatitis, Allergic contact dermatitis, Discoid eczema, Sebaceous glands, Inflammatory dermatitis, Facial rash",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:0,numberOfDimensionsCitations:0,numberOfTotalCitations:0,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"February 5th 2019",dateEndSecondStepPublish:"March 19th 2019",dateEndThirdStepPublish:"May 18th 2019",dateEndFourthStepPublish:"August 6th 2019",dateEndFifthStepPublish:"October 5th 2019",remainingDaysToSecondStep:"2 years",secondStepPassed:!0,currentStepOfPublishingProcess:5,editedByType:null,kuFlag:!1,biosketch:null,coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"203520",title:"Dr.",name:"Eleni",middleName:null,surname:"Papakonstantinou",slug:"eleni-papakonstantinou",fullName:"Eleni Papakonstantinou",profilePictureURL:"https://mts.intechopen.com/storage/users/203520/images/system/203520.jpg",biography:"Dr. med. Eleni Papakonstantinou is a Doctor of Medicine graduate and board certified Dermatologist-Venereologist. She studied medicine at the Aristotle University of Thessaloniki, in Greece and she continued with her dermatology specialty in Germany (2012-2017) at the University of Magdeburg and Hannover Medical School, where she completed her dissertation in 2016 with research work on atopic dermatitis in children. During this time she gained wide experience in the whole dermatological field with special focus on the diagnosis and treatment of chronic inflammatory skin diseases and also the prevention and treatment of melanocytic and non-melanocytic skin tumors. Her research interests were beside atopic dermatitis and pruritus also the pathophysiology of blistering dermatoses. In addition to lectures at german and international congresses, she has published several articles in german and international journals and her work has been awarded with various prizes (poster prize of the German Dermatological Society for the project: 'Bullous pemphigoid and comorbidities' (DDG Leipzig 2016), 'Michael Hornstein Memorial Scholarship' (EADV Athens 2016), travel grant (EAACI Vienna 2016). Since 2017, she works as a specialist dermatologist in private practice in Dortmund, in Germany. Parallel she co-administrates an international dermatologic network, Wikiderm International and she writes a dermatology public guide for patients, as she is convinced that evidence-based knowledge has to be shared not only with colleagues but also with patients.",institutionString:"Private Practice, Dermatology and Venereology",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"0",institution:null}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"16",title:"Medicine",slug:"medicine"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"270941",firstName:"Sandra",lastName:"Maljavac",middleName:null,title:"Ms.",imageUrl:"https://mts.intechopen.com/storage/users/270941/images/7824_n.jpg",email:"sandra.m@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:"6550",title:"Cohort Studies in Health Sciences",subtitle:null,isOpenForSubmission:!1,hash:"01df5aba4fff1a84b37a2fdafa809660",slug:"cohort-studies-in-health-sciences",bookSignature:"R. Mauricio Barría",coverURL:"https://cdn.intechopen.com/books/images_new/6550.jpg",editedByType:"Edited by",editors:[{id:"88861",title:"Dr.",name:"R. Mauricio",surname:"Barría",slug:"r.-mauricio-barria",fullName:"R. Mauricio Barría"}],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:"58186",title:"SOX Genes and Cancer",doi:"10.5772/intechopen.72433",slug:"sox-genes-and-cancer",body:'\nCancer is caused by alterations in the control and activity of genes that in turn regulate cell growth and differentiation, leading to abnormal cell proliferation [1]. It is a multi-step process leading to profound metabolic and behavioral changes in a cell. The hallmarks of cancer include sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, activating invasion and metastasis, genome instability, inflammation, reprogramming of energy metabolism and evading immune destruction [2]. Most human malignancies are caused by somatic alterations within the cancer genome either through gain-of-function mutations in proto-oncogenes or loss-of-function mutations in tumor suppressor genes. Remarkable progress in cancer research has been made in the last 10 years. However, the detailed molecular mechanisms of cancer remain largely un-elucidated.
\nA transcription factor (TF) might be defined as any molecule participating, alone or as part of a complex, in the binding to a gene’s enhancer response element or promoter, with the ultimate outcome being the up- or down-regulation of expression of that gene [3]. TFs are key genes involved in the regulation of gene expression. The human genome encodes over 2000 different TF-coding genes, many of which are expressed in a cell type-specific manner to coordinate gene expression programs underlying a vast array of cellular processes [4]. TFs are commonly deregulated in the pathogenesis of human cancer. For instance, TP53 and MYC, which encode the TFs p53 (tumor suppressor protein 53) and c-Myc respectively, are among the most frequently changed genes across all cancers [5, 6].
\nSex determining region Y (SRY)-related high-mobility group (HMG) box (SOX) family comprises more than 20 members, which have been shown to involve in regulation of many biological processes such as embryonic development, cell-fate decision, lineage commitment, determination and differentiation [7, 8, 9]. This transcription factor family is divided into 10 subgroups based on the level of amino acid conservation within the HMG box and the presence of other motifs. In this review, we discuss the current understanding on the association between SOX genes and cancer. We particularly emphasize the role of several representative SOX subgroup proteins (SOX2, SOX4, SOX9 and SOX11) in cancer initiation and development.
\nSOX genes are part of a larger family of HMG proteins. SOX proteins bind similar DNA motifs [(A/T)(A/T)CAA(A/T)G] through their HMG domain, which is highly conserved among SOX gene family. Due to the low affinity between SOX proteins and DNA, cofactors are usually required to stabilize their interactions with DNA [9]. Based on the degree of conservation of their HMG-box and the presence of defined HMG-independent structural domains, SOX proteins are organized into 10 subfamilies: SOXA-SOXJ. For example, the SOXA group consists only of SRY; SOXB group comprises of two subgroups (SOXB1 and SOXB2); SOXB1 includes SOX1, SOX2, and SOX3, whereas SOXB2 proteins include SOX14 and SOX21; SOXC group includes SOX4, SOX11, and SOX12; SOXD group includes SOX5, SOX6, and SOX13; SOXE group includes SOX8, SOX9, and SOX10; and SOXF group includes SOX7, SOX17, and SOX18; SOXG (SOX15) and SOXH (SOX30) proteins are structurally related to SOXB1 and SOXD proteins, respectively [10, 11, 12, 13]. Individual members within the same SOX group share similar biochemical properties and thus have overlapping biological functions. However, SOX proteins from different groups have distinct biological functions [9]. SOX gene family has been demonstrated to play important roles in various biological processes including, but not limited to development, tissue homeostasis and regeneration, reprogramming [9, 14, 15, 16].
\nIn vertebrates, SOX genes are well known regulators of numerous developmental processes. Accumulating evidences have shown that SOX proteins are co-expressed in various developing tissues in an overlapping manner and show functional redundancy. The transcriptional activities of SOX proteins are regulated via three major pathways: (1) the expression levels of SOX proteins are regulated in specific cell types and tissues with precise timing (2) SOX proteins are regulated by posttranslational modification (3) the partners of SOX proteins are regulated to not only influence the specific recognition of the binding sites of SOX-partner complexes on the target genes, but also determine transcription activities and significantly enhance the activation/repression potential. For instance, SOXB1 and SOXB2 proteins are important for the development of the central nervous system and foregut system [17, 18, 19]. SOXD proteins are important for the development of cartilage tissues. In mouse embryos, SOX5, SOX6, SOX9 and collagen II are co-expressed in all cartilaginous sites at around 12.5 dpc. After 17.5 dpc, the chondrocytes become hypertrophic in the growth plate cartilages, the expression of above SOX genes are inhibited and disappear in the hypertrophic chondrocytes [20]. The expression patterns of SOXE genes are important for the development of reproductive system. SOX8, SOX9 and SOX10 are expressed in the overlapping temporal and spatial expression patterns during gonads development, indicating the overlapping roles of these genes in mammalian sex determination and subsequent male sexual development [21, 22]. The members of SOXF group play important roles in the development of cardio-vascular system and extraembryonic endoderm. SOX7 and SOX17 are crucial endoderm lineage-determining regulators and are involved in the later stage of extraembryonic differentiation [23, 24, 25].
\nSOX2 is an important marker for stem and progenitor cell populations in many adult tissues. SOX2 positive cells have been detected in progenitors of various tissues such as adult retina, trachea, tongue epithelium, dermal papilla of the hair follicle, adult testes, forestomach, glandular stomach, anus, cervix, esophagus, lens and dental epithelium [26, 27, 28, 29, 30]. Conditional SOX2 deletion significantly influences cell proliferation. In trachea, SOX2 expression is required to sustain tissue homeostasis by controlling the number of proliferating epithelial cells as well as the proportion of basal, ciliated and Clara cells [28]. However, whether SOX2 expression is required for homeostasis in other adult tissues needs further investigation. In addition to maintaining tissue homeostasis, SOX2 plays an important role for tissue regeneration and repair. For instance, the basal stem cells could repair the damaged tracheal epithelium in mice within 7–10 days. The number of basal stem cells was significantly lower in the trachea with SOX2-deficience. Therefore, the injured trachea was unable to undergo efficient tissue repair. SOX2 is also important for peripheral nerve regeneration. When there is injury, mature adult Schwann cells dedifferentiate to a progenitor cell-like state by re-expressing Sox2 [31].
\nThe expression of four transcription factors, Oct4/Sox2/cMyc/Klf4, was able to convert differentiated cells to pluripotent cells [32]. SOX2 is indispensable for the success of this reprogramming process. However, the biological function of SOX2 seems to be closely correlated with its levels. SOX2 overexpression can promote differentiation and reduce the reprogramming efficiency of neural progenitor cells. In addition to SOX2, SOX1 and SOX3, which are also members of SOXB1 family, can replace SOX2 during the reprogramming process. SOX15 or SOX18 was also able to generate the pluripotent cells but less efficient than SOXB1 family [33].
\nMany members of SOX gene family have been demonstrated to be closely correlated with tumorigenesis [34, 35]. Below, we discuss the involvement of several SOX genes that have been most extensively studied in human malignancies so far. \nTable 1\n listed these SOX genes and their clinical relevance in cancers.
\nSOX genes | \nDeregulation | \nPotential clinical significance | \nReference | \n
---|---|---|---|
SOX2 | \nLung, esophagus and oral cancer↑ | \nPromote tumor progression | \n[36] | \n
\n | Melanoma↑ | \nEnhance the self-renewal capacity of cancer stem cells | \n[37] | \n
\n | Glioblastoma ↑ | \nAssociated with tumor aggressiveness and worse prognosis | \n[38, 39] | \n
\n | Gastric cancer↓ | \nPromote tumor progression | \n[40] | \n
SOX4 | \nOral cancer ↑ | \nPromote tumor initiation and development | \n[41, 42] | \n
\n | Prostate cancer↑ | \nAssociated with worse prognosis | \n[43, 44] | \n
\n | Leukemia↑ | \nPromote tumor progression | \n[45] | \n
\n | Primary gallbladder carcinoma↓ | \nAssociated with worse prognosis | \n[46] | \n
SOX9 | \nPapillary thyroid cancer↑ | \nPromote tumor progression | \n[47] | \n
\n | Breast cancer ↑ | \nAssociated with chemoresistance | \n[48] | \n
\n | Gastric cancer ↑ | \nPromote tumorigenesis | \n[49] | \n
\n | Cervical carcinoma↓ | \nPromote tumor progression | \n[50] | \n
SOX11 | \nBreast cancer↑ | \nPromote tumor progression | \n[51] | \n
\n | Mantle cell lymphoma↑ | \nPromote tumor progression | \n[52, 53, 54] | \n
\n | Epithelial ovarian cancer↓ | \nAssociated with worse prognosis | \n[55] | \n
\n | Gastric cancer↓ | \nAssociated with worse prognosis | \n\n |
Deregulation of typical SOX genes and their clinical relevance in cancers.
The SOX2 gene is located on chromosome 3q26.3–q27, it belongs to the SOXB1 group and encodes for 317 amino acids [56, 57]. SOX2 is one of the key transcription factors for induced pluripotent stem cells establishment, stem cell maintenance, and lineage fate determinant. Deregulation of SOX2 has been associated with various diseases such as anophthalmia-esophageal-genital (AEG) syndrome and bilateral anaphthalmia/microphthalmia, anterior pituitary hypoplasia, hypogonadotropic hypogonadism hypothalamic hamartoma, sensorineural hearing loss, and esophageal atresia [58, 59]. In addition to the above diseases, increasing evidence has revealed there is a strong relationship between SOX2 and cancer. Cancer stem cells are key drivers of tumorigenesis and may be responsible for tumor initiation, growth and spawning metastases. SOX2-postive cancer stem cells were able to drive tumor initiation and therapy resistance in various types of cancers, indicating that it is a common phenomenon that SOX2 might mastermind the tumor initiating potential of cancer cells [60].
\nSOX2 silencing significantly suppresses the tumorigenicity of glioblastoma tumor-initiating cells (TICs) [38]. Importantly, high levels of SOX2 have been associated with tumor aggressiveness and worse prognosis in glioblastoma, indicating targeting SOX2 might be an effective strategy for the treatment of glioblastoma [39]. SOX2 is also amplified in squamous cell carcinomas of the lung, the esophagus, and the oral cavity. SOX2 amplification and SOX2 protein overexpression might be responsible for the tumor initiation and progression in squamous cell carcinomas derived from different organ sites [36]. SOX2 was found to be critical for maintaining the sphere-forming capacity of DU145 prostate cancer stem cells (PCSCs). It promoted the self-renewal of the PCSC population by regulating downstream of EGFR signaling [61]. Similarly, SOX2 was highly expressed in melanoma stem cells. SOX2 suppression remarkably inhibited self-renewal in melanoma spheres and in putative melanoma stem cells with high aldehyde dehydrogenase activity. On the contrary, SOX2 overexpression in melanoma cells enhanced their self-renewal in vitro. Animal models showed that SOX2 was critical for tumor initiation and continuous tumor growth. These data suggested that SOX2 was an important factor for self-renewal and tumorigenicity of melanoma-initiating cells [37].
\nThere are conflicting results regarding the role of SOX2 in gastric cancer. For instance, SOX2 was dispensable for self-renewal of gastric stem cells. In addition, loss of SOX2 promoted tumor formation in Apc-deficient gastric cells in vivo and in vitro by inducing Tcf/Lef-dependent transcription and upregulating intestinal metaplasia-associated genes, suggesting SOX2 acted as a tumor suppressor in gastric cancer [62]. In addition, the expression level of SOX2 expression was frequently downregulated in gastric cancers. Ectopic expression of SOX2 inhibited cell growth through cell-cycle arrest and apoptosis in gastric cells. Moreover, the gastric cancers with SOX2 methylation had a significantly worse survival than those without this methylation [40]. However, SOX2 was found to enhance the tumorigenicity and chemoresistance of cancer stem-like cells derived from gastric cancer, suggesting SOX2 plays an oncogenic role in gastric cancer [63]. SOX2 inhibition reduced cell proliferation and migration, promoted apoptosis and induced changes in cell cycle in vitro as well as suppressed the tumorigenic potential of gastric cancer cells in vivo [64]. The contradictory findings regarding the role of SOX2 in gastric cancer further support the fact that the outcome of SOX2 activation is closely correlated with tumor origin and cellular context. Future experiments with lineage tracing and gain- and loss-of-function mouse models are required to clarify the role of SOX2 in gastric cancer. SOX2 is frequently regarded as an oncogene in lung SCCs, but previous studies indicated that higher SOX2 levels predicted favorable outcome in lung SCCs [65, 66]. The underlying reasons accounting for the contradictory role of SOX2 in lung SCCs warrant further exploration.
\nSOX4, one of group-C SOX genes, plays an important role in the regulation of transcription during developmental processes such as embryonic cardiac development, nervous system development, osteoblastic differentiation, and thymocyte development [67]. SOX4 gene is located on 6p22.3 and encodes a protein of 474 amino acids with three distinguishable domains: an HMG box, a glycine-rich region, and a serine-rich region. SOX4 is considered as one of the members of epithelial-mesenchymal transition (EMT)-transcriptional inducers. EMT is a key developmental program that is often activated during organismal development and the progression of epithelial tumors to metastatic cancers and may promote therapeutic resistance, indicating that SOX4 might be a potential therapeutic target for cancer treatment.
\nRecently, multiple studies have reported altered expression of SOX4 in human cancers. Our group demonstrated that SOX4 was significantly upregulated when oral lichen planus (OLP) progressed to oral squamous cell carcinoma (OSCC). In addition, downregulation of SOX4 suppressed the proliferation, migration and invasion of oral cancer cells. These findings suggest that SOX4 might play a critical role in the progression of OLP to OSCC [41]. Similarly, the expression level of SOX4 was remarkably overexpressed in OSCC tissues compared to adjacent normal mucosa. Also SOX4 was important for maintaining the oncogenic phenotypes of oral cancer cells by promoting cell survival and increasing chemoradioresistance [68]. High SOX4 expression levels were positively correlated with adverse clinicopathological parameters of OSCC, indicating that SOX4 might be significantly associated with poor prognosis of OSCC [42]. In addition to OSCC, SOX4 plays an oncogenic role in other malignancies. SOX4 was overexpressed in prostate cancer (PCa) and higher SOX4 levels predicted unfavorable prognosis [43]. Upregulation of SOX4 in PCa was mechanistically induced by PTEN loss due to the activation of PI3K-AKT–mTOR signaling [44]. SOX4 was able to directly regulate the expression of the epigenetic modifier Ezh2 in breast cancer, indicating SOX4 might be indispensable for tumor progression [69]. SOX4 might combine with oncogenic Ras together to promote tumorigenesis in vivo [70]. SOX4 was a direct target of C/EBPα and SOX4 suppression reduced the self-renewal of leukemic cells and restored their differentiation, indicating that SOX4 overexpression resulting from inactivation of C/EBPα promoted leukemia development [45].
\nHowever, it should be noted that SOX4 might also function as a tumor suppressor in tumorigenesis. For instance, SOX4 was indispensable for p53 activation in response to DNA damage. In addition, SOX4 could stabilize p53 protein by inhibiting Mdm2-mediated p53 ubiquitination and degradation, suggesting that SOX4 might suppress the progression DNA damage response-associated cancer [71]. In primary gallbladder carcinoma (PGC), SOX4 upregulation was significantly associated with favorable clinical parameters. In addition, SOX4 overexpression predicted better survival [46]. The expression level of SOX4 was significantly reduced in metastatic melanoma compared with that in dysplastic nevi and primary melanoma. In addition, SOX4 suppression promoted the migration and invasion of melanoma cells in an NF-κB p50-dependent manner [72]. Taken together, these findings indicate that the concrete role of SOX4 is closely associated with tumor microenvironment and might be tissue specific.
\nThe SOXE group comprises three members named SOX8, SOX9 and SOX10. SoxE proteins are important for the development of nervous system and neural crest progenitors. SOX9 was first described as a candidate gene for campomelic dysplasia (CD), a genetic condition that affects the development of the skeleton and reproductive system [73]. SOX9 has been demonstrated to greatly contribute to the organogenesis and development of many tissue types, such as the stomach, pancreas, tooth and craniofacial tissues. In addition, SOX9 is also a master regulator of cartilage development. It is indispensable for roles in the chondrogenic lineage progression of mesenchymal stem cells [74].
\nRecent studies have reported that SOX9 is aberrantly expressed in several types of cancers. Higher expression levels of SOX9 are correlated with a poor prognosis in patients with Chordoma. In addition, SOX9 downregulation suppressed the oncogenic behaviors of Chordoma cell in vitro, suggesting that SOX9 might function as an oncogene in Chordoma [75]. The expression of SOX9 was upregulated in papillary thyroid cancer (PTC) tissues and cell lines. Downregulation of SOX9 inhibited the proliferation, colony formation, migration, invasion, as well as EMT phenotype of PTC cells. ERα–RUNX2 complex activated the SOX9 expression and promoted endocrine resistance and metastases [76]. In breast cancer, up-regulation of SOX9 expression was closely correlated with tamoxifen (TAM) resistance [77]. The SOX9 levels were significantly higher in osteosarcoma tissues compared with the adjacent normal tissues. However, CLDN8 expression was significantly lower in osteosarcoma tissues. Knockdown of SOX9 inhibited the proliferation and migration but promoted the apoptosis of human osteosarcoma cell lines by downregulating CLDN8 [47]. FOXK2 was overexpressed in colorectal cancer tissues and associated with poor prognosis. In fact, FOXK2 was shown to be transcriptionally activated by SOX9, suggesting that SOX9-FOXK2 axis plays a critical role in the development of colorectal cancer [48]. SOX9 upregulation was associated with Helicobacter pylori infection, elevated carcinoembryonic antigen–related cell adhesion molecule 1 (CEACAM1) and gastrokine 1 (GKN1) inactivation. SOX9 knockdown suppressed the tumorigenic capacity of gastric cancer cells by inhibiting the downstream β-catenin signaling pathway [49]. Interestingly, SOX2 was expressed in highly proliferative but minimally invasive lung cancer cells; in contrast, cells with highly invasiveness capacity exhibited increased SOX9 expression but reduced SOX2 expression. The switch between SOX2 and SOX9 expression is epigenetically controlled and is important for determining cancer cell plasticity and metastatic progression [78]. Ectopic expression of SOX9 enhanced growth, invasion, and angiogenesis, whereas silencing of endogenous SOX9 markedly impaired tumor growth in prostate cancer. High SOX9 levels drove tumorigenesis by reactivating the Wnt/β − catenin signaling in a subset of prostate cancer, indicating WNT inhibition might beneficial for the effective treatment of prostate cancer [79]. SOX9 was critical for maintaining proliferation, self-renewal, and tumorigenicity in liver cancer stem cells (CSCs), and SOX9 overexpression was positively correlated with worse survival in HCC patients [80]. Although most studies showed that SOX9 played an oncogenic role in cancer development. Excopic expression of SOX9 was found to suppress cell growth, clonal capacity and colonosphere formation by inhibiting Wnt/ß-catenin signaling pathway and c-myc expression in colorectal cancer, suggesting that SOX9 might be a tumor suppressor in colorectal cancer [81]. SOX9 expression was progressively decreased in cervical carcinoma in situ and especially in invasive cervical carcinoma, compared with normal cervix tissue. Lastly, SOX9 overexpression in cervical carcinoma cells inhibited cell growth in vitro and tumor formation in vivo, and vice versa [50].
\nSimilar to SOX4, SOX11 is also a transcriptional activator that falls in the subgroup C. The Sox11 gene is mapped at chromosome 2p25.3 and the human SOX11 protein has 441 amino acids and 46.7 kDa molecular weight. It contains two functional domains: a HMG box DNA-binding domain and a transactivation domain [82]. SOX11 plays an important role in embryogenesis and tissue remodeling. Sox11 expression in most tissues is transient and thus little SOX11 expression has been found in terminally differentiated adult tissues. The role of SOX11 in the tumor microenvironment is cancer type-dependent.
\nOur recent studies have demonstrated that SOX11 plays a tumor promotion role in the development of head and neck cancer (HNC) [83]. We have employed a liquid chromatography–tandem mass spectrometry (LC–MS/MS) based approach to identify novel targets that may interact with SOX11 in HNC cells. The proteins that strongly bind to SOX11 in HNC cells may be important for maintaining the activity, stability and function of SOX11 or be regulated by SOX11. Gene ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis indicated that many potential SOX11-binding partners were associated with protein synthesis, cell metabolism and cell–cell adhesion. We speculated that upregulation of SOX11 might firstly activate the aggressive phenotypes of HNC cells by modulating the oncoprotein synthesis and altering cellular metabolism. Then it might further promote invasion and metastasis by affecting cell–cell adhesion system and formation and release of extracellular exosomes. One of the identified proteins, heat shock protein 90 alpha (HSP90α), was selected for further investigation. A biochemical interaction is validated between SOX11 and HSP90α through the co-immunoprecipitation with Western blot analysis. In addition, we have found that downregulation of HSP90α inhibits the malignant phenotypes of HNC cells and HSP90α upregulation is significantly associated with worse clinical outcome of HNC, suggesting HSP90α might serve as a potential prognostic biomarker and therapeutic target for HNC [84].
\nAberrant expression of SOX11 has been reported in other types of cancer. SOX11 levels were negatively correlated with the tumorigenic capacity of glioma-initiating cells [85]. Similarly, epithelial ovarian cancer patients with lower SOX11 suffered poorer recurrence-free survival [55]. SOX11 mRNA was downregulated in both gastric cancer (GC) cell lines and primary GC tissues. SOX11 gene promoter hyper-methylation was significantly associated with worse clinical parameters and poorer prognosis, suggesting that SOX11 might function as a tumor suppressor in gastric cancer [86]. The methylation frequency of serum SOX11 promoter in hepatocellular carcinoma (HCC) patients was significantly higher than that in chronic hepatitis B (CHB) patients. In addition, significant difference of serum SOX11 promoter methylation in HCC patients with vascular invasion and those without vascular invasion was found. Moreover, serum SOX11 promoter methylation was found to be more sensitive than serum alpha-fetoprotein for discriminating HCC from CHB [87]. Previous studies also reported SOX11 functions an oncogene during tumorigenesis. SOX11 upregulation can promote oncogenic behaviors of ductal carcinoma in situ (DCIS) cells both in vitro and in vivo, indicating that SOX11 contributes to the progression of ductal carcinoma in situ to invasive breast cancer [88]. Similarly, SOX11 is an important regulator of multiple basal-like breast cancers (BLBCs) phenotypes, including growth, migration, invasion, and expression of signature BLBC genes. In addition, high SOX11 expression was also found to be a poor prognostic indicator of survival in women with breast cancer [51].
\nSOX11 is expressed in virtually all aggressive mantle cell lymphoma (MCL) and at lower levels in a subgroup of Burkitt and acute lymphoblastic lymphomas, but not in other lymphoid neoplasms. The in vivo tumorigenic potential of SOX11 in a MCL xenograft model has been demonstrated, indicating that SOX11 functions as an oncogene in MCL [52]. In addition, SOX11 can block the terminal B-cell differentiation through direct positive regulation of PAX5 and promote angiogenesis in MCL through regulating platelet-derived growth factor A [52, 53]. Patients with SOX11-negative MCL exhibited more frequent non-nodal presentation and better survival compared with patients with SOX11-positive MCL [54]. However, there is contradictory result bout the association between SOX11 and survival in MCL. The overall survival was shorter in patients with SOX11-negative MCL compared to the patients with SOX11-positive MCL [89]. The relationship between SOX11 expression and survival of patients with MCL remains uncertain.
\nIn conclusion, recent studies have started to uncover important functions of the SOX genes as regulators of cancer initiation and progression. Our understanding of the role of SOX genes is, however, still at its infancy. Contradicting results regarding the role of SOX genes have been reported in different types of cancer. This suggests that the molecular functions of SOX genes in tumorigenesis need to be examined carefully in tissue-specific setting.
\nSOX | sex determining region Y box |
HMG | high mobility group |
MCL | mantle cell lymphoma |
HNC | head and neck cancer |
EMT | epithelial-mesenchymal transition |
TF | transcription factor |
HSP90α | heat shock protein 90 alpha |
KEGG | Kyoto Encyclopedia of Genes and Genomes |
LC–MS/MS | liquid chromatography–tandem mass spectrometry |
A vast majority of microorganisms in the world exist within biofilms, which are weak hydrogels that often form at various interfaces [1]. The biofilms consist of up to 98% water, and they are typically composed of polymicrobial aggregates that are encased in extrapolymeric substances (EPS) [2, 3, 4, 5]. Besides acting as a protective barrier, the EPS, which is made of DNA, proteins, and polysaccharides, aid in adhesion and water retention [4]. Pseudomonas aeruginosa is a well-known opportunistic human pathogen that is a common cause of hospital-acquired infections in burn wounds and eyes [6, 7, 8], and it is known to create persistent infection in cystic fibrosis (CF) patients [8, 9, 10, 11, 12, 13, 14, 15], having resistance to many classes of antibiotics [16, 17, 18]. PAO1, a medically-relevant strain of P. aeruginosa that is used in this study, acts as the model for biofilm-forming bacteria. To grow, bacterial cultures need water, a source of carbon, a source of nitrogen, and trace amounts of salts. The lysogeny broth (LB) is a complex and non-selective medium; many different types of bacteria can grow on non-selective medium. Lysogeny broth was formulated by Giusseppe Bertani in 1951 to optimize Shigella growth, but it has since become the standard for growing many bacterial cultures [19]. Lysogeny broth is composed of: 1% tryptone (source of amino acids); 0.5% yeast extract (source of vitamins, amino acids, nitrogen, and carbon); [20] and 1% NaCl (provides osmotic balance) [21]. Yeast extract is made from baker’s yeast (Saccharomyces cerevisiae) grown to a high concentration and then exposed to high temperature or osmotic shock, killing the yeast and starting autolysis of the cells through the yeast’s own enzymes [20, 22, 23]. The resulting extract solution is further filtered and spray-dried into a powder [20]. Proteins make up the most significant component of the powdered yeast extract at 62.5–73.8 wt% [20]. The average molecular weight of the yeast extract is 438 Da with 59.1% of the total under 300 Da [23]. Using additions of glycerol, glucose, sucrose, sodium chloride (NaCl), and silver nitrate (AgNO3), this paper investigates various modifications of the LB medium for their effects on the biofilm.
Both the biofilm’s structure and the cell-to-cell communication mechanism of the bacteria, known as quorum sensing (QS), are affected by their environment and the medium composition [24]. Quorum sensing controls additional properties that influence biofilm structures of bacteria, such as the production of extracellular DNA, proteins, mucus, and lipids [24, 25, 26]. When the growth environment becomes more viscous through the addition of glycerol, strains of Pseudomonas produced high-molecular-weight EPS and developed more robust biofilms [27]. The nutritional condition, such as the carbon source, influences the QS-associated swarming motility of P. aeruginosa [25]. While glucose supplementation limits bacterial motility, producing scattered, mushroom-like microcolonies, increasing the concentration of glucose from 0 to 2.7% caused an increase in the overall formation of biofilm [24, 25, 28, 29].
High osmolarity had a detrimental effect on biofilm of P. fluorescens, at roughly 0.4 Osm L−1 of either NaCl or sucrose, and the formation of biofilm decreased by four-fold as compared to lower concentrations of each component [30]. Similarly, mutant strains of P. aeruginosa that are found in CF patients transition from a non-mucoid to an alginate-overproducing state under osmotic stress that is induced by concentrations of 0.2–0.5 M NaCl (~1.2–3%) or 10% sucrose [31]. Silver has broad-spectrum antimicrobial effects on gram-negative bacteria that are well-documented [32, 33]. For instance, for concentrations of silver sulfadiazine that are lower than 0.16 μg mL−1, planktonic growth of P. aeruginosa was unchanged; however, at or above this threshold amount, the concentration of the planktonic bacteria was reduced by five orders of magnitude [34]. Silver sulfadiazine was even effective against mature biofilms above a threshold dose of 1 μg mL−1, and at concentrations of 10 μg mL−1, it can completely eradicate a pre-established biofilm of P. aeruginosa [34].
The following sections of this study cover three different methods of characterizing biofilms: (i) rheology to quantify the impact of the modified medium on the mechanical strength of the biofilm; (ii) ferning to characterize the mass transport of the salts through the polymer matrix of the biofilm during desiccation; and (iii) birefringence to observe self-assembly behavior of the solute in the biofilm.
The study of flow and deformation of matter (rheology) enables characterization of its structure and mechanical properties. Rheology is an especially valuable tool for understanding a vast range of “soft matter” that falls between liquid and solid phases [35]. Soft matter can be divided into four classes: (1) polymers, a long repeating chain of monomers which for biological samples include proteins, DNA, and cellulose; (2) colloids, a large category of materials that describe a suspension of one material into another medium such as aerosols, foams, emulsions, suspensions, and pastes; (3) amphiphiles, molecules with dual characteristics where one end of the molecule likes the solvent (hydrophilic), while the other end does not (hydrophobic) include surfactants that are amphiphiles at the air-water interface; and (4) liquid crystals, rod or disk shaped molecules that self-assemble to form orientation order but not positional order, resulting in an anisotropic fluid [35, 36].
Rheological techniques can characterize the strength and behavior of clinically relevant biological fluids such as mucus, blood plasma, and bacterial biofilm. More importantly, we can also use rheological measurements to drive the treatment of the biofluids toward a favorable clinical outcome. A rheological testing can quantify the viscous and elastic properties of a material. Two main modes of testing exist on a rotational rheometer: (1) steady-shear testing mode (Figure 1a–d), where the material is sheared between a stationary bottom plate and rotating top plate at a given stress or strain; and (2) the oscillation mode (Figure 1e–g), where the top plate oscillates back and forth at a set frequency and amplitude.
Shear and oscillatory rheological techniques. (a) In a two-plate steady-shear system where the top plate is moving, the velocity (v) of the fluid is dependent on the gap height (h). (b) Samples can exhibit several different flow behaviors of stress versus strain rate, including (1) ideally viscous Newtonian fluid; (2) shear-thinning fluid; (3) shear-thickening fluid; and (4) yield stress fluid. Yield stress materials have a minimum stress (τy) that must be overcome before flow starts. (c) The stress-strain curve demonstrates a material with (2) no yield stress and (4) a material with a clear yield stress calculated using the tangent crossover point method. (d) The viscosity-shear rate plot shows (1) Newtonian fluid; (2) shear-thinning fluid with no yield stress reaching zero-shear viscosity (η0); (3) shear-thickening fluid; and (4) shear-thinning fluid with yield stress. (e) In a two-plate system the top plate can oscillate back and forth at set amplitude or frequency for oscillatory rheology tests. The amplitude sweep test has constant frequency (ω0) with changing strain amplitude while the frequency sweep test has constant strain amplitude (γ0) with changing frequency. (f) During the amplitude sweep test, the strain values up to the limit of the strain where the G′ and G″ values are constant (γL) are called the linear viscoelastic region (LVR). The point where G″ crosses over G′ is called the flow point (γf) [72]. (g) In a frequency sweep, when G′ > G″ materials are said to be solid-like and when G″ > G′, materials are said to be liquid-like.
From the shear-flow sweep test, the stress (τ) versus shear rate (
Two main types of oscillatory testing exist (Figure 1e–g). An amplitude sweep test oscillates the upper plate back and forth at a set frequency (ω0) at increasing strains (Figure 1e). On the modulus (G′—elastic; G″—viscous) versus strain plot (Figure 1f), the plateau is the linear viscoelastic region (LVR), and the strain limit of the region is γL. A frequency sweep test oscillates at a set amplitude (γ0), which has been determined previously from the amplitude sweep test to be within the LVR, at increasing frequency (Figure 1e). The frequency sweep describes how the material acts when the material is stressed for different periods. For example, when Silly Putty is stressed quickly by throwing it on the floor, it bounces back, acting like a rigid solid. However, when the Silly Putty sits at rest and experiences low stress over a long period of time, it spreads out, acting like a viscous fluid. The frequency sweep (Figure 1g) reveals if the material is solid-like (G′ > G″) or liquid-like (G″ > G′) and if the behavior is frequency dependent (G′(ω), G″(ω)) or independent. Stable gels and suspensions are typically solid-like and frequency-independent, so these types of materials are called “gel-like.”
Previous studies on biofilm rheology using various techniques of rheological measurement have found the elastic modulus (G′) to range in order of magnitude from 10−2 to 104 Pa for bulk biofilms at solid-liquid interfaces using plate-on-plate methods, while the values of yield stress (τy) range in order of magnitude from 10−1 to 105 Pa [2, 37, 38, 39, 40, 41, 42]. The wide-ranging values of G′ and τy in the literature reflect the variability in the compositions of the biofilms, diversity of growth mediums, variability of growth conditions, and most importantly, natural variability of response of the microorganisms, even to the same medium and growth conditions. This chapter uses the techniques established in our previously published work on the non-destructive development and characterization of rheological properties of biofilms [43]. Using this non-destructive method, the measured values of elastic modulus and yield stress of PAO1 that were grown in standard LB medium were both between 0.1 and 10 Pa [43].
Biological fluids like tears, cervical mucus, and saliva are all shown to self-assemble into fractal-like patterns of crystallization when they are dried [44, 45]. A fractal is a structure that is made of smaller parts that resemble the bigger parts, with a high degree of organization and self-similarity. This structure can be characterized with a specific fractal dimension [44]. Fractal dimension is a measure of complexity of the fractal pattern [46]. Random nucleations of salts initiate the process of crystallization, where its growth is limited by the diffusion of salt through the polymer matrix (proteins or macromolecules) [47]. Therefore, the combined effects of ionic strength, osmolarity, and the size and concentration of macromolecules control the behavior of crystallization, where too little or too much of one factor can dramatically alter the pattern of crystallization [48, 49]. A typical crystallization of biosaline proceeds in the following manner: (i) salt nucleation initiates the process of crystallization; (ii) the nucleation point grows with some symmetry into a highly-branched structure whose growth is modified by the interaction of the salt with the biological matter; (iii) the branches do not overlap or merge [47, 50, 51]. The process of crystallization of biofluids is called “arborization,” “ferning,” or “dendritic growth” in various literature [45]. In this paper, the general formation of salt crystals will continue to be called crystallization, while the specific crystallization of the biofluids that result in fractal patterns will be called ferns.
The ferning patterns of the dried samples of tears and saliva have been used for years as a supplementary diagnostic tool [49, 52]. The ferning patterns in saliva and in tears exhibit different morphologies; saliva produces linear ferns with branching angles of 90°, while ferns from tears have more curvature with tightly packed branches with acute angles. Ferning patterns from tears and saliva are traditionally classified in a qualitative manner according to Rolando’s system as Type I to Type IV [53]. Type I has the most ferning and the highest concentration of protein, while Type IV has no ferning and the lowest amount of protein [49]. Samples of tears from healthy individuals typically exhibit robust, highly-branched ferning patterns (Type I and II), while samples from patients with eye or immune diseases show little to no ferning (Type III and IV) [48, 49, 52]. Through analysis of X-ray microscopy and scanning electron microscopy (SEM), the molecular structure of the ferns from tears is revealed to be composed of NaCl, KCl, and proteins [48]. In addition to helping detect infection, saliva ferning pattern has been shown to be useful for tracking ovulation cycle from highest fertility level during estrus to lowest fertility level during diestrus [54].
Cervical mucus is a heterogeneous hydrogel that changes over the course of an animal’s reproductive cycle [44, 45, 55]. Regardless of the source, human or otherwise, high levels of estrogen are produced during ovulation or peak fertility, resulting in linear ferns with branching angles of 90°, while no ferning is found during the period of low fertility when progesterone is dominant [44, 45]. During ovulation, the cervical mucus is over 98% water with its highest level of salt while both water content and salt content drops during low fertility period [45]. The low salt content during low fertility period is the cause of the lack of ferning pattern.
SEM analysis of ferns from gelatin-NaCl mixture revealed that the backbone of the ferning pattern was a series of interlocking crystalline blocks that were 10–30 μm in size [47]. When the fractal dimension of bovine cervical mucus (BCM) that was taken during ovulation was determined using the box-counting method, it was about 1.7, characteristic of diffusion-limited growth processes [44, 46]. Box counting method is based on counting non-empty boxes making up a fractal pattern on a grid [46]. A diffusion limitation was observed with the gelatin-NaCl mix as well. The ferning pattern became much less geometric and increasingly random at higher gelatin-to-NaCl ratios, where more diffusion limitation occurs due to the crosslinking of the gelatin, and the ferning ceased at extremely high gelatin-to-NaCl ratios [47]. Furthermore, the ferning pattern developed curvatures at evaporation rates above a threshold value of 11 μm s−1 [47].
Bacterial biofilms produce ferning patterns that are similar to gelatin and mucus samples [50, 56]. Upon evaporation of droplets of solutions of various salts with cells of E. coli and Bacillus subtilis, ferning patterns emerged where the crystallized top layer covered a base layer that consisted of bacterial cells. The structure of the E. coli ferns was linear with branching angles of 90°, similar to cervical mucus. Neither sterile saline solutions nor E. coli in pure water produced ferning, confirming the previous findings that ferning results from balanced proportions of salts and macromolecules [50, 56]. Bacteria inside the crystalline structure were effectively in a state of suspended animation that was capable of reanimation after rehydration, even a week later [50]. This crystallization was hypothesized to be a form of biomineralization [50], which occurs when biological organisms produce organo-mineral hybrids that give the organism mechanical strength and hardness. Examples of biomineralization that are found in nature include bones, teeth, shells, corals, and algal silica [57]. Previous studies on strain PAO1 of P. aeruginosa in flow cell reactors have shown biomineralization of calcium carbonate within the EPS of the biofilm [58]. SEM of the ferning sample of E. coli revealed a 3D structure that was composed of dried EPS, bacteria, and salts, with the salts concentrated in the crystalline region, consistent with the previously mentioned studies [50].
Studying the ferning pattern and complexity of biofluids or biogels gives a simple and indirect measurement of the structures within the material that guide or hinder the movement of ions that ultimately form these distinct crystallization patterns. While much of the ferning patterns seen in biofluids are linear patterns with 90° branching angles, tightly packed and curved ferning patterns can be expected to develop in environments that induce fast evaporation such as in low-viscosity fluids or environments that are highly diffusion limited such as in high macromolecule to salt ratio fluids.
One of the techniques of self-assembly for small particles is through depletion attraction in a solvent during solvent evaporation [59, 60]. Depletion attraction is an entropic force that becomes relevant when the particles in the solvent move close enough together that their excluded volumes overlap [61]. This overlap increases the osmotic pressure in the surrounding fluid and further pushes the particles together [59]. These highly ordered or anisotropic solution is described as having a liquid crystal phase and this phase is birefringent, which means that their ordered state will split light into two beams with perpendicular polarization [36, 60, 62]. Liquid crystal phases have been observed with many different types of biopolymers such as DNA, peptides, glycopolymers, proteoglycans, viruses, collagen, cellulose, phages, and chitin [60, 61, 63]. Liquid crystals form: (i) nematic phase where the molecules form directional order but no positional order; (ii) smectic phase with positional order; or (iii) chiral phase with twisting order [60]. Of these, biopolymers most commonly have nematic phase.
P. aeruginosa that exists in a viscous or anaerobic environment is stimulated to transcribe filamentous Pf bacteriophages that are about 2 μm in length and 6 nm in diameter [64]. In P. aeruginosa biofilm, the filamentous phage self-assembles through depletion attraction, with the biopolymers exerting the osmotic force that bundles the phage strands. These highly ordered anisotropic regions of nematic phase liquid crystals are birefringent, possessing a large negative charge, and the anisotropy was shown to increase with the ionic strength and the molecular weight [64, 65]. Birefringence is not only a direct indicator of molecular order, but it is an indicator for P. aeruginosa biofilm strength, surface adhesivity, desiccation tolerance, and antibiotic resistance [62, 64]. The filamentous bacteriophages facilitate chronic infection of P. aeruginosa in the host by promoting a less invasive, less inflammatory but more resistant, more persistent form of P. aeruginosa [66]. In addition, Pf phages can bind iron to inhibit the metabolic activity of other pathogens such as Aspergillus fumigatus [67].
Liquid crystal methods provide the means to study the structure and behavior of filamentous bacteriophages without perturbation [65]. Moreover, liquid crystal analysis, specifically through detection of its birefringence, was used to detect analytes such as glucose, cholesterol, E. coli, and even viruses such as Ebola and HIV [68]. This detection method was made possible through enzymatic reaction in response to analytes within the mesophase of the normally optically isotropic lipidic cubic phases that results in the formation of strongly birefringent liquid crystal phases that are easily detected optically [68]. The exogenous and endogenous birefringence from various classes of analytes were exploited to make simple and cheap detection tool that was proposed as a new diagnostic tool that can be utilized in industry or in the field to detect biothreats [68].
Biofilm is composed of motile bacterial cells, non-motile bacterial aggregates, and mucoid hydrogels of EPS that have a heterogeneous, highly-porous microstructure, allowing diffusion of water, nutrients, waste, and electrolytes [26, 69]. A complex set of interactions between the electrolytes, solutes, bacteria, and biopolymers dictate the strength, bacterial resistance, and infection persistence of the biofilm. The objective of this study is to characterize the behavior of the bacterial culture in the presence of various environmental conditions, including a highly viscous media, nutrient-enhanced media, high osmolarity media, and antimicrobial media. The interaction of the bacterial culture with its nutrient environment is measured as a function of the strength of its biofilm through rheological analysis, while its ferning pattern characterizes the mass transport through the environment in the biofilm. Additionally, birefringence inside a biofilm provides insight into the solute interaction with the biofilm.
The strain of Pseudomonas aeruginosa that was used for the entire study was the laboratory-adapted wild-type strain, PAO1. Miller lysogeny broth (LB) was prepared from BD Difco dry powder and autoclaved. Five different types of chemical modifications were made to the lysogeny broth: (i) glycerol was added to form between 1 and 15 v/v% in LB medium; (ii) glucose was added to form concentrations between 0.5 and 4.5 w/v% in LB; (iii) sucrose was added to form concentrations between 0.5 and 4.5 w/v% in LB; (iv) NaCl added to form concentrations between 1.5 and 5 w/v% in LB; and (v) AgNO3 added to form concentrations between 0.001 and 1 mM in LB. Modified LB medium in a petri dish (3.6 mL) was inoculated with an overnight culture of PAO1 (0.4 mL) and was incubated for 6 days at 37°C. Some of the dishes of modified LB medium were kept sterile and incubated along with the biofilm samples to act as a negative control.
The sample rheology was measured on the Discovery Hybrid Rheometer 3 (DHR3, TA Instruments, USA) using a 40-mm stainless steel plate geometry at 25°C. The measurements took place in the following order:
Pre-stressed: 0.1 Pa, 2 minutes
Frequency sweep: γ0 = 0.1 (biofilm), γ0 = 0.005 (sterile LB), ω
Stress sweep: τ
Detailed description of the sample inoculation, the incubation, and the rheological measurement methods are located in our previous work [43].
The biofilm samples were dried in the incubator, forming ferning patterns that were large enough to be easily seen by the unaided eye. In this paper, the previous qualitative method for ferning characterization was converted to a quantitative method of image analysis by calculating the coverage area, the fractal dimension, and the complexity score (degree of branching) of the ferning pattern. This analysis was completed by taking photographs of the surface of the petri dish, converting the photographs to black and white image on MATLAB (Figure S4,
Microscopic images of the biofilm in its liquid and its dried ferning state were taken using an Eclipse Ti-S inverted microscope (Nikon, Japan). The polarized images were produced with polarized filters.
Data from the sweeps of frequency showed the difference in the viscoelasticity of the samples of biofilm (filled square) and the samples of sterile LB medium (unfilled circle) that were incubated for 6 days (Figure 2). For brevity, the term “unmodified LB” will refer to the standard LB medium without chemical alterations, while “modified LB” will refer to any of the five chemical additions to standard LB medium (glycerol, glucose, sucrose, NaCl, and AgNO3). The sweep of frequency of the biofilm showed frequency-independent, elastic modulus (G′) dominance over the viscous modulus (G″) for all of the samples, as expected for a weak gel (Figure S3,
Modulus |G*| calculated from the sweep of frequency showing the biofilm (filled square) and sterile LB medium (unfilled circle) samples. The results of the (a) sweep of frequency from ω ∈[0.1, 1] rad s−1 (biofilm γo = 0.1 and sterile LB medium γo = 0.005) of biofilm samples that were grown in unmodified LB medium and of sterile unmodified LB medium. The mean modulus |G*| was 0.015 Pa for biofilm and 0.0015 Pa for sterile unmodified LB medium. (b–f) The mean modulus |G*| is plotted (red) with relative errors that were calculated from standard error to ensure symmetry (n ≥ 3). The average |G*| of biofilm that was grown in modified LB medium with the following concentrations (b) 1–15 v/v% glycerol, (c) 0.5–4.5 w/v% glucose, (d) 0.5–4.5 w/v% sucrose, (d) 1.5–5 w/v% NaCl and (e) 0.001–1 mM AgNO3 are shown. The gray regions in (b) and (f) represent inhibiting concentrations that had no biofilm growth.
The values of yield stress were derived from the experiments of increasing strain, where the yield stress is the point of offset of a stress-versus-strain curve. The stress-versus-strain data of the unmodified LB biofilm (filled square) and sterile unmodified LB samples (unfilled circle) showed that the samples of biofilm exhibited an appreciable yield stress (Figure 3a). After yielding, the material stress was constant (<1 Pa) at high strain, while the samples of sterile medium demonstrated no yield stress. In fact, none of the sterile modified or unmodified LB mediums had an appreciable yield stress (Figure S2,
(a) The stress versus strain data of biofilm that was grown in unmodified LB medium (filled square) and of samples of sterile unmodified LB medium (unfilled circle). (b–f) For the mean yield stress of biofilm that was grown in unmodified LB medium (red square), the standard error bars were converted to relative errors to ensure symmetry on the y-axis (n ≥ 7). Plots of yield stress τy of the biofilms that were grown in modified LB medium at the following concentrations (b) 1–15 v/v% glycerol, (c) 0.5–4.5 w/v% glucose, (d) 0.5–4.5 w/v% sucrose, (e) 1.5–5 w/v% NaCl and (f) 0.001–1 mM AgNO3 are shown. The mean τy was 0.32 Pa for the unmodified LB biofilms, while the LB medium did not have a yield stress. The gray regions in (b) and (f) represent inhibiting concentrations that had no biofilm growth.
With the addition of glycerol (0–15 v/v%), the complex modulus of the biofilm increased by almost an order of magnitude between 0 and 2% glycerol, remained constant between 2 and 10%, and experienced a dramatic drop in modulus for concentrations greater than 10% to modulus values that are comparable to sterile LB (Figure 2b). The yield stress of the biofilm showed similar trends, increasing by one order of magnitude with glycerol from 0 to 10% until concentrations of glycerol that were greater than 10% impeded the growth of biofilm, also resulting in no yield stress (Figure 3b). The addition of glycerol increased the viscosity of the medium as well as inducing high osmolarity (1.4 Osm L−1 at 10%), promoting stronger biofilm. Other studies with glycerol-supplemented medium saw an increase in the production of EPS by biofilm, consistent with the present study [27, 70]. The glycerol can trigger pathways of production of EPS; [27] however, at high concentrations of glycerol, the diffusion-limiting environment of the highly viscous solution with high osmotic pressure (>4 Osm L−1 at >10%) appeared to inhibit growth. The complex modulus of the modified LB medium, on the other hand, stayed relatively constant with glycerol addition. The dramatic drop in the modulus of biofilm samples that were grown in medium that was modified with >10% glycerol corresponded with an apparent lack of biofilm in the Petri dishes, as the dishes appeared clear and yellow instead of opaque and greenish (Figure S1,
The modulus of the biofilm increased by one order of magnitude by increasing the concentration of glucose from 0 to 4.5% (Figure 2c), indicating that glucose was being utilized by the bacteria as an additional source of carbon which promoted growth and development of a stronger network of biofilm. The rheological results of the sterile glucose-modified LB medium did not change significantly from the unmodified LB medium. The values of yield stress followed the same trend, where the biofilm that was grown in glucose-modified LB medium had yield stresses that were an order of magnitude larger than the unmodified LB biofilm (Figure 3c). A previous study observed the same effect, finding that the addition of glucose up to the highest level tested, which was 2.7%, enhanced biofilm production [29]. The maximum addition of glucose (4.5%) induced osmotic pressure of 0.25 Osm L−1, which did not cause inhibiting effects.
Based on the rheology, sucrose did not increase biofilm production, as no change existed in the modulus (Figure 2d) or yield stress (Figure 3d) of the biofilm. In previous studies, concentrations of sucrose above 10% in medium for P. aeruginosa resulted in biofilm with mucoid development, while P. fluorescens started to experience adverse effects above 15% at which point the biofilm dramatically decreased [30, 31]. In those studies, bacterial culture reached an inhibiting level of sucrose at 15% due to osmotic pressure (0.44 Osm L−1) [30]. In the present work, samples of PAO1 experienced a maximum of 0.13 Osm L−1 in osmotic pressure from modification with sucrose, which is well below the reported osmotic level for inhibition. P. aeruginosa may not be capable of utilizing sucrose, so in contrast to the simpler glucose, sucrose had little impact on the rheological properties of the biofilm.
Unmodified LB medium already consists of sodium chloride (NaCl) at a concentration of 1%, and the modified concentration varied from 1 to 5% of NaCl. The complex modulus of biofilm remained constant for concentrations below 2.5% and increased by one order of magnitude for concentrations between 2.5 and 5%, while the modulus of the sterile modified LB medium was not affected by the concentration of NaCl (Figure 2e). Similarly, the yield stress increased as the concentration of NaCl was increased greater than 2.5% (Figure 3e). NaCl is already required for bacterial growth to provide osmotic balance, but a larger amount of salts appeared to promote stronger biofilm. The change in the biofilm could be caused by the higher salinity or osmolarity, making the environment hostile, triggering a higher level of production of alginate and other types of EPS as a countermeasure. Previous studies found that concentrations of NaCl between about 1 and 3% increased production of biofilms in S. aureus and P. aeruginosa, while concentrations of about 6% of NaCl prevented growth of biofilm in S. aureus [29, 31]. At concentrations of NaCl above 10%, no biofilm growth was observed, and the plate quickly crystalized to cubes of salt (Figure S6,
Silver has antimicrobial properties that can inhibit bacterial growth and development of biofilm. Supplementation of silver nitrate (AgNO3) to the modified LB medium has no impact on the complex modulus (Figure 2f) or the yield stress of the biofilm for concentrations below 0.1 mM (Figure 3f). Past this concentration, the modulus instantly reduced to the same level as the sterile modified LB medium, and the yield stress disappeared. Correspondingly, the plates of biofilm at the higher silver concentrations appeared clear and less viscous, resembling sterile modified LB medium (Figure S1,
The rheological parameters of elastic modulus and yield stress are useful measures of the strength of a biofilm. The complex modulus and the yield stress of the biofilms increased with the addition of glucose, which served as an additional source of carbon, but they were unaffected by addition of sucrose, which is a complex sugar that the bacteria could not utilize. The strength increased to an extent with osmolarity (glycerol and NaCl) and dramatically reduced to their sterile baseline at concentrations that were higher than the inhibitory threshold of an antimicrobial agent (AgNO3). Samples with higher rheological properties correlated with a biofilm that appeared more viscous than the unmodified LB biofilm, while samples with lower modulus, and lacking a yield stress, such as high concentrations of glycerol and silver ions, appeared less viscous and free of biofilm. The values of modulus and yield stress for the samples of biofilm displayed the same medium dependent response; therefore, either measurement would be a useful metric of the strength of biofilm. Out of the five chemical modifications, three modifications increased the strength of the biofilm when compared to the unmodified LB biofilm: glycerol for concentrations up to 10%, glucose for concentrations at least up to 4.5%, and NaCl for concentrations higher than 2.5%. One of the chemicals, sucrose, had no measurable effect on the strength of the biofilm for concentrations at least up to 4.5%, while another modifier, AgNO3, inhibited bacterial growth at a concentration above 0.1 mM.
After the plates were dried over a span of weeks in the incubator, they were photographed, and the photographs were converted to black and white images and cropped (Table S1,
A guide for the ferning complexity score of the dried biofilm ferning pattern.
The ferning coverage was calculated quantitatively based on the percent of white pixels in the black and white images that were converted from its original photograph (Figure 5a). A photograph of the ferning on a plate of unmodified LB biofilm showed high ferning coverage (top photos), while the plate of sterile unmodified LB medium was noticeably absent of ferning with low calculated coverage (bottom photos). Even without biofilm growth, the sterile coverage values were not zero because the lighting and the glare of the plate surface produced some pixel artifacts. Figure 5b–f shows the mean coverage of the plates of unmodified LB biofilm (red filled square, n = 12) and of the plates of sterile unmodified LB medium (red unfilled circle, n = 7) plotted with the data of the modified LB medium. The left black y-axis is the ferning coverage, while the right gray y-axis is the qualitative ferning complexity score for biofilm (gray filled square) and the sterile LB medium (gray unfilled circle).
(a) The original photograph was converted to a black and white image before the ferning coverage was calculated from the processed image. An example of ferns from biofilm that was grown in unmodified LB medium with 46.2% ferning coverage and from a plate of sterile unmodified LB medium showing zero ferning coverage. (b–f) Ferning coverage (left y-axis in black) and complexity score (right y-axis in gray) of biofilm that was grown in modified LB medium (coverage: black filled squares; complexity: Gray filled squares) and of sterile plates (coverage: black unfilled circles; complexity: Gray unfilled circles). The mean coverage and standard deviation of biofilm that was grown in unmodified LB medium (n = 12) and in sterile unmodified LB medium (n = 7) are plotted in red across figures (b–f). The results of the biofilm that was grown in modified LB medium with (b) glycerol, (c) glucose, (d) sucrose, (e) NaCl and (f) AgNO3 are shown. The change in morphology of the biofilm ferning pattern with (b) glycerol at concentrations of 2% (top left) and 10% (top right); (c) glucose at concentrations of 0.5% (top left) and 4.5% (top right); (d) sucrose at concentrations of 0.5% (top left) and 4.5% (top right); (e) NaCl at concentrations of 1.5% (top left) and 5% (top right); and (f) AgNO3 at concentrations of 0.001 mM (top left) and 1 mM (top right) are shown. The gray regions in (b) and (f) represent inhibiting concentrations that had no biofilm growth.
With the addition of glycerol, the ferning pattern of the samples of biofilm initially changed from a complexity score of 5 and a coverage of 47% (unmodified LB biofilm) to a complexity score of 8 (Figure 5b). The change in ferning morphology from the orthogonal form to the acute branching form occurred at the lowest tested concentration of glycerol (Figure 5b: 2% plate, top left). However, as the concentration of glycerol increased, the ferning coverage dropped dramatically, reaching zero at around 8%. From both the visual inspection and the rheological measurement, samples below 10% had strong biofilm. However, a large amount of glycerol prevented the sample from completely drying, leaving the surface of the sample looking shiny and wet, causing both the ferning coverage and the complexity score to drop between 4 and 10% glycerol (Figure 5b: 10% plate, top right). The plates with concentrations of glycerol above 10% never dried, so no photographs were taken, and values of the coverage and complexity score were assumed to be zero. Sterile LB medium coverage and complexity score did not change from the unmodified values of about zero.
In samples that were modified with the addition of glucose, the ferning coverage remained consistent, while the complexity score changed from 5 to 8 at 2.5% and then held steady at higher concentrations of glucose (Figure 5c). The pattern on the plates transitioned from standard orthogonal ferning at low concentrations of glucose (Figure 5c: 0.5%, top left) to acute branching at high concentrations of glucose (Figure 5c: 4.5%, top right). The coverage and the complexity score on the sterile plate remained unchanged from the standard values.
The desiccated plates of medium modified with sucrose had the most unusual patterns (Figure 5d). Both the coverage (47–30%) and the complexity score (5–3) dropped when the concentration of sucrose increased from 0 to 2%. However, with further increase from 2 to 4% sucrose, the coverage increased to 50%, while the complexity score continued to show less degrees of branching. Similar to glycerol, sucrose is hygroscopic, so plates appeared shinier and somewhat wet with increasing concentration of sucrose. At the same time, the ferning on the surface evolved (Table S1,
With further addition of sodium chloride (NaCl) to the modified LB medium, the ferning coverage remained consistently around 50%, and the complexity score remained around 5 (Figure 5e). Still, a change to the pattern exists, as the ferns evolved from thin branches (Figure 5e: 1.5%, top left) to a more pronounced branching with large crystalline formations with increasing concentration of NaCl (Figure 5e: 5%, top right). While the ferning branches became wider with the further addition of NaCl, the complexity score did not change. The orthogonal morphology and the non-overlapping crystallization appear to naturally limit the maximum coverage of the ferning pattern, resulting in a consistent 40–50% coverage. The sterile dishes with modified LB medium that contained the same amount of salt did not produce ferning patterns, so the coverage and complexity score remained zero.
The complexity score for the plates that were treated with silver nitrate (AgNO3) remained 5 for concentrations below 0.1 mM, but at higher concentrations, no biofilm growth occurred, resulting in a complexity score of 1 (Figure 5f). Even with no measurable biofilm, the plates contained clusters of dried materials that resembled nucleation points (Figure 5f: 1 mM, top right). For concentration below 0.1 mM of silver nitrate, the ferning patterns were orthogonal (Figure 5f: 0.001 mM, top left), and the coverage was in the range of 30–40%. Finally, the coverage dropped below 10% at concentrations that were greater than the inhibiting concentration of 0.1 mM. The coverage did not completely drop to 0, as beige clusters were left behind on the plate, which was the same reason that the complexity score was 1 for the highest concentration even though no biofilm was present.
Similar to the dependence of rheological properties of the biofilm on the nutrient environment, the ferning pattern was dependent on the properties of the bacterial biofilm, so it changed with the composition of the medium. No ferning existed on plates that lacked biofilm. The presence of biofilm, confirmed rheologically and visually, correlated with robust ferning patterns. Using the same box-counting method, ferning patterns on the samples of unmodified LB biofilm had a fractal dimension of 1.8 (Figure S5,
The complexity score and the ferning coverage was higher for stronger biofilms (higher G* and τy) that caused more limitations in mass transfer, and both values dropped to nearly zero when no biofilm was present. The morphology of ferns with a complexity score of 8 that were produced by the biofilms with higher elasticity was similar to random/acute-angled branching ferns that were produced under conditions of increased diffusion limitation in a previous study [47]. Exceptions were the plates that appeared to never fully dry due to the high concentration of hygroscopic materials like sucrose or glycerol. So, even as the rheological properties of the biofilm increased (glycerol) or stayed constant (sucrose), the complexity score and coverage dropped with increasing amounts of the modifying chemical. The ferning coverage never exceeded 60%, indicating a natural growth limitation that was based on the available space and the morphology of the ferns. The videos of the ferning process demonstrated how these branches quickly started and stopped growing without any of the branches overlapping (Video S1,
The ferning patterns of the biofilms were large (visible without microscopy on the order of centimeters) with most of the patterns consisting of orthogonal branches, and the ferns were reproducible in coverage and complexity score. The ferning patterns that were formed by the biofilm had the same morphology as ferning patterns of saliva, cervical mucus, E. coli, salt-gel, or salt-protein [44, 47, 49, 50]. From reports in the literature and the results in this work, the orthogonal or oblique branching seemed to be the most common type of ferning with the examples of branches with acute angles being rare [47]. The cause of the change in the morphology of the fern in biofilms from 90° angles to acute angles is not immediately clear. However, other studies have reported that the gelatin-to-salt ratio was the key factor controlling the ferning morphology of salt-gelatin mixtures [47]. Therefore, the samples with higher rheological properties (glycerol and glucose samples), which arguably has a higher amount of EPS, may have produced branching with acute angles due to the increased EPS-to-salt ratio. Thus, the acute-angle morphology dominated when the biofilms had larger rheological values, indicating higher EPS-to-salt ratio, while orthogonal-branching morphology dominated at intermediate ratios with no ferning at extremely high or low values of the EPS-to-salt ratio.
Analyzing the pre-desiccation biofilm that was grown in 5% NaCl under polarized filters showed the entire sample sample lit with birefringent strands (Figure 6). The Pf bacteriophages produced by P. aeruginosa are known to self-assemble into liquid crystals that exhibit birefringence [64]. The birefringent strands (black arrows) are 50–100 μm in length, and they are evenly distributed throughout the sample (Figure 6a and b). A magnified view of the strands revealed that each strand was a bundle of smaller strands that were surrounded by cell clusters (yellow arrows) and biofilm (Figure 6c). The bacteriophages are about 6 μm in length, so the bundle was likely composed of hundreds of individual Pf phages that were assembled into one strand [64]. These birefringent strand clusters did not exist in samples lacking biofilm. A plate with 10% NaCl LB medium formed sheets of salt crystals, no visible biofilm, and no birefringent strands (Figure S6,
Polarized microscopic images of inoculated samples of PAO1 in modified LB medium with a concentration of 5% NaCl. (a and b) Birefringent fragments exist throughout the liquid medium. (c) The birefringent thread-like fragments (black arrows) of about 50–100 μm in length were dispersed within medium that was full of bacterial clusters (yellow arrows).
The 5% NaCl sample that was previously analyzed (Figure 6) was desiccated (Figure 7a) and examined with and without a polarized filter (Figure 7b–k). The red lines outlined the specific regions of the fern under the microscope. The region outlined in the circle (Figure 7b–e) was the square crystalline structure on the plate. Without a filter this region showed a cubic structure with a length of 4–5 mm per side with a nucleation point in the center and thin diagonal lines running through it with cavernous voids coming from the sides of the structure (Figure 7b). The center of the ferning structure showed cuboid lattice-like patterns of growth emerging from the seed point (Figure 7e). Similarly, the previous study of the ferning pattern in a gelatin-salt mix revealed interlocking salt blocks with a length of 10–30 μm on a side that formed the backbone of the ferning structure [47].
Desiccated biofilm that was grown in LB medium with 5% NaCl. (a) Ferning pattern from the bottom of the petri dish. The regions that are outlined in red were inspected under the microscope. (b–e) The cubic piece at the top right corner of the plate (red circle): (b) seen under normal light; (c and d) seen through a polarized filter at different magnifications; (e) focused on the seed point of crystallization. (f and k) The ferning region of the plate (red square): (f–h) different regions of the fern under normal light at different magnifications; (i and j) seen through a polarized filter at different magnifications; (k) viewed at a different angle of polarization.
With a polarized filter, bright birefringent regions lit throughout the square (Figure 7c). A closer look at the center of the square revealed two forms of birefringent structures, large red and gold star formations (~0.5 mm in diameter) and red and gold strands that were about 50 μm in diameter (Figure 7d). In contrast to the birefringent strands that were scattered throughout the sample (black arrows), the birefringent stars (white arrows) were only in the crystallized ferns. Each birefringent strand that was visible in Figure 7c was a bundle of even smaller birefringent strands (Figure 6c). Therefore, the formation of the birefringent star demonstrated that having an even higher order of self-assembly during desiccation was possible such that the bundled strands further merged into a star formation. The alternating red and gold coloring indicated that the strands with matching orientations cluster together, but they must not have formed the entire cluster, as no star formation existed with only one color.
From the linear ferning section that was outlined by the red square (Figure 7f–k), the branches appeared to be about 1 mm in width with a distinct centerline running through each branch (Figure 7f). A magnified view of one of these branches revealed latticed or layered networks emanating from this central line (blue arrows) and cavities (pink arrows) that were present throughout the structure (Figure 7g). Some of the cavities were large, tunneling deep into the ferning structure (Figure 7h). Under polarized light, the branch was shown to have dozens of the star-shaped red and gold birefringent bundles (Figure 7i). Changing the angle of the polarized filter changed the color of the birefringent region from red and gold to gold and green (Figure 7k). The star-shaped birefringent clusters only existed within the crystal regions of the fern pattern, while the strands were scattered throughout the plate regardless of the ferning pattern (Figure 7j). This localization of the morphologies implied that the birefringent strands were produced within the biofilm; thus, they could be found throughout the material, while the formations of the birefringent stars were created as a result of crystallization, so they were only found within the crystalline regions. Clusters of bacterial cells appeared to be entrapped within the crystallized fern (yellow arrows), especially around the extremities of the ferning structure (Figure 7c and j). Similarly entrapped bacterial clusters were capable of reanimation at least a week after desiccation within the ferning structure [50]. Therefore, clusters of P. aeruginosa that were seen in Figure 7c and j may be in a suspended animation state as well, though this hypothesis was not tested during this study.
In environments that contained high viscosity (glycerol), high osmolarity (glycerol, NaCl), and high concentrations of simple carbon (glucose), the elasticity and the yield stress of the biofilm increased. Silver nitrate had an inhibiting effect on the biofilm formation, but only at concentrations that were greater than 0.1 mM. Similarly, concentrations of glycerol greater than 10% completely inhibited biofilm growth. However, the complex carbon structure of sucrose meant that it could not be utilized as an additional carbon source by PAO1 in the same way that glucose was utilized. Therefore, sucrose did not change the rheological properties of the biofilm. So, P. aeruginosa developed stronger biofilm under nutrient-rich conditions, certain levels of osmotic stress, and certain levels of diffusion limitation. However, it would not develop biofilm when the osmotic stress or diffusion limitation exceeded an inhibition amount or when an antimicrobial agent exceeded its inhibition concentration.
While the rheological properties of biofilm revealed information about the strength of the biofilm, the morphology of the ferning pattern best described the interactions between the electrolytes and the EPS in the biofilm. Typically, the biofilm had ferning coverage of about 50% and a ferning complexity score of 5. The ferning complexity increased with the strength of the biofilm (high complex modulus and yield stress), as stronger biofilm increased diffusion limitation that was experienced by the solutes within the matrix. The coverage and complexity score both dropped to zero when no biofilm formed, so the macromolecule-to-salt ratio was too low for ferning to occur, as with high concentrations of silver nitrate and glycerol. Many of the analysis methods of biofluid ferning patterns were qualitative and subjective, which is currently problematic considering its use as an indicator of certain medical symptoms. The image analysis and ferning classification method that was presented here could easily be applied to the other fields to give more quantitative values to the analysis of ferning biofluids.
The birefringence that was produced by liquid crystals within the samples of biofilm had two different morphologies, bundled strands that were about 50 μm in length in hydrated biofilm and star-shaped bundle of strands that were almost ten times larger inside the crystalline region of the ferning pattern. So, in addition to the self-assembly of the phages to strands inside the biofilm, a more complex assembly took place during crystallization in the biofilm that produced this tertiary structure. During the ferning process, clusters of bacteria became entrapped within the crystalline phase. Other researchers have found that these entrapped bacteria are in suspended animation state and that they could be brought back to life upon rehydration. If PAO1 can also reanimate, then ferning is yet another mechanism that P. aeruginosa could utilize to survive extreme conditions, similar to how liquid crystals formed by phages enhanced the resistance and persistence of P. aeruginosa.
The authors would like to thank Dr. Skip Rochefort for consulting on the rheology tests and Kristin Marshall for her help with the image conversion work. Additionally, the authors would like to thank Marisa Thierheimer, Curran Gahan, and Dalton Myas for helping with experimental preparation.
We do not have any conflict of interests to declare.
This work would not be possible without funding from Medical Research Foundation of Oregon.
The supplemental documents for this section may be found at:
IntechOpen publishes different types of publications
",metaTitle:"Types of publications",metaDescription:"IntechOpen publishes different types of publications",metaKeywords:null,canonicalURL:null,contentRaw:'[{"type":"htmlEditorComponent","content":"IntechOpen Edited Volumes are integrated collections of chapters about particular topics that present new areas of research or novel syntheses of existing research and, as such, represent perspectives from various authors.
\\n\\nEdited Volumes can be comprised of different types of chapters:
\\n\\nRESEARCH CHAPTER – A research chapter reports the results of original research thus contributing to the body of knowledge in a particular area of study.
\\n\\nREVIEW CHAPTER – A review chapter analyzes or examines research previously published by other scientists, rather than reporting new findings thus summarizing the current state of understanding on a topic.
\\n\\nCASE STUDY – A case study involves an in-depth, and detailed examination of a particular topic.
\\n\\nPERSPECTIVE CHAPTER – A perspective chapter offers a new point of view on existing problems, fundamental concepts, or common opinions on a specific topic. Perspective chapters can propose or support new hypotheses, or discuss the significance of newly achieved innovations. Perspective chapters can focus on current advances and future directions on a topic and include both original data and personal opinion.
\\n\\nINTRODUCTORY CHAPTER – An introductory chapter states the purpose and goals of the book. The introductory chapter is written by the Academic Editor.
\\n\\nMonographs is a self-contained work on a particular subject, or an aspect of it, written by one or more authors. Monographs usually have between 130 and 500 pages.
\\n\\nTYPES OF MONOGRAPHS:
\\n\\nSingle or multiple author manuscript
\\n\\nCompacts provide a mid-length publishing format that bridges the gap between journal articles, book chapters, and monographs, and cover content across all scientific disciplines.
\\n\\nCompacts are the preferred publishing option for brief research reports on new topics, in-depth case studies, dissertations, or essays exploring new ideas, issues, or broader topics on the research subject. Compacts usually have between 50 and 130 pages.
\\n\\nCollection of papers presented at conferences, workshops, symposiums, or scientific courses, published in book format
\\n"}]'},components:[{type:"htmlEditorComponent",content:"IntechOpen Edited Volumes are integrated collections of chapters about particular topics that present new areas of research or novel syntheses of existing research and, as such, represent perspectives from various authors.
\n\nEdited Volumes can be comprised of different types of chapters:
\n\nRESEARCH CHAPTER – A research chapter reports the results of original research thus contributing to the body of knowledge in a particular area of study.
\n\nREVIEW CHAPTER – A review chapter analyzes or examines research previously published by other scientists, rather than reporting new findings thus summarizing the current state of understanding on a topic.
\n\nCASE STUDY – A case study involves an in-depth, and detailed examination of a particular topic.
\n\nPERSPECTIVE CHAPTER – A perspective chapter offers a new point of view on existing problems, fundamental concepts, or common opinions on a specific topic. Perspective chapters can propose or support new hypotheses, or discuss the significance of newly achieved innovations. Perspective chapters can focus on current advances and future directions on a topic and include both original data and personal opinion.
\n\nINTRODUCTORY CHAPTER – An introductory chapter states the purpose and goals of the book. The introductory chapter is written by the Academic Editor.
\n\nMonographs is a self-contained work on a particular subject, or an aspect of it, written by one or more authors. Monographs usually have between 130 and 500 pages.
\n\nTYPES OF MONOGRAPHS:
\n\nSingle or multiple author manuscript
\n\nCompacts provide a mid-length publishing format that bridges the gap between journal articles, book chapters, and monographs, and cover content across all scientific disciplines.
\n\nCompacts are the preferred publishing option for brief research reports on new topics, in-depth case studies, dissertations, or essays exploring new ideas, issues, or broader topics on the research subject. Compacts usually have between 50 and 130 pages.
\n\nCollection of papers presented at conferences, workshops, symposiums, or scientific courses, published in book format
\n"}]},successStories:{items:[]},authorsAndEditors:{filterParams:{sort:"featured,name"},profiles:[{id:"6700",title:"Dr.",name:"Abbass A.",middleName:null,surname:"Hashim",slug:"abbass-a.-hashim",fullName:"Abbass A. Hashim",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/6700/images/1864_n.jpg",biography:"Currently I am carrying out research in several areas of interest, mainly covering work on chemical and bio-sensors, semiconductor thin film device fabrication and characterisation.\nAt the moment I have very strong interest in radiation environmental pollution and bacteriology treatment. The teams of researchers are working very hard to bring novel results in this field. 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. After obtaining a Master's degree in Mechanical Engineering, he continued his PhD studies in Robotics at the Vienna University of Technology. Here he worked as a robotic researcher with the university's Intelligent Manufacturing Systems Group as well as a guest researcher at various European universities, including the Swiss Federal Institute of Technology Lausanne (EPFL). During this time he published more than 20 scientific papers, gave presentations, served as a reviewer for major robotic journals and conferences and most importantly he co-founded and built the International Journal of Advanced Robotic Systems- world's first Open Access journal in the field of robotics. Starting this journal was a pivotal point in his career, since it was a pathway to founding IntechOpen - Open Access publisher focused on addressing academic researchers needs. Alex is a personification of IntechOpen key values being trusted, open and entrepreneurial. Today his focus is on defining the growth and development strategy for the company.",institutionString:null,institution:{name:"TU Wien",country:{name:"Austria"}}},{id:"19816",title:"Prof.",name:"Alexander",middleName:null,surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/19816/images/1607_n.jpg",biography:"Alexander I. Kokorin: born: 1947, Moscow; DSc., PhD; Principal Research Fellow (Research Professor) of Department of Kinetics and Catalysis, N. Semenov Institute of Chemical Physics, Russian Academy of Sciences, Moscow.\r\nArea of research interests: physical chemistry of complex-organized molecular and nanosized systems, including polymer-metal complexes; the surface of doped oxide semiconductors. He is an expert in structural, absorptive, catalytic and photocatalytic properties, in structural organization and dynamic features of ionic liquids, in magnetic interactions between paramagnetic centers. The author or co-author of 3 books, over 200 articles and reviews in scientific journals and books. He is an actual member of the International EPR/ESR Society, European Society on Quantum Solar Energy Conversion, Moscow House of Scientists, of the Board of Moscow Physical Society.",institutionString:null,institution:{name:"Semenov Institute of Chemical Physics",country:{name:"Russia"}}},{id:"62389",title:"PhD.",name:"Ali Demir",middleName:null,surname:"Sezer",slug:"ali-demir-sezer",fullName:"Ali Demir Sezer",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/62389/images/3413_n.jpg",biography:"Dr. Ali Demir Sezer has a Ph.D. from Pharmaceutical Biotechnology at the Faculty of Pharmacy, University of Marmara (Turkey). He is the member of many Pharmaceutical Associations and acts as a reviewer of scientific journals and European projects under different research areas such as: drug delivery systems, nanotechnology and pharmaceutical biotechnology. Dr. Sezer is the author of many scientific publications in peer-reviewed journals and poster communications. Focus of his research activity is drug delivery, physico-chemical characterization and biological evaluation of biopolymers micro and nanoparticles as modified drug delivery system, and colloidal drug carriers (liposomes, nanoparticles etc.).",institutionString:null,institution:{name:"Marmara University",country:{name:"Turkey"}}},{id:"61051",title:"Prof.",name:"Andrea",middleName:null,surname:"Natale",slug:"andrea-natale",fullName:"Andrea Natale",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"100762",title:"Prof.",name:"Andrea",middleName:null,surname:"Natale",slug:"andrea-natale",fullName:"Andrea Natale",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"St David's Medical Center",country:{name:"United States of America"}}},{id:"107416",title:"Dr.",name:"Andrea",middleName:null,surname:"Natale",slug:"andrea-natale",fullName:"Andrea Natale",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Texas Cardiac Arrhythmia",country:{name:"United States of America"}}},{id:"64434",title:"Dr.",name:"Angkoon",middleName:null,surname:"Phinyomark",slug:"angkoon-phinyomark",fullName:"Angkoon Phinyomark",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/64434/images/2619_n.jpg",biography:"My name is Angkoon Phinyomark. I received a B.Eng. degree in Computer Engineering with First Class Honors in 2008 from Prince of Songkla University, Songkhla, Thailand, where I received a Ph.D. degree in Electrical Engineering. My research interests are primarily in the area of biomedical signal processing and classification notably EMG (electromyography signal), EOG (electrooculography signal), and EEG (electroencephalography signal), image analysis notably breast cancer analysis and optical coherence tomography, and rehabilitation engineering. I became a student member of IEEE in 2008. During October 2011-March 2012, I had worked at School of Computer Science and Electronic Engineering, University of Essex, Colchester, Essex, United Kingdom. In addition, during a B.Eng. I had been a visiting research student at Faculty of Computer Science, University of Murcia, Murcia, Spain for three months.\n\nI have published over 40 papers during 5 years in refereed journals, books, and conference proceedings in the areas of electro-physiological signals processing and classification, notably EMG and EOG signals, fractal analysis, wavelet analysis, texture analysis, feature extraction and machine learning algorithms, and assistive and rehabilitative devices. I have several computer programming language certificates, i.e. Sun Certified Programmer for the Java 2 Platform 1.4 (SCJP), Microsoft Certified Professional Developer, Web Developer (MCPD), Microsoft Certified Technology Specialist, .NET Framework 2.0 Web (MCTS). I am a Reviewer for several refereed journals and international conferences, such as IEEE Transactions on Biomedical Engineering, IEEE Transactions on Industrial Electronics, Optic Letters, Measurement Science Review, and also a member of the International Advisory Committee for 2012 IEEE Business Engineering and Industrial Applications and 2012 IEEE Symposium on Business, Engineering and Industrial Applications.",institutionString:null,institution:{name:"Joseph Fourier University",country:{name:"France"}}},{id:"55578",title:"Dr.",name:"Antonio",middleName:null,surname:"Jurado-Navas",slug:"antonio-jurado-navas",fullName:"Antonio Jurado-Navas",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/55578/images/4574_n.png",biography:"Antonio Jurado-Navas received the M.S. degree (2002) and the Ph.D. degree (2009) in Telecommunication Engineering, both from the University of Málaga (Spain). He first worked as a consultant at Vodafone-Spain. From 2004 to 2011, he was a Research Assistant with the Communications Engineering Department at the University of Málaga. In 2011, he became an Assistant Professor in the same department. From 2012 to 2015, he was with Ericsson Spain, where he was working on geo-location\ntools for third generation mobile networks. Since 2015, he is a Marie-Curie fellow at the Denmark Technical University. His current research interests include the areas of mobile communication systems and channel modeling in addition to atmospheric optical communications, adaptive optics and statistics",institutionString:null,institution:{name:"University of Malaga",country:{name:"Spain"}}}],filtersByRegion:[{group:"region",caption:"North America",value:1,count:5774},{group:"region",caption:"Middle and South America",value:2,count:5240},{group:"region",caption:"Africa",value:3,count:1721},{group:"region",caption:"Asia",value:4,count:10411},{group:"region",caption:"Australia and Oceania",value:5,count:897},{group:"region",caption:"Europe",value:6,count:15812}],offset:12,limit:12,total:118381},chapterEmbeded:{data:{}},editorApplication:{success:null,errors:{}},ofsBooks:{filterParams:{hasNoEditors:"0",sort:"dateEndThirdStepPublish",topicId:"6,5"},books:[{type:"book",id:"9662",title:"Vegetation Index and Dynamics",subtitle:null,isOpenForSubmission:!0,hash:"0abf2a59ee63fc1ba4fb64d77c9b1be7",slug:null,bookSignature:"Dr. Eusebio Cano Carmona, Dr. Ricardo Quinto Canas, Dr. Ana Cano Ortiz and Dr. Carmelo Maria Musarella",coverURL:"https://cdn.intechopen.com/books/images_new/9662.jpg",editedByType:null,editors:[{id:"87846",title:"Dr.",name:"Eusebio",surname:"Cano Carmona",slug:"eusebio-cano-carmona",fullName:"Eusebio Cano Carmona"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9659",title:"Fibroblasts - Advances in Cancer, Autoimmunity and Inflammation",subtitle:null,isOpenForSubmission:!0,hash:"926fa6446f6befbd363fc74971a56de2",slug:null,bookSignature:"Ph.D. Mojca Frank Bertoncelj and Ms. Katja Lakota",coverURL:"https://cdn.intechopen.com/books/images_new/9659.jpg",editedByType:null,editors:[{id:"328755",title:"Ph.D.",name:"Mojca",surname:"Frank Bertoncelj",slug:"mojca-frank-bertoncelj",fullName:"Mojca Frank Bertoncelj"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"8977",title:"Protein Kinase - New Opportunities, Challenges and Future Perspectives",subtitle:null,isOpenForSubmission:!0,hash:"6d200cc031706a565b554fdb1c478901",slug:null,bookSignature:"Dr. Rajesh Kumar Singh",coverURL:"https://cdn.intechopen.com/books/images_new/8977.jpg",editedByType:null,editors:[{id:"329385",title:"Dr.",name:"Rajesh",surname:"Singh",slug:"rajesh-singh",fullName:"Rajesh Singh"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10557",title:"Elaeis guineensis",subtitle:null,isOpenForSubmission:!0,hash:"79500ab1930271876b4e0575e2ed3966",slug:null,bookSignature:"Dr. Hesam Kamyab",coverURL:"https://cdn.intechopen.com/books/images_new/10557.jpg",editedByType:null,editors:[{id:"225957",title:"Dr.",name:"Hesam",surname:"Kamyab",slug:"hesam-kamyab",fullName:"Hesam Kamyab"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10218",title:"Flagellar Motility in Cells",subtitle:null,isOpenForSubmission:!0,hash:"5fcc15570365a82d9f2c4816f4e0ee2e",slug:null,bookSignature:"Prof. Yusuf Bozkurt",coverURL:"https://cdn.intechopen.com/books/images_new/10218.jpg",editedByType:null,editors:[{id:"90846",title:"Prof.",name:"Yusuf",surname:"Bozkurt",slug:"yusuf-bozkurt",fullName:"Yusuf Bozkurt"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10750",title:"Solanum tuberosum - a Promising Crop for Starvation Problem",subtitle:null,isOpenForSubmission:!0,hash:"516eb729eadf0d1a9d1d2e6bf31e8e9c",slug:null,bookSignature:"Prof. Mustafa Yildiz and Dr. Yasin Ozgen",coverURL:"https://cdn.intechopen.com/books/images_new/10750.jpg",editedByType:null,editors:[{id:"141637",title:"Prof.",name:"Mustafa",surname:"Yildiz",slug:"mustafa-yildiz",fullName:"Mustafa Yildiz"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10797",title:"Cell Culture",subtitle:null,isOpenForSubmission:!0,hash:"2c628f4757f9639a4450728d839a7842",slug:null,bookSignature:"Prof. Xianquan Zhan",coverURL:"https://cdn.intechopen.com/books/images_new/10797.jpg",editedByType:null,editors:[{id:"223233",title:"Prof.",name:"Xianquan",surname:"Zhan",slug:"xianquan-zhan",fullName:"Xianquan Zhan"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10772",title:"Parasitic Plants",subtitle:null,isOpenForSubmission:!0,hash:"31abd439b5674c91d18ad77dbc52500f",slug:null,bookSignature:"Dr. Ana Maria Gonzalez and Dr. Hector Sato",coverURL:"https://cdn.intechopen.com/books/images_new/10772.jpg",editedByType:null,editors:[{id:"281854",title:"Dr.",name:"Ana Maria",surname:"Gonzalez",slug:"ana-maria-gonzalez",fullName:"Ana Maria Gonzalez"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10737",title:"Equus",subtitle:null,isOpenForSubmission:!0,hash:"258ffafc92a7c9550bb85f004d7402e7",slug:null,bookSignature:"Associate Prof. Adriana Pires Neves",coverURL:"https://cdn.intechopen.com/books/images_new/10737.jpg",editedByType:null,editors:[{id:"188768",title:"Associate Prof.",name:"Adriana",surname:"Pires Neves",slug:"adriana-pires-neves",fullName:"Adriana Pires Neves"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10777",title:"Plant Reproductive Ecology - Recent Advances",subtitle:null,isOpenForSubmission:!0,hash:"3fbf391f2093649bcf3bd674f7e32189",slug:null,bookSignature:"Dr. Balkrishna Ghimire",coverURL:"https://cdn.intechopen.com/books/images_new/10777.jpg",editedByType:null,editors:[{id:"206647",title:"Dr.",name:"Balkrishna",surname:"Ghimire",slug:"balkrishna-ghimire",fullName:"Balkrishna Ghimire"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10749",title:"Legumes",subtitle:null,isOpenForSubmission:!0,hash:"49d3123cde96adbe706adadebebc5ebb",slug:null,bookSignature:"Dr. Jose Carlos Jimenez-Lopez",coverURL:"https://cdn.intechopen.com/books/images_new/10749.jpg",editedByType:null,editors:[{id:"33993",title:"Dr.",name:"Jose Carlos",surname:"Jimenez-Lopez",slug:"jose-carlos-jimenez-lopez",fullName:"Jose Carlos Jimenez-Lopez"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10751",title:"Bovine Science",subtitle:null,isOpenForSubmission:!0,hash:"9e3eb325f9fce20e6cefbce1c26d647a",slug:null,bookSignature:"Dr. Muhammad Abubakar",coverURL:"https://cdn.intechopen.com/books/images_new/10751.jpg",editedByType:null,editors:[{id:"112070",title:"Dr.",name:"Muhammad",surname:"Abubakar",slug:"muhammad-abubakar",fullName:"Muhammad Abubakar"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}],filtersByTopic:[{group:"topic",caption:"Agricultural and Biological Sciences",value:5,count:19},{group:"topic",caption:"Biochemistry, Genetics and Molecular Biology",value:6,count:5},{group:"topic",caption:"Business, Management and Economics",value:7,count:2},{group:"topic",caption:"Chemistry",value:8,count:8},{group:"topic",caption:"Computer and Information Science",value:9,count:6},{group:"topic",caption:"Earth and Planetary Sciences",value:10,count:7},{group:"topic",caption:"Engineering",value:11,count:21},{group:"topic",caption:"Environmental Sciences",value:12,count:2},{group:"topic",caption:"Immunology and Microbiology",value:13,count:4},{group:"topic",caption:"Materials Science",value:14,count:6},{group:"topic",caption:"Mathematics",value:15,count:1},{group:"topic",caption:"Medicine",value:16,count:25},{group:"topic",caption:"Neuroscience",value:18,count:2},{group:"topic",caption:"Pharmacology, Toxicology and Pharmaceutical Science",value:19,count:3},{group:"topic",caption:"Physics",value:20,count:3},{group:"topic",caption:"Psychology",value:21,count:4},{group:"topic",caption:"Robotics",value:22,count:1},{group:"topic",caption:"Social Sciences",value:23,count:3},{group:"topic",caption:"Technology",value:24,count:1},{group:"topic",caption:"Veterinary Medicine and Science",value:25,count:1}],offset:12,limit:12,total:24},popularBooks:{featuredBooks:[{type:"book",id:"9521",title:"Antimicrobial Resistance",subtitle:"A One Health Perspective",isOpenForSubmission:!1,hash:"30949e78832e1afba5606634b52056ab",slug:"antimicrobial-resistance-a-one-health-perspective",bookSignature:"Mihai Mareș, Swee Hua Erin Lim, Kok-Song Lai and Romeo-Teodor Cristina",coverURL:"https://cdn.intechopen.com/books/images_new/9521.jpg",editors:[{id:"88785",title:"Prof.",name:"Mihai",middleName:null,surname:"Mares",slug:"mihai-mares",fullName:"Mihai Mares"}],equalEditorOne:{id:"190224",title:"Dr.",name:"Swee Hua Erin",middleName:null,surname:"Lim",slug:"swee-hua-erin-lim",fullName:"Swee Hua Erin Lim",profilePictureURL:"https://mts.intechopen.com/storage/users/190224/images/system/190224.png",biography:"Dr. Erin Lim is presently working as an Assistant Professor in the Division of Health Sciences, Abu Dhabi Women\\'s College, Higher Colleges of Technology in Abu Dhabi, United Arab Emirates and is affiliated as an Associate Professor to Perdana University-Royal College of Surgeons in Ireland, Selangor, Malaysia. She obtained her Ph.D. from Universiti Putra Malaysia in 2010 with a National Science Fellowship awarded from the Ministry of Science, Technology and Innovation Malaysia and has been actively involved in research ever since. Her main research interests include analysis of carriage and transmission of multidrug resistant bacteria in non-conventional settings, besides an interest in natural products for antimicrobial testing. She is heavily involved in the elucidation of mechanisms of reversal of resistance in bacteria in addition to investigating the immunological analyses of diseases, development of vaccination and treatment models in animals. She hopes her work will support the discovery of therapeutics in the clinical setting and assist in the combat against the burden of antibiotic resistance.",institutionString:"Abu Dhabi Women’s College",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"3",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"Perdana University",institutionURL:null,country:{name:"Malaysia"}}},equalEditorTwo:{id:"221544",title:"Dr.",name:"Kok-Song",middleName:null,surname:"Lai",slug:"kok-song-lai",fullName:"Kok-Song Lai",profilePictureURL:"https://mts.intechopen.com/storage/users/221544/images/system/221544.jpeg",biography:"Dr. Lai Kok Song is an Assistant Professor in the Division of Health Sciences, Abu Dhabi Women\\'s College, Higher Colleges of Technology in Abu Dhabi, United Arab Emirates. He obtained his Ph.D. in Biological Sciences from Nara Institute of Science and Technology, Japan in 2012. Prior to his academic appointment, Dr. Lai worked as a Senior Scientist at the Ministry of Science, Technology and Innovation, Malaysia. His current research areas include antimicrobial resistance and plant-pathogen interaction. His particular interest lies in the study of the antimicrobial mechanism via membrane disruption of essential oils against multi-drug resistance bacteria through various biochemical, molecular and proteomic approaches. Ultimately, he hopes to uncover and determine novel biomarkers related to antibiotic resistance that can be developed into new therapeutic strategies.",institutionString:"Higher Colleges of Technology",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"8",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"Higher Colleges of Technology",institutionURL:null,country:{name:"United Arab Emirates"}}},equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"10020",title:"Operations Management",subtitle:"Emerging Trend in the Digital Era",isOpenForSubmission:!1,hash:"526f0dbdc7e4d85b82ce8383ab894b4c",slug:"operations-management-emerging-trend-in-the-digital-era",bookSignature:"Antonella Petrillo, Fabio De Felice, Germano Lambert-Torres and Erik Bonaldi",coverURL:"https://cdn.intechopen.com/books/images_new/10020.jpg",editors:[{id:"181603",title:"Dr.",name:"Antonella",middleName:null,surname:"Petrillo",slug:"antonella-petrillo",fullName:"Antonella Petrillo"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9560",title:"Creativity",subtitle:"A Force to Innovation",isOpenForSubmission:!1,hash:"58f740bc17807d5d88d647c525857b11",slug:"creativity-a-force-to-innovation",bookSignature:"Pooja Jain",coverURL:"https://cdn.intechopen.com/books/images_new/9560.jpg",editors:[{id:"316765",title:"Dr.",name:"Pooja",middleName:null,surname:"Jain",slug:"pooja-jain",fullName:"Pooja Jain"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9385",title:"Renewable Energy",subtitle:"Technologies and Applications",isOpenForSubmission:!1,hash:"a6b446d19166f17f313008e6c056f3d8",slug:"renewable-energy-technologies-and-applications",bookSignature:"Tolga Taner, Archana Tiwari and Taha Selim Ustun",coverURL:"https://cdn.intechopen.com/books/images_new/9385.jpg",editors:[{id:"197240",title:"Associate Prof.",name:"Tolga",middleName:null,surname:"Taner",slug:"tolga-taner",fullName:"Tolga Taner"}],equalEditorOne:{id:"186791",title:"Dr.",name:"Archana",middleName:null,surname:"Tiwari",slug:"archana-tiwari",fullName:"Archana Tiwari",profilePictureURL:"https://mts.intechopen.com/storage/users/186791/images/system/186791.jpg",biography:"Dr. Archana Tiwari is Associate Professor at Amity University, India. Her research interests include renewable sources of energy from microalgae and further utilizing the residual biomass for the generation of value-added products, bioremediation through microalgae and microbial consortium, antioxidative enzymes and stress, and nutraceuticals from microalgae. She has been working on algal biotechnology for the last two decades. She has published her research in many international journals and has authored many books and chapters with renowned publishing houses. She has also delivered talks as an invited speaker at many national and international conferences. Dr. Tiwari is the recipient of several awards including Researcher of the Year and Distinguished Scientist.",institutionString:"Amity University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"3",totalChapterViews:"0",totalEditedBooks:"1",institution:{name:"Amity University",institutionURL:null,country:{name:"India"}}},equalEditorTwo:{id:"197609",title:"Prof.",name:"Taha Selim",middleName:null,surname:"Ustun",slug:"taha-selim-ustun",fullName:"Taha Selim Ustun",profilePictureURL:"https://mts.intechopen.com/storage/users/197609/images/system/197609.jpeg",biography:"Dr. Taha Selim Ustun received a Ph.D. in Electrical Engineering from Victoria University, Melbourne, Australia. He is a researcher with the Fukushima Renewable Energy Institute, AIST (FREA), where he leads the Smart Grid Cybersecurity Laboratory. Prior to that, he was a faculty member with the School of Electrical and Computer Engineering, Carnegie Mellon University, Pittsburgh, PA, USA. His current research interests include power systems protection, communication in power networks, distributed generation, microgrids, electric vehicle integration, and cybersecurity in smart grids. He serves on the editorial boards of IEEE Access, IEEE Transactions on Industrial Informatics, Energies, Electronics, Electricity, World Electric Vehicle and Information journals. Dr. Ustun is a member of the IEEE 2004 and 2800, IEC Renewable Energy Management WG 8, and IEC TC 57 WG17. He has been invited to run specialist courses in Africa, India, and China. He has delivered talks for the Qatar Foundation, the World Energy Council, the Waterloo Global Science Initiative, and the European Union Energy Initiative (EUEI). His research has attracted funding from prestigious programs in Japan, Australia, the European Union, and North America.",institutionString:"Fukushima Renewable Energy Institute, AIST (FREA)",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"National Institute of Advanced Industrial Science and Technology",institutionURL:null,country:{name:"Japan"}}},equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"8985",title:"Natural Resources Management and Biological Sciences",subtitle:null,isOpenForSubmission:!1,hash:"5c2e219a6c021a40b5a20c041dea88c4",slug:"natural-resources-management-and-biological-sciences",bookSignature:"Edward R. Rhodes and Humood Naser",coverURL:"https://cdn.intechopen.com/books/images_new/8985.jpg",editors:[{id:"280886",title:"Prof.",name:"Edward R",middleName:null,surname:"Rhodes",slug:"edward-r-rhodes",fullName:"Edward R Rhodes"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"10192",title:"Background and Management of Muscular Atrophy",subtitle:null,isOpenForSubmission:!1,hash:"eca24028d89912b5efea56e179dff089",slug:"background-and-management-of-muscular-atrophy",bookSignature:"Julianna Cseri",coverURL:"https://cdn.intechopen.com/books/images_new/10192.jpg",editors:[{id:"135579",title:"Dr.",name:"Julianna",middleName:null,surname:"Cseri",slug:"julianna-cseri",fullName:"Julianna Cseri"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"10065",title:"Wavelet Theory",subtitle:null,isOpenForSubmission:!1,hash:"d8868e332169597ba2182d9b004d60de",slug:"wavelet-theory",bookSignature:"Somayeh Mohammady",coverURL:"https://cdn.intechopen.com/books/images_new/10065.jpg",editors:[{id:"109280",title:"Dr.",name:"Somayeh",middleName:null,surname:"Mohammady",slug:"somayeh-mohammady",fullName:"Somayeh Mohammady"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9644",title:"Glaciers and the Polar Environment",subtitle:null,isOpenForSubmission:!1,hash:"e8cfdc161794e3753ced54e6ff30873b",slug:"glaciers-and-the-polar-environment",bookSignature:"Masaki Kanao, Danilo Godone and Niccolò Dematteis",coverURL:"https://cdn.intechopen.com/books/images_new/9644.jpg",editors:[{id:"51959",title:"Dr.",name:"Masaki",middleName:null,surname:"Kanao",slug:"masaki-kanao",fullName:"Masaki Kanao"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9243",title:"Coastal Environments",subtitle:null,isOpenForSubmission:!1,hash:"8e05e5f631e935eef366980f2e28295d",slug:"coastal-environments",bookSignature:"Yuanzhi Zhang and X. San Liang",coverURL:"https://cdn.intechopen.com/books/images_new/9243.jpg",editors:[{id:"77597",title:"Prof.",name:"Yuanzhi",middleName:null,surname:"Zhang",slug:"yuanzhi-zhang",fullName:"Yuanzhi Zhang"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"7847",title:"Medical Toxicology",subtitle:null,isOpenForSubmission:!1,hash:"db9b65bea093de17a0855a1b27046247",slug:"medical-toxicology",bookSignature:"Pınar Erkekoglu and Tomohisa Ogawa",coverURL:"https://cdn.intechopen.com/books/images_new/7847.jpg",editors:[{id:"109978",title:"Prof.",name:"Pınar",middleName:null,surname:"Erkekoglu",slug:"pinar-erkekoglu",fullName:"Pınar Erkekoglu"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9027",title:"Human Blood Group Systems and Haemoglobinopathies",subtitle:null,isOpenForSubmission:!1,hash:"d00d8e40b11cfb2547d1122866531c7e",slug:"human-blood-group-systems-and-haemoglobinopathies",bookSignature:"Osaro Erhabor and Anjana Munshi",coverURL:"https://cdn.intechopen.com/books/images_new/9027.jpg",editors:[{id:"35140",title:null,name:"Osaro",middleName:null,surname:"Erhabor",slug:"osaro-erhabor",fullName:"Osaro Erhabor"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"8558",title:"Aerodynamics",subtitle:null,isOpenForSubmission:!1,hash:"db7263fc198dfb539073ba0260a7f1aa",slug:"aerodynamics",bookSignature:"Mofid Gorji-Bandpy and Aly-Mousaad Aly",coverURL:"https://cdn.intechopen.com/books/images_new/8558.jpg",editors:[{id:"35542",title:"Prof.",name:"Mofid",middleName:null,surname:"Gorji-Bandpy",slug:"mofid-gorji-bandpy",fullName:"Mofid Gorji-Bandpy"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}}],offset:12,limit:12,total:5252},hotBookTopics:{hotBooks:[],offset:0,limit:12,total:null},publish:{},publishingProposal:{success:null,errors:{}},books:{featuredBooks:[{type:"book",id:"9521",title:"Antimicrobial Resistance",subtitle:"A One Health Perspective",isOpenForSubmission:!1,hash:"30949e78832e1afba5606634b52056ab",slug:"antimicrobial-resistance-a-one-health-perspective",bookSignature:"Mihai Mareș, Swee Hua Erin Lim, Kok-Song Lai and Romeo-Teodor Cristina",coverURL:"https://cdn.intechopen.com/books/images_new/9521.jpg",editors:[{id:"88785",title:"Prof.",name:"Mihai",middleName:null,surname:"Mares",slug:"mihai-mares",fullName:"Mihai Mares"}],equalEditorOne:{id:"190224",title:"Dr.",name:"Swee Hua Erin",middleName:null,surname:"Lim",slug:"swee-hua-erin-lim",fullName:"Swee Hua Erin Lim",profilePictureURL:"https://mts.intechopen.com/storage/users/190224/images/system/190224.png",biography:"Dr. Erin Lim is presently working as an Assistant Professor in the Division of Health Sciences, Abu Dhabi Women\\'s College, Higher Colleges of Technology in Abu Dhabi, United Arab Emirates and is affiliated as an Associate Professor to Perdana University-Royal College of Surgeons in Ireland, Selangor, Malaysia. She obtained her Ph.D. from Universiti Putra Malaysia in 2010 with a National Science Fellowship awarded from the Ministry of Science, Technology and Innovation Malaysia and has been actively involved in research ever since. Her main research interests include analysis of carriage and transmission of multidrug resistant bacteria in non-conventional settings, besides an interest in natural products for antimicrobial testing. She is heavily involved in the elucidation of mechanisms of reversal of resistance in bacteria in addition to investigating the immunological analyses of diseases, development of vaccination and treatment models in animals. She hopes her work will support the discovery of therapeutics in the clinical setting and assist in the combat against the burden of antibiotic resistance.",institutionString:"Abu Dhabi Women’s College",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"3",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"Perdana University",institutionURL:null,country:{name:"Malaysia"}}},equalEditorTwo:{id:"221544",title:"Dr.",name:"Kok-Song",middleName:null,surname:"Lai",slug:"kok-song-lai",fullName:"Kok-Song Lai",profilePictureURL:"https://mts.intechopen.com/storage/users/221544/images/system/221544.jpeg",biography:"Dr. Lai Kok Song is an Assistant Professor in the Division of Health Sciences, Abu Dhabi Women\\'s College, Higher Colleges of Technology in Abu Dhabi, United Arab Emirates. He obtained his Ph.D. in Biological Sciences from Nara Institute of Science and Technology, Japan in 2012. Prior to his academic appointment, Dr. Lai worked as a Senior Scientist at the Ministry of Science, Technology and Innovation, Malaysia. His current research areas include antimicrobial resistance and plant-pathogen interaction. His particular interest lies in the study of the antimicrobial mechanism via membrane disruption of essential oils against multi-drug resistance bacteria through various biochemical, molecular and proteomic approaches. Ultimately, he hopes to uncover and determine novel biomarkers related to antibiotic resistance that can be developed into new therapeutic strategies.",institutionString:"Higher Colleges of Technology",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"8",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"Higher Colleges of Technology",institutionURL:null,country:{name:"United Arab Emirates"}}},equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"10020",title:"Operations Management",subtitle:"Emerging Trend in the Digital Era",isOpenForSubmission:!1,hash:"526f0dbdc7e4d85b82ce8383ab894b4c",slug:"operations-management-emerging-trend-in-the-digital-era",bookSignature:"Antonella Petrillo, Fabio De Felice, Germano Lambert-Torres and Erik Bonaldi",coverURL:"https://cdn.intechopen.com/books/images_new/10020.jpg",editors:[{id:"181603",title:"Dr.",name:"Antonella",middleName:null,surname:"Petrillo",slug:"antonella-petrillo",fullName:"Antonella Petrillo"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9560",title:"Creativity",subtitle:"A Force to Innovation",isOpenForSubmission:!1,hash:"58f740bc17807d5d88d647c525857b11",slug:"creativity-a-force-to-innovation",bookSignature:"Pooja Jain",coverURL:"https://cdn.intechopen.com/books/images_new/9560.jpg",editors:[{id:"316765",title:"Dr.",name:"Pooja",middleName:null,surname:"Jain",slug:"pooja-jain",fullName:"Pooja Jain"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9385",title:"Renewable Energy",subtitle:"Technologies and Applications",isOpenForSubmission:!1,hash:"a6b446d19166f17f313008e6c056f3d8",slug:"renewable-energy-technologies-and-applications",bookSignature:"Tolga Taner, Archana Tiwari and Taha Selim Ustun",coverURL:"https://cdn.intechopen.com/books/images_new/9385.jpg",editors:[{id:"197240",title:"Associate Prof.",name:"Tolga",middleName:null,surname:"Taner",slug:"tolga-taner",fullName:"Tolga Taner"}],equalEditorOne:{id:"186791",title:"Dr.",name:"Archana",middleName:null,surname:"Tiwari",slug:"archana-tiwari",fullName:"Archana Tiwari",profilePictureURL:"https://mts.intechopen.com/storage/users/186791/images/system/186791.jpg",biography:"Dr. Archana Tiwari is Associate Professor at Amity University, India. Her research interests include renewable sources of energy from microalgae and further utilizing the residual biomass for the generation of value-added products, bioremediation through microalgae and microbial consortium, antioxidative enzymes and stress, and nutraceuticals from microalgae. She has been working on algal biotechnology for the last two decades. She has published her research in many international journals and has authored many books and chapters with renowned publishing houses. She has also delivered talks as an invited speaker at many national and international conferences. Dr. Tiwari is the recipient of several awards including Researcher of the Year and Distinguished Scientist.",institutionString:"Amity University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"3",totalChapterViews:"0",totalEditedBooks:"1",institution:{name:"Amity University",institutionURL:null,country:{name:"India"}}},equalEditorTwo:{id:"197609",title:"Prof.",name:"Taha Selim",middleName:null,surname:"Ustun",slug:"taha-selim-ustun",fullName:"Taha Selim Ustun",profilePictureURL:"https://mts.intechopen.com/storage/users/197609/images/system/197609.jpeg",biography:"Dr. Taha Selim Ustun received a Ph.D. in Electrical Engineering from Victoria University, Melbourne, Australia. He is a researcher with the Fukushima Renewable Energy Institute, AIST (FREA), where he leads the Smart Grid Cybersecurity Laboratory. Prior to that, he was a faculty member with the School of Electrical and Computer Engineering, Carnegie Mellon University, Pittsburgh, PA, USA. His current research interests include power systems protection, communication in power networks, distributed generation, microgrids, electric vehicle integration, and cybersecurity in smart grids. He serves on the editorial boards of IEEE Access, IEEE Transactions on Industrial Informatics, Energies, Electronics, Electricity, World Electric Vehicle and Information journals. Dr. Ustun is a member of the IEEE 2004 and 2800, IEC Renewable Energy Management WG 8, and IEC TC 57 WG17. He has been invited to run specialist courses in Africa, India, and China. He has delivered talks for the Qatar Foundation, the World Energy Council, the Waterloo Global Science Initiative, and the European Union Energy Initiative (EUEI). His research has attracted funding from prestigious programs in Japan, Australia, the European Union, and North America.",institutionString:"Fukushima Renewable Energy Institute, AIST (FREA)",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"National Institute of Advanced Industrial Science and Technology",institutionURL:null,country:{name:"Japan"}}},equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"8985",title:"Natural Resources Management and Biological Sciences",subtitle:null,isOpenForSubmission:!1,hash:"5c2e219a6c021a40b5a20c041dea88c4",slug:"natural-resources-management-and-biological-sciences",bookSignature:"Edward R. Rhodes and Humood Naser",coverURL:"https://cdn.intechopen.com/books/images_new/8985.jpg",editors:[{id:"280886",title:"Prof.",name:"Edward R",middleName:null,surname:"Rhodes",slug:"edward-r-rhodes",fullName:"Edward R Rhodes"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"10192",title:"Background and Management of Muscular Atrophy",subtitle:null,isOpenForSubmission:!1,hash:"eca24028d89912b5efea56e179dff089",slug:"background-and-management-of-muscular-atrophy",bookSignature:"Julianna Cseri",coverURL:"https://cdn.intechopen.com/books/images_new/10192.jpg",editors:[{id:"135579",title:"Dr.",name:"Julianna",middleName:null,surname:"Cseri",slug:"julianna-cseri",fullName:"Julianna Cseri"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"10065",title:"Wavelet Theory",subtitle:null,isOpenForSubmission:!1,hash:"d8868e332169597ba2182d9b004d60de",slug:"wavelet-theory",bookSignature:"Somayeh Mohammady",coverURL:"https://cdn.intechopen.com/books/images_new/10065.jpg",editors:[{id:"109280",title:"Dr.",name:"Somayeh",middleName:null,surname:"Mohammady",slug:"somayeh-mohammady",fullName:"Somayeh Mohammady"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9243",title:"Coastal Environments",subtitle:null,isOpenForSubmission:!1,hash:"8e05e5f631e935eef366980f2e28295d",slug:"coastal-environments",bookSignature:"Yuanzhi Zhang and X. San Liang",coverURL:"https://cdn.intechopen.com/books/images_new/9243.jpg",editors:[{id:"77597",title:"Prof.",name:"Yuanzhi",middleName:null,surname:"Zhang",slug:"yuanzhi-zhang",fullName:"Yuanzhi Zhang"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9644",title:"Glaciers and the Polar Environment",subtitle:null,isOpenForSubmission:!1,hash:"e8cfdc161794e3753ced54e6ff30873b",slug:"glaciers-and-the-polar-environment",bookSignature:"Masaki Kanao, Danilo Godone and Niccolò Dematteis",coverURL:"https://cdn.intechopen.com/books/images_new/9644.jpg",editors:[{id:"51959",title:"Dr.",name:"Masaki",middleName:null,surname:"Kanao",slug:"masaki-kanao",fullName:"Masaki Kanao"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"7847",title:"Medical Toxicology",subtitle:null,isOpenForSubmission:!1,hash:"db9b65bea093de17a0855a1b27046247",slug:"medical-toxicology",bookSignature:"Pınar Erkekoglu and Tomohisa Ogawa",coverURL:"https://cdn.intechopen.com/books/images_new/7847.jpg",editors:[{id:"109978",title:"Prof.",name:"Pınar",middleName:null,surname:"Erkekoglu",slug:"pinar-erkekoglu",fullName:"Pınar Erkekoglu"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}}],latestBooks:[{type:"book",id:"9243",title:"Coastal Environments",subtitle:null,isOpenForSubmission:!1,hash:"8e05e5f631e935eef366980f2e28295d",slug:"coastal-environments",bookSignature:"Yuanzhi Zhang and X. San Liang",coverURL:"https://cdn.intechopen.com/books/images_new/9243.jpg",editedByType:"Edited by",editors:[{id:"77597",title:"Prof.",name:"Yuanzhi",middleName:null,surname:"Zhang",slug:"yuanzhi-zhang",fullName:"Yuanzhi Zhang"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10020",title:"Operations Management",subtitle:"Emerging Trend in the Digital Era",isOpenForSubmission:!1,hash:"526f0dbdc7e4d85b82ce8383ab894b4c",slug:"operations-management-emerging-trend-in-the-digital-era",bookSignature:"Antonella Petrillo, Fabio De Felice, Germano Lambert-Torres and Erik Bonaldi",coverURL:"https://cdn.intechopen.com/books/images_new/10020.jpg",editedByType:"Edited by",editors:[{id:"181603",title:"Dr.",name:"Antonella",middleName:null,surname:"Petrillo",slug:"antonella-petrillo",fullName:"Antonella Petrillo"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9521",title:"Antimicrobial Resistance",subtitle:"A One Health Perspective",isOpenForSubmission:!1,hash:"30949e78832e1afba5606634b52056ab",slug:"antimicrobial-resistance-a-one-health-perspective",bookSignature:"Mihai Mareș, Swee Hua Erin Lim, Kok-Song Lai and Romeo-Teodor Cristina",coverURL:"https://cdn.intechopen.com/books/images_new/9521.jpg",editedByType:"Edited by",editors:[{id:"88785",title:"Prof.",name:"Mihai",middleName:null,surname:"Mares",slug:"mihai-mares",fullName:"Mihai Mares"}],equalEditorOne:{id:"190224",title:"Dr.",name:"Swee Hua Erin",middleName:null,surname:"Lim",slug:"swee-hua-erin-lim",fullName:"Swee Hua Erin Lim",profilePictureURL:"https://mts.intechopen.com/storage/users/190224/images/system/190224.png",biography:"Dr. Erin Lim is presently working as an Assistant Professor in the Division of Health Sciences, Abu Dhabi Women\\'s College, Higher Colleges of Technology in Abu Dhabi, United Arab Emirates and is affiliated as an Associate Professor to Perdana University-Royal College of Surgeons in Ireland, Selangor, Malaysia. She obtained her Ph.D. from Universiti Putra Malaysia in 2010 with a National Science Fellowship awarded from the Ministry of Science, Technology and Innovation Malaysia and has been actively involved in research ever since. Her main research interests include analysis of carriage and transmission of multidrug resistant bacteria in non-conventional settings, besides an interest in natural products for antimicrobial testing. She is heavily involved in the elucidation of mechanisms of reversal of resistance in bacteria in addition to investigating the immunological analyses of diseases, development of vaccination and treatment models in animals. She hopes her work will support the discovery of therapeutics in the clinical setting and assist in the combat against the burden of antibiotic resistance.",institutionString:"Abu Dhabi Women’s College",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"3",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"Perdana University",institutionURL:null,country:{name:"Malaysia"}}},equalEditorTwo:{id:"221544",title:"Dr.",name:"Kok-Song",middleName:null,surname:"Lai",slug:"kok-song-lai",fullName:"Kok-Song Lai",profilePictureURL:"https://mts.intechopen.com/storage/users/221544/images/system/221544.jpeg",biography:"Dr. Lai Kok Song is an Assistant Professor in the Division of Health Sciences, Abu Dhabi Women\\'s College, Higher Colleges of Technology in Abu Dhabi, United Arab Emirates. He obtained his Ph.D. in Biological Sciences from Nara Institute of Science and Technology, Japan in 2012. Prior to his academic appointment, Dr. Lai worked as a Senior Scientist at the Ministry of Science, Technology and Innovation, Malaysia. His current research areas include antimicrobial resistance and plant-pathogen interaction. His particular interest lies in the study of the antimicrobial mechanism via membrane disruption of essential oils against multi-drug resistance bacteria through various biochemical, molecular and proteomic approaches. Ultimately, he hopes to uncover and determine novel biomarkers related to antibiotic resistance that can be developed into new therapeutic strategies.",institutionString:"Higher Colleges of Technology",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"8",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"Higher Colleges of Technology",institutionURL:null,country:{name:"United Arab Emirates"}}},equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9560",title:"Creativity",subtitle:"A Force to Innovation",isOpenForSubmission:!1,hash:"58f740bc17807d5d88d647c525857b11",slug:"creativity-a-force-to-innovation",bookSignature:"Pooja Jain",coverURL:"https://cdn.intechopen.com/books/images_new/9560.jpg",editedByType:"Edited by",editors:[{id:"316765",title:"Dr.",name:"Pooja",middleName:null,surname:"Jain",slug:"pooja-jain",fullName:"Pooja Jain"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9669",title:"Recent Advances in Rice Research",subtitle:null,isOpenForSubmission:!1,hash:"12b06cc73e89af1e104399321cc16a75",slug:"recent-advances-in-rice-research",bookSignature:"Mahmood-ur- Rahman Ansari",coverURL:"https://cdn.intechopen.com/books/images_new/9669.jpg",editedByType:"Edited by",editors:[{id:"185476",title:"Dr.",name:"Mahmood-Ur-",middleName:null,surname:"Rahman Ansari",slug:"mahmood-ur-rahman-ansari",fullName:"Mahmood-Ur- Rahman Ansari"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10192",title:"Background and Management of Muscular Atrophy",subtitle:null,isOpenForSubmission:!1,hash:"eca24028d89912b5efea56e179dff089",slug:"background-and-management-of-muscular-atrophy",bookSignature:"Julianna Cseri",coverURL:"https://cdn.intechopen.com/books/images_new/10192.jpg",editedByType:"Edited by",editors:[{id:"135579",title:"Dr.",name:"Julianna",middleName:null,surname:"Cseri",slug:"julianna-cseri",fullName:"Julianna Cseri"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9550",title:"Entrepreneurship",subtitle:"Contemporary Issues",isOpenForSubmission:!1,hash:"9b4ac1ee5b743abf6f88495452b1e5e7",slug:"entrepreneurship-contemporary-issues",bookSignature:"Mladen Turuk",coverURL:"https://cdn.intechopen.com/books/images_new/9550.jpg",editedByType:"Edited by",editors:[{id:"319755",title:"Prof.",name:"Mladen",middleName:null,surname:"Turuk",slug:"mladen-turuk",fullName:"Mladen Turuk"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10065",title:"Wavelet Theory",subtitle:null,isOpenForSubmission:!1,hash:"d8868e332169597ba2182d9b004d60de",slug:"wavelet-theory",bookSignature:"Somayeh Mohammady",coverURL:"https://cdn.intechopen.com/books/images_new/10065.jpg",editedByType:"Edited by",editors:[{id:"109280",title:"Dr.",name:"Somayeh",middleName:null,surname:"Mohammady",slug:"somayeh-mohammady",fullName:"Somayeh Mohammady"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9313",title:"Clay Science and Technology",subtitle:null,isOpenForSubmission:!1,hash:"6fa7e70396ff10620e032bb6cfa6fb72",slug:"clay-science-and-technology",bookSignature:"Gustavo Morari Do Nascimento",coverURL:"https://cdn.intechopen.com/books/images_new/9313.jpg",editedByType:"Edited by",editors:[{id:"7153",title:"Prof.",name:"Gustavo",middleName:null,surname:"Morari Do Nascimento",slug:"gustavo-morari-do-nascimento",fullName:"Gustavo Morari Do Nascimento"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9888",title:"Nuclear Power Plants",subtitle:"The Processes from the Cradle to the Grave",isOpenForSubmission:!1,hash:"c2c8773e586f62155ab8221ebb72a849",slug:"nuclear-power-plants-the-processes-from-the-cradle-to-the-grave",bookSignature:"Nasser Awwad",coverURL:"https://cdn.intechopen.com/books/images_new/9888.jpg",editedByType:"Edited by",editors:[{id:"145209",title:"Prof.",name:"Nasser",middleName:"S",surname:"Awwad",slug:"nasser-awwad",fullName:"Nasser Awwad"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},subject:{topic:{id:"16",title:"Medicine",slug:"medicine",parent:{title:"Health Sciences",slug:"health-sciences"},numberOfBooks:1511,numberOfAuthorsAndEditors:39573,numberOfWosCitations:21767,numberOfCrossrefCitations:11544,numberOfDimensionsCitations:29307,videoUrl:null,fallbackUrl:null,description:null},booksByTopicFilter:{topicSlug:"medicine",sort:"-publishedDate",limit:12,offset:0},booksByTopicCollection:[{type:"book",id:"10192",title:"Background and Management of Muscular Atrophy",subtitle:null,isOpenForSubmission:!1,hash:"eca24028d89912b5efea56e179dff089",slug:"background-and-management-of-muscular-atrophy",bookSignature:"Julianna Cseri",coverURL:"https://cdn.intechopen.com/books/images_new/10192.jpg",editedByType:"Edited by",editors:[{id:"135579",title:"Dr.",name:"Julianna",middleName:null,surname:"Cseri",slug:"julianna-cseri",fullName:"Julianna Cseri"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9027",title:"Human Blood Group Systems and Haemoglobinopathies",subtitle:null,isOpenForSubmission:!1,hash:"d00d8e40b11cfb2547d1122866531c7e",slug:"human-blood-group-systems-and-haemoglobinopathies",bookSignature:"Osaro Erhabor and Anjana Munshi",coverURL:"https://cdn.intechopen.com/books/images_new/9027.jpg",editedByType:"Edited by",editors:[{id:"35140",title:null,name:"Osaro",middleName:null,surname:"Erhabor",slug:"osaro-erhabor",fullName:"Osaro Erhabor"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9406",title:"Clinical Implementation of Bone Regeneration and Maintenance",subtitle:null,isOpenForSubmission:!1,hash:"875a140c01518fa7a9bceebd688b0147",slug:"clinical-implementation-of-bone-regeneration-and-maintenance",bookSignature:"Mike Barbeck, Nahum Rosenberg, Patrick Rider, Željka Perić Kačarević and Ole Jung",coverURL:"https://cdn.intechopen.com/books/images_new/9406.jpg",editedByType:"Edited by",editors:[{id:"204918",title:"Dr.",name:"Mike",middleName:null,surname:"Barbeck",slug:"mike-barbeck",fullName:"Mike Barbeck"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9122",title:"Cosmetic Surgery",subtitle:null,isOpenForSubmission:!1,hash:"207026ca4a4125e17038e770d00ee152",slug:"cosmetic-surgery",bookSignature:"Yueh-Bih Tang",coverURL:"https://cdn.intechopen.com/books/images_new/9122.jpg",editedByType:"Edited by",editors:[{id:"202122",title:"Prof.",name:"Yueh-Bih",middleName:null,surname:"Tang",slug:"yueh-bih-tang",fullName:"Yueh-Bih Tang"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9134",title:"Recent Advances in Digital System Diagnosis and Management of Healthcare",subtitle:null,isOpenForSubmission:!1,hash:"ff00a5718f23cb880b7337b1c36b5434",slug:"recent-advances-in-digital-system-diagnosis-and-management-of-healthcare",bookSignature:"Kamran Sartipi and Thierry Edoh",coverURL:"https://cdn.intechopen.com/books/images_new/9134.jpg",editedByType:"Edited by",editors:[{id:"29601",title:"Dr.",name:"Kamran",middleName:null,surname:"Sartipi",slug:"kamran-sartipi",fullName:"Kamran Sartipi"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9569",title:"Methods in Molecular Medicine",subtitle:null,isOpenForSubmission:!1,hash:"691d3f3c4ac25a8093414e9b270d2843",slug:"methods-in-molecular-medicine",bookSignature:"Yusuf Tutar",coverURL:"https://cdn.intechopen.com/books/images_new/9569.jpg",editedByType:"Edited by",editors:[{id:"158492",title:"Prof.",name:"Yusuf",middleName:null,surname:"Tutar",slug:"yusuf-tutar",fullName:"Yusuf Tutar"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9157",title:"Neurodegenerative Diseases",subtitle:"Molecular Mechanisms and Current Therapeutic Approaches",isOpenForSubmission:!1,hash:"bc8be577966ef88735677d7e1e92ed28",slug:"neurodegenerative-diseases-molecular-mechanisms-and-current-therapeutic-approaches",bookSignature:"Nagehan Ersoy Tunalı",coverURL:"https://cdn.intechopen.com/books/images_new/9157.jpg",editedByType:"Edited by",editors:[{id:"82778",title:"Ph.D.",name:"Nagehan",middleName:null,surname:"Ersoy Tunalı",slug:"nagehan-ersoy-tunali",fullName:"Nagehan Ersoy Tunalı"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9839",title:"Outdoor Recreation",subtitle:"Physiological and Psychological Effects on Health",isOpenForSubmission:!1,hash:"5f5a0d64267e32567daffa5b0c6a6972",slug:"outdoor-recreation-physiological-and-psychological-effects-on-health",bookSignature:"Hilde G. Nielsen",coverURL:"https://cdn.intechopen.com/books/images_new/9839.jpg",editedByType:"Edited by",editors:[{id:"158692",title:"Ph.D.",name:"Hilde G.",middleName:null,surname:"Nielsen",slug:"hilde-g.-nielsen",fullName:"Hilde G. Nielsen"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9139",title:"Topics in Primary Care Medicine",subtitle:null,isOpenForSubmission:!1,hash:"ea774a4d4c1179da92a782e0ae9cde92",slug:"topics-in-primary-care-medicine",bookSignature:"Thomas F. Heston",coverURL:"https://cdn.intechopen.com/books/images_new/9139.jpg",editedByType:"Edited by",editors:[{id:"217926",title:"Dr.",name:"Thomas F.",middleName:null,surname:"Heston",slug:"thomas-f.-heston",fullName:"Thomas F. Heston"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9785",title:"Endometriosis",subtitle:null,isOpenForSubmission:!1,hash:"f457ca61f29cf7e8bc191732c50bb0ce",slug:"endometriosis",bookSignature:"Courtney Marsh",coverURL:"https://cdn.intechopen.com/books/images_new/9785.jpg",editedByType:"Edited by",editors:[{id:"255491",title:"Dr.",name:"Courtney",middleName:null,surname:"Marsh",slug:"courtney-marsh",fullName:"Courtney Marsh"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9018",title:"Some RNA Viruses",subtitle:null,isOpenForSubmission:!1,hash:"a5cae846dbe3692495fc4add2f60fd84",slug:"some-rna-viruses",bookSignature:"Yogendra Shah and Eltayb Abuelzein",coverURL:"https://cdn.intechopen.com/books/images_new/9018.jpg",editedByType:"Edited by",editors:[{id:"278914",title:"Ph.D.",name:"Yogendra",middleName:null,surname:"Shah",slug:"yogendra-shah",fullName:"Yogendra Shah"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9523",title:"Oral and Maxillofacial Surgery",subtitle:null,isOpenForSubmission:!1,hash:"5eb6ec2db961a6c8965d11180a58d5c1",slug:"oral-and-maxillofacial-surgery",bookSignature:"Gokul Sridharan",coverURL:"https://cdn.intechopen.com/books/images_new/9523.jpg",editedByType:"Edited by",editors:[{id:"82453",title:"Dr.",name:"Gokul",middleName:null,surname:"Sridharan",slug:"gokul-sridharan",fullName:"Gokul Sridharan"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}],booksByTopicTotal:1511,mostCitedChapters:[{id:"19013",doi:"10.5772/21983",title:"Cell Responses to Surface and Architecture of Tissue Engineering Scaffolds",slug:"cell-responses-to-surface-and-architecture-of-tissue-engineering-scaffolds",totalDownloads:9697,totalCrossrefCites:109,totalDimensionsCites:230,book:{slug:"regenerative-medicine-and-tissue-engineering-cells-and-biomaterials",title:"Regenerative Medicine and Tissue Engineering",fullTitle:"Regenerative Medicine and Tissue Engineering - Cells and Biomaterials"},signatures:"Hsin-I Chang and Yiwei Wang",authors:[{id:"45747",title:"Dr.",name:"Hsin-I",middleName:null,surname:"Chang",slug:"hsin-i-chang",fullName:"Hsin-I Chang"},{id:"53659",title:"Ms.",name:"Yiwei",middleName:null,surname:"Wang",slug:"yiwei-wang",fullName:"Yiwei Wang"}]},{id:"46479",doi:"10.5772/57353",title:"Floating Drug Delivery Systems for Eradication of Helicobacter pylori in Treatment of Peptic Ulcer Disease",slug:"floating-drug-delivery-systems-for-eradication-of-helicobacter-pylori-in-treatment-of-peptic-ulcer-d",totalDownloads:1995,totalCrossrefCites:79,totalDimensionsCites:180,book:{slug:"trends-in-helicobacter-pylori-infection",title:"Trends in Helicobacter pylori Infection",fullTitle:"Trends in Helicobacter pylori Infection"},signatures:"Yousef Javadzadeh and Sanaz Hamedeyazdan",authors:[{id:"94276",title:"Prof.",name:"Yousef",middleName:null,surname:"Javadzadeh",slug:"yousef-javadzadeh",fullName:"Yousef Javadzadeh"},{id:"98229",title:"Dr.",name:"Sanaz",middleName:null,surname:"Hamedeyazdan",slug:"sanaz-hamedeyazdan",fullName:"Sanaz Hamedeyazdan"}]},{id:"25512",doi:"10.5772/30872",title:"Epidemiology of Psychological Distress",slug:"epidemiology-of-psychological-distress",totalDownloads:8066,totalCrossrefCites:57,totalDimensionsCites:145,book:{slug:"mental-illnesses-understanding-prediction-and-control",title:"Mental Illnesses",fullTitle:"Mental Illnesses - Understanding, Prediction and Control"},signatures:"Aline Drapeau, Alain Marchand and Dominic Beaulieu-Prévost",authors:[{id:"84582",title:"Dr.",name:"Aline",middleName:null,surname:"Drapeau",slug:"aline-drapeau",fullName:"Aline Drapeau"},{id:"84605",title:"Dr.",name:"Alain",middleName:null,surname:"Marchand",slug:"alain-marchand",fullName:"Alain Marchand"},{id:"84606",title:"Dr.",name:"Dominic",middleName:null,surname:"Beaulieu-Prévost",slug:"dominic-beaulieu-prevost",fullName:"Dominic Beaulieu-Prévost"}]}],mostDownloadedChaptersLast30Days:[{id:"43758",title:"Anxiety Disorders in Pregnancy and the Postpartum Period",slug:"anxiety-disorders-in-pregnancy-and-the-postpartum-period",totalDownloads:39763,totalCrossrefCites:11,totalDimensionsCites:20,book:{slug:"new-insights-into-anxiety-disorders",title:"New Insights into Anxiety Disorders",fullTitle:"New Insights into Anxiety Disorders"},signatures:"Roberta Anniverno, Alessandra Bramante, Claudio Mencacci and Federico Durbano",authors:[{id:"157077",title:"Dr.",name:"Federico",middleName:null,surname:"Durbano",slug:"federico-durbano",fullName:"Federico Durbano"},{id:"166382",title:"Dr.",name:"Roberta",middleName:null,surname:"Anniverno",slug:"roberta-anniverno",fullName:"Roberta Anniverno"}]},{id:"70711",title:"Fetal Growth Restriction",slug:"fetal-growth-restriction",totalDownloads:1706,totalCrossrefCites:1,totalDimensionsCites:1,book:{slug:"growth-disorders-and-acromegaly",title:"Growth Disorders and Acromegaly",fullTitle:"Growth Disorders and Acromegaly"},signatures:"Edurne Mazarico Gallego, Ariadna Torrecillas Pujol, Alex Joan Cahuana Bartra and Maria Dolores Gómez Roig",authors:[{id:"202446",title:"Ph.D.",name:"Maria Dolores",middleName:null,surname:"Gómez Roig",slug:"maria-dolores-gomez-roig",fullName:"Maria Dolores Gómez Roig"},{id:"311835",title:"Dr.",name:"Edurne",middleName:null,surname:"Mazarico",slug:"edurne-mazarico",fullName:"Edurne Mazarico"}]},{id:"70405",title:"Hemostasis in Cardiac Surgery: How We Do it with Limited Resources",slug:"hemostasis-in-cardiac-surgery-how-we-do-it-with-limited-resources",totalDownloads:2694,totalCrossrefCites:0,totalDimensionsCites:0,book:{slug:null,title:"Contemporary Applications of Biologic Hemostatic Agents across Surgical Specialties - Volume 1",fullTitle:"Contemporary Applications of Biologic Hemostatic Agents across Surgical Specialties - Volume 1"},signatures:"Fevzi Sarper Türker",authors:null},{id:"64851",title:"Herbal Medicines in African Traditional Medicine",slug:"herbal-medicines-in-african-traditional-medicine",totalDownloads:9954,totalCrossrefCites:10,totalDimensionsCites:17,book:{slug:"herbal-medicine",title:"Herbal Medicine",fullTitle:"Herbal Medicine"},signatures:"Ezekwesili-Ofili Josephine Ozioma and Okaka Antoinette Nwamaka\nChinwe",authors:[{id:"191264",title:"Prof.",name:"Josephine",middleName:"Ozioma",surname:"Ezekwesili-Ofili",slug:"josephine-ezekwesili-ofili",fullName:"Josephine Ezekwesili-Ofili"},{id:"211585",title:"Prof.",name:"Antoinette",middleName:null,surname:"Okaka",slug:"antoinette-okaka",fullName:"Antoinette Okaka"}]},{id:"59779",title:"Effective Communication in Nursing",slug:"effective-communication-in-nursing",totalDownloads:6504,totalCrossrefCites:2,totalDimensionsCites:4,book:{slug:"nursing",title:"Nursing",fullTitle:"Nursing"},signatures:"Maureen Nokuthula Sibiya",authors:[{id:"73330",title:"Dr.",name:"Nokuthula",middleName:null,surname:"Sibiya",slug:"nokuthula-sibiya",fullName:"Nokuthula Sibiya"}]},{id:"64858",title:"The Neurobiology of Anorexia Nervosa",slug:"the-neurobiology-of-anorexia-nervosa",totalDownloads:892,totalCrossrefCites:0,totalDimensionsCites:0,book:{slug:"anorexia-and-bulimia-nervosa",title:"Anorexia and Bulimia Nervosa",fullTitle:"Anorexia and Bulimia Nervosa"},signatures:"Ashley Higgins",authors:null},{id:"63771",title:"The Role of Catheter Reshaping at the Angiographic Success",slug:"the-role-of-catheter-reshaping-at-the-angiographic-success",totalDownloads:536,totalCrossrefCites:0,totalDimensionsCites:0,book:{slug:"angiography",title:"Angiography",fullTitle:"Angiography"},signatures:"Yakup Balaban",authors:[{id:"252647",title:"Associate Prof.",name:"Yakup",middleName:null,surname:"Balaban",slug:"yakup-balaban",fullName:"Yakup Balaban"}]},{id:"61866",title:"Plants Secondary Metabolites: The Key Drivers of the Pharmacological Actions of Medicinal Plants",slug:"plants-secondary-metabolites-the-key-drivers-of-the-pharmacological-actions-of-medicinal-plants",totalDownloads:5564,totalCrossrefCites:13,totalDimensionsCites:32,book:{slug:"herbal-medicine",title:"Herbal Medicine",fullTitle:"Herbal Medicine"},signatures:"Rehab A. Hussein and Amira A. El-Anssary",authors:[{id:"212117",title:"Dr.",name:"Rehab",middleName:null,surname:"Hussein",slug:"rehab-hussein",fullName:"Rehab Hussein"},{id:"221140",title:"Dr.",name:"Amira",middleName:null,surname:"El-Anssary",slug:"amira-el-anssary",fullName:"Amira El-Anssary"}]},{id:"17956",title:"Sexual and Reproductive Function in Chronic Kidney Disease and Effect of Kidney Transplantation",slug:"sexual-and-reproductive-function-in-chronic-kidney-disease-and-effect-of-kidney-transplantation",totalDownloads:11790,totalCrossrefCites:1,totalDimensionsCites:1,book:{slug:"after-the-kidney-transplant-the-patients-and-their-allograft",title:"After the Kidney Transplant",fullTitle:"After the Kidney Transplant - The Patients and Their Allograft"},signatures:"Mahboob Lessan-Pezeshki and Shirin Ghazizadeh",authors:[{id:"26564",title:"Prof.",name:"Mahboob",middleName:null,surname:"Lessan Pezeshki",slug:"mahboob-lessan-pezeshki",fullName:"Mahboob Lessan Pezeshki"},{id:"26571",title:"Prof.",name:"Shirin",middleName:null,surname:"Ghazizadeh",slug:"shirin-ghazizadeh",fullName:"Shirin Ghazizadeh"}]},{id:"64747",title:"Bone Development and Growth",slug:"bone-development-and-growth",totalDownloads:3711,totalCrossrefCites:6,totalDimensionsCites:9,book:{slug:"osteogenesis-and-bone-regeneration",title:"Osteogenesis and Bone Regeneration",fullTitle:"Osteogenesis and Bone Regeneration"},signatures:"Rosy Setiawati and Paulus Rahardjo",authors:null}],onlineFirstChaptersFilter:{topicSlug:"medicine",limit:3,offset:0},onlineFirstChaptersCollection:[{id:"75604",title:"Normal Puerperium",slug:"normal-puerperium",totalDownloads:0,totalDimensionsCites:null,doi:"10.5772/intechopen.96348",book:{title:"Midwifery"},signatures:"Subrat Panda, Ananya Das, Arindam Mallik and Surajit Ray Baruah"},{id:"75596",title:"The Use of a Dynamic Elastomeric Fabric Orthotic Intervention in Adolescents and Adults with Scoliosis",slug:"the-use-of-a-dynamic-elastomeric-fabric-orthotic-intervention-in-adolescents-and-adults-with-scolios",totalDownloads:0,totalDimensionsCites:null,doi:"10.5772/intechopen.96391",book:{title:"Spinal Deformities in Adolescents, Adults and Older Adults"},signatures:"Martin Matthews and James Wynne"},{id:"75582",title:"Elimination of Plasmodium vivax Malaria: Problems and Solutions",slug:"elimination-of-plasmodium-vivax-malaria-problems-and-solutions",totalDownloads:1,totalDimensionsCites:null,doi:"10.5772/intechopen.96604",book:{title:"Current Topics and Emerging Issues in Malaria Elimination"},signatures:"Liwang Cui, Awtum Brashear, Lynette Menezes and John Adams"}],onlineFirstChaptersTotal:652},preDownload:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[{type:"book",id:"10176",title:"Microgrids and Local Energy Systems",subtitle:null,isOpenForSubmission:!0,hash:"c32b4a5351a88f263074b0d0ca813a9c",slug:null,bookSignature:"Prof. Nick Jenkins",coverURL:"https://cdn.intechopen.com/books/images_new/10176.jpg",editedByType:null,editors:[{id:"55219",title:"Prof.",name:"Nick",middleName:null,surname:"Jenkins",slug:"nick-jenkins",fullName:"Nick Jenkins"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}}],offset:8,limit:8,total:1},route:{name:"profile.detail",path:"/profiles/98161/su-wen",hash:"",query:{},params:{id:"98161",slug:"su-wen"},fullPath:"/profiles/98161/su-wen",meta:{},from:{name:null,path:"/",hash:"",query:{},params:{},fullPath:"/",meta:{}}}},function(){var e;(e=document.currentScript||document.scripts[document.scripts.length-1]).parentNode.removeChild(e)}()