\r\n\tEqually, the interlinkages that the adrenal gland has in the human body create the premises both for the description of the intimate mechanisms that induce adrenal diseases on other tissues and organs and also for strategic considerations when it comes to treatment.
\r\n\r\n\tThis book, which is aimed at both endocrinologists and practitioners in other medical fields, therefore offers an insight into the mysteries of adrenal disease and a comprehensive overview of the current state of knowledge of this gland, providing an easy-to-follow format that focuses on the most important developments in the field of etiopathogenesis, clinical and paraclinical diagnosis, and treatment of these conditions.
",isbn:"978-1-80356-687-0",printIsbn:"978-1-80356-686-3",pdfIsbn:"978-1-80356-688-7",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,isSalesforceBook:!1,hash:"86c26879d83ac24206ed5476b6cde7fd",bookSignature:"Dr. Diana Loreta Paun",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11853.jpg",keywords:"Cushing Syndrome, Etiopathogenesis, Diagnosis, Treatment, Minimally Invasive Technique, Adrenalectomy, Adrenal Diseases, Perioperative Management, Adrenal Cancer, Genetics, Adrenal Mass, Imaging",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"March 22nd 2022",dateEndSecondStepPublish:"May 26th 2022",dateEndThirdStepPublish:"July 25th 2022",dateEndFourthStepPublish:"October 13th 2022",dateEndFifthStepPublish:"December 12th 2022",remainingDaysToSecondStep:"8 days",secondStepPassed:!1,currentStepOfPublishingProcess:2,editedByType:null,kuFlag:!1,biosketch:"Practitioner endocrinologist, associate professor, researcher, and manager of the National Institute of Endocrinology in Romania, coordinator of investment research and training projects, funded by European funds. Dr. Paun is a member of The Romanian Association of Clinical Endocrinology, member and president(2011-2012, 2017-2019) of The Romanian Chapter of the AACE (American Association of Clinical Endocrinologists). Dr. Păun was appointed State Advise (2015) and was appointed Presidental Advisor (2019).",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"190860",title:"Dr.",name:"Diana Loreta",middleName:null,surname:"Paun",slug:"diana-loreta-paun",fullName:"Diana Loreta Paun",profilePictureURL:"https://mts.intechopen.com/storage/users/190860/images/system/190860.jpg",biography:"PĂUN DIANA LORETA, MD, PhD, FACE\r\nBorn on: February 1st, 1968 on Bucharest\r\nEmployed to: “Carol Davila”, University of Medicine and Pharmacy\r\nPosition: endocrinologist, Ph.D, Associate Professor of Endocrinology\r\nFellow of the American College of Endocrinology\r\nExperience: General Manager of “CI Parhon” Institute of Endocrinology, Bucharest, 2006-2015.\r\nMaster in Public Health\r\nQualifications in: Diabetology, Osteoporosis, Endocrine Ultrasonography, Public Health. Training in molecular biology laboratory techniques – Max-Planck-Institut für Psychiatrie, Dept. of Chemie u. Endokrinologie, München, 2002\r\nOccupational field: Clinical, Educational and Research activities, Management, Healthcare services.\r\nPostgraduate courses in: Informatics, Clinical Endocrinology, Infertility, Sexology, Public Health etc.\r\nProfessional career:\r\nChemistry-Biology High School graduated on 1986, Faculty of Medicine graduated on 1992, Th.Burghele Hospital doctor on probation during 1993–1994\r\nendocrinology resident to CI Parhon Institute of Endocrinology 1994-1998\r\nendocrinologist since 1998\r\nAssistant Professor, Lecturer, Associated Professor of Endocrinology, Carol Davila University of Medicine and Pharmacy, Bucuresti, Romania\r\nPublications: papers presented on national and international meetings, articles publishised in well-known journals, author and coauthor in monographs and clinical guides book.\r\nParticipation on research projects and clinical trials: Director and member of the team in research projects and in clinical trials.",institutionString:"Carol Davila University of Medicine and Pharmacy",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"2",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"Carol Davila University of Medicine and Pharmacy",institutionURL:null,country:{name:"Romania"}}}],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:"455410",firstName:"Dajana",lastName:"Jusic",middleName:null,title:"Mrs.",imageUrl:"https://mts.intechopen.com/storage/users/455410/images/20500_n.jpeg",email:"dajana.j@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:"9500",title:"Recent Advances in Bone Tumours and Osteoarthritis",subtitle:null,isOpenForSubmission:!1,hash:"ea4ec0d6ee01b88e264178886e3210ed",slug:"recent-advances-in-bone-tumours-and-osteoarthritis",bookSignature:"Hiran Amarasekera",coverURL:"https://cdn.intechopen.com/books/images_new/9500.jpg",editedByType:"Edited by",editors:[{id:"67634",title:"Dr.",name:"Hiran",surname:"Amarasekera",slug:"hiran-amarasekera",fullName:"Hiran Amarasekera"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1591",title:"Infrared Spectroscopy",subtitle:"Materials Science, Engineering and Technology",isOpenForSubmission:!1,hash:"99b4b7b71a8caeb693ed762b40b017f4",slug:"infrared-spectroscopy-materials-science-engineering-and-technology",bookSignature:"Theophile Theophanides",coverURL:"https://cdn.intechopen.com/books/images_new/1591.jpg",editedByType:"Edited by",editors:[{id:"37194",title:"Dr.",name:"Theophile",surname:"Theophanides",slug:"theophile-theophanides",fullName:"Theophile Theophanides"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3161",title:"Frontiers in Guided Wave Optics and Optoelectronics",subtitle:null,isOpenForSubmission:!1,hash:"deb44e9c99f82bbce1083abea743146c",slug:"frontiers-in-guided-wave-optics-and-optoelectronics",bookSignature:"Bishnu Pal",coverURL:"https://cdn.intechopen.com/books/images_new/3161.jpg",editedByType:"Edited by",editors:[{id:"4782",title:"Prof.",name:"Bishnu",surname:"Pal",slug:"bishnu-pal",fullName:"Bishnu Pal"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3092",title:"Anopheles mosquitoes",subtitle:"New insights into malaria vectors",isOpenForSubmission:!1,hash:"c9e622485316d5e296288bf24d2b0d64",slug:"anopheles-mosquitoes-new-insights-into-malaria-vectors",bookSignature:"Sylvie Manguin",coverURL:"https://cdn.intechopen.com/books/images_new/3092.jpg",editedByType:"Edited by",editors:[{id:"50017",title:"Prof.",name:"Sylvie",surname:"Manguin",slug:"sylvie-manguin",fullName:"Sylvie Manguin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"371",title:"Abiotic Stress in Plants",subtitle:"Mechanisms and Adaptations",isOpenForSubmission:!1,hash:"588466f487e307619849d72389178a74",slug:"abiotic-stress-in-plants-mechanisms-and-adaptations",bookSignature:"Arun Shanker and B. Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"72",title:"Ionic Liquids",subtitle:"Theory, Properties, New Approaches",isOpenForSubmission:!1,hash:"d94ffa3cfa10505e3b1d676d46fcd3f5",slug:"ionic-liquids-theory-properties-new-approaches",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/72.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"314",title:"Regenerative Medicine and Tissue Engineering",subtitle:"Cells and Biomaterials",isOpenForSubmission:!1,hash:"bb67e80e480c86bb8315458012d65686",slug:"regenerative-medicine-and-tissue-engineering-cells-and-biomaterials",bookSignature:"Daniel Eberli",coverURL:"https://cdn.intechopen.com/books/images_new/314.jpg",editedByType:"Edited by",editors:[{id:"6495",title:"Dr.",name:"Daniel",surname:"Eberli",slug:"daniel-eberli",fullName:"Daniel Eberli"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"57",title:"Physics and Applications of Graphene",subtitle:"Experiments",isOpenForSubmission:!1,hash:"0e6622a71cf4f02f45bfdd5691e1189a",slug:"physics-and-applications-of-graphene-experiments",bookSignature:"Sergey Mikhailov",coverURL:"https://cdn.intechopen.com/books/images_new/57.jpg",editedByType:"Edited by",editors:[{id:"16042",title:"Dr.",name:"Sergey",surname:"Mikhailov",slug:"sergey-mikhailov",fullName:"Sergey Mikhailov"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1373",title:"Ionic Liquids",subtitle:"Applications and Perspectives",isOpenForSubmission:!1,hash:"5e9ae5ae9167cde4b344e499a792c41c",slug:"ionic-liquids-applications-and-perspectives",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/1373.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"76199",title:"Volatilomics of Natural Products: Whispers from Nature",doi:"10.5772/intechopen.97228",slug:"volatilomics-of-natural-products-whispers-from-nature",body:'Volatilomics indicates the qualitative and quantitative study of the volatilome, defined as the complex blend of volatile organic compounds (VOCs) originating from different biosynthetic pathways and emitted by living organisms [1]. VOCs are small molecules (below 500 Da), with hydrophobic character, low boiling points, and high vapor pressure at ambient temperature. Unconjugated volatiles can freely diffuse across membranes to be released from flowers, fruits, and vegetative tissues into the atmosphere and from roots into the soil to be perceived at short and long-distance. Therefore, plants and animals use VOCs for chemical communication with the surrounding ecosystem, and plants also use them as attractors for pollinators and defense against herbivory and biotic and abiotic stress [2, 3, 4, 5].
The study of VOCs of plants has focused not only on the qualitative and quantitative composition of the volatile fraction but on the bioactive compounds as well as flavors and fragrances [6, 7]. Similarly, the understanding of fruits’ sensorial attributes is of great interest as quality control, as well as in the determination of origin mark, and the performance of ecological studies aimed at the establishment of the relationship between the ripening stage and the incidence of fruit diseases for insect or microorganism attack [8, 9, 10].
Microorganisms produce a plethora of important microbial volatile organic compounds (mVOCs), that play an essential role in inter- and intra-kingdom connections. The study of mVOCs has allowed, for example, to detect terpenes, compounds normally associated with plants, also in fungi and bacteria [11]. Also, these compounds are related to ecological interactions between living organisms found in the soil, including the rhizosphere [12].
In addition, several studies of VOCs from animals not only have allowed decoding the signal of the animal chemical communication but also have demonstrated the potential use of that knowledge in early disease’s diagnostics. For example, recent studies have shown novel practice for the detection of biomarkers to identify the intoxication using unusual biological fluids like ear wax, being fast, economic, and noninvasive bioanalysis, with minimal sample preparation and very versatile to identify the first signals of intoxication [13, 14].
Differently to the genomes, the volatilome changes continuously across time, and its composition depends on external and internal factors, such as the environmental conditions, and/or the physiological state [15]. Therefore, the study of the volatilome is not a simple task and the researchers in this area entail multiple challenges derived from the chemical complexity of the samples and the superposition of VOCs signals as proper of the ecosystems. Thus, sensitive yet unbiased methodologies are needed to provide researchers with comprehensive and accurate representations of a plant species’ volatile metabolome.
However, current methodologies are limited in their ability to isolate, and even more critically to identify, many of the compounds present in each sample. In volatile metabolomics, the emitted metabolites are already isolated from tissues, they need to be temporarily trapped, and eventually preconcentrated, in a way that allows them to be released unadulterated for separation and identification.
A variety of technologies have been developed. In these methods, the sample of interest is enclosed in a collection chamber and the released volatiles present in the airspace surrounding the sample, headspace (HS), are trapped onto an adsorbent. And are subsequently analyzed by gas chromatography in combination with mass spectrometry (GC–MS) as the method of choice for volatilomics.
Hence, in the next sections of this chapter, we will provide an overview of the volatilome study process, including the main practical and theoretical aspects of volatiles capture, sample preparation, and the main analytical techniques employed to monitor VOCs, together with the chemoinformatics tools used for volatilome dereplication, elucidation, annotation, and interpretation of data.
Sample acquisition in volatilomics experiments requires consistency, therefore due to the high variability of chemical structures, concentrations levels, sample types, and physiological variations, other variables different than metabolites (addressed as meta-variables from now on) should be controlled or at least carefully monitored in order to evaluate their effect on the study outcome. Some important variables that should be taken into account include replicate number, taxonomic identification, geographic location, phenotypic or phylogenetic variant, sample weight, phenotypic characteristics, sex, developmental stage, health status, collection date, and time. Photographs should be taken. A useful reference for registering meta-variables is the ReDU Sample Information Template. (https://docs.google.com/spreadsheets/d/1v71bnUd8fiXX51zuZIUAvYETWmpwFQj-M3mu4CNsHBU/edit?usp=sharing) [16] build by the collaborative Global Natural Products Social Networking (GNPS) (https://gnps.ucsd.edu/ProteoSAFe/static/gnps-splash.jsp) [17] where researchers can add new meta-variables and share their data in an open-source and collaborative environment.
The plant volatilome is defined as the complex blend of essential oils (EOs) and VOCs fed by different biosynthetic pathways and emitted by plants, constitutively and/or after induction, as a defense strategy against biotic and abiotic stress. Plants have a vast diversity in their range of metabolites and their concentrations, as there are hundreds of thousands of metabolites in different categories. As such, there is no single analytical technique that has the capability of extracting and detecting the whole metabolome [18].
Plant volatile emissions are linked to the physiological status of the emitter, therefore special care must be taken to control the plant-growing environment as well as all variables concerning the developmental stage of the plant to limit unwanted fluctuations in metabolism that might affect collected. These include the time of day, photoperiod, temperature, humidity, water conditions, collection site altitude, plant age, climate, and soil type so that a careful experimental design is recommended. Whenever possible, growth chambers must be used for plant cultivation and volatile collection [19, 20]. EOs and VOCs can be extracted and analyzed from both fresh and dried plant materials. When using fresh material, particular attention must be paid to the health status of plants, since microbial and other infections may alter metabolites production. Plants must not show necrotic areas and be at the same developmental stage if comparative analyses are needed. Since the content of water may vary, it is a good practice to use some of the fresh material to calculate the dry matter percentage [21].
Since volatile emissions from many plant species vary with respect to the time of day, and different organs in the plant are known to produce and/or accumulate different profiles of secondary metabolites, collection strategies should consider volatile sampling over an extended period of time and from the investigated organ or entire plant, to prevent unintentional exclusion of volatile components in the sampled mixture. Also, when running VOCs analyses from living plants it must be remembered that rooted plants in pots respond differently than cuttings, and that soil in pots may contain microorganisms that can produce VOCs [22, 23]. Once a plant part is collected, at least two herbarium samples should be prepared and identified or authenticated by a taxonomist. One of these voucher specimens should be deposited in a local national herbarium. A card with details of the place, altitude, environment, and photographs should be attached to the herbarium sample, in case a recollection of the plant material is necessary. Although depositing herbarium samples is a basic step in performing phytochemical investigation, many researchers in the past neglected this step and thus were unable to reproduce their work [23, 24, 25].
Living flowers change their volatile profile in a continuous way that depends on intrinsic and extrinsic factors. Once cut, flowers undergo rapid deterioration and loose volatiles. Flower volatiles allow discrimination between different plants and attract insects for pollination when they are released. The amount of emission is not uniform through time, with some differences between diurnal and nocturnal emission levels, and between reproduction phases. The volatile compounds emitted by flowers are mainly aliphatics, terpenoids, benzenoids, and phenylpropanoids. Flower volatiles require special methods for their isolation with preconcentration and can be obtained from the air surrounding the living or excised flower, or from the flower tissues themselves. The selected extraction technique determines the composition of the isolated volatiles mixture [26, 27].
Fruits are very complex samples, rich in a great number of different classes of metabolites, including volatile, semi-volatile, and no volatile compounds. The flavor is one of the most important characteristics to value the quality of fruit. Volatile and semi-volatile compounds usually are responsible for aroma fruit, and their study has conducive to identify both positive and negative sensory attributes [28]. VOCs are produced in trace amounts, and although they are easily perceptible by the human nose, their sampling and monitoring can be challenging at an analytical level [29]. The volatile fraction of fruits is composed of hundreds of different chemical substances that can vary according to the type of fruit, but the emitted compounds can be grouped according to the chemical function mainly into esters, alcohols, aldehydes, ketones, lactones, and terpenoids [29]. Moreover, VOCs emitted by fruit depend on the production conditions (cultivars, state of maturity, post-harvest treatment, and storage) the sample format (whole fruit, sliced, wet, dry), and the type of analysis (in-field or in-lab). Capturing volatiles in-situ is a challenge, as small amounts of VOCs are released and diffuse in a large volume of air, which requires highly efficient sampling techniques to capture them. Solid-phase microextraction (SPME) and solid-phase extraction (SPE) are usually the most profitable techniques for the capture of fruit volatiles in-situ. Once the volatile compounds are retained in an adsorbent material, their storage and transport are facilitated. On the other hand, in laboratory capture of VOCs from fruits, can be efficiently performed by solvent or gas-based extraction techniques, such as Soxhlet, simultaneous distillation extraction, purge and trap, and headspace, among others.
Analysis of mVOCs is commonly performed under controlled culture media, temperature, and agitation. Also, the percentage of humidity and exposure to UV–visible light among other growing conditions should be taken into account. In order to account for reproducibility of the experiments, laboratory tests on microorganisms must be performed using international reference strains e.g.: American Type Culture Collection (ATCC), instead of clinical or field isolations, or even strains isolated and saved in the research group for a long time. Because the emission of VOCs can vary in terms of presence or absence, and in terms of fluctuation in concentration, throughout the life span of the microorganisms (which can be from a few hours to days), it is advisable to perform analyses both in the exponential or logarithmic growth phase, as well as in the stationary phase [12, 30, 31]. During the exponential phase, the microorganism is reactivating its biosynthetic pathways after having been in a state of latency. Therefore, in this stage, there is generally a high concentration of some metabolites that are part of the first stages of the biosynthetic pathways, which can later diminish and disappear in the exponential phase. The stationary phase is achieved when the initial metabolic processes have been reached and occurs when the survival process of the species begins [32]. The metabolic changes produced in these two stages of microbial culture are fundamental to understanding and solving research questions [33, 34]. The determination of each of the culture phases is commonly done with a measurement of the absorption of light in the visible region between 500 and 650 nm for liquid growth medium. This is achieved by counting the colony-forming units (CFU) in the solid medium. The sampling time for analysis of mVOCs must coincide with those obtained in the growth curves, correctly differentiating the exponential and stationary phases.
For conducting volatile sampling from animals, the specimens could be either raised in captivity at controlled vivaria or extracted from their natural environments. Proper training in animal manipulation is an important aspect to be fulfilled before performing animal experimentation, as well as an approved permit by the Institution in charge to validates the procedures. Also, when animals are to be collected in their habitats, it is necessary to review if a Convention on International Trade in Endangered Species of Wild Fauna and Flora (CITES) permit is needed for protected species. A specialist should validate taxonomic identification and, in those cases, where sample collection involves euthanization of specimens that should be registered at a recognized Museum, and voucher numbers should be annotated and published on the research paper. In the same way, as other organisms could be sampled by different methods, almost all animals could be sampled in vivo, but in some cases, tissue extraction could be preferred for guaranteeing detection of less abundant metabolites. Some techniques applied for VOCs analysis from terrestrial arthropods [35, 36, 37, 38, 39], aquatic organisms [40, 41, 42], mammals [43, 44, 45, 46, 47, 48], birds [49, 50], reptiles [51, 52], fishes [53], and amphibians [37, 38, 54, 55, 56, 57] include headspace-adsorbent traps, polydimethylsiloxane (PDMS) patches, swabs and stir bar sorptive extraction (SBSE).
Sample preparation is one of the most important steps in the analytical process. The goal of sample preparation is to efficiently isolate target analytes from potential interferences and to extract as many VOCs as possible to provide a true representation of the studied system.
Some steps of pre-treatment of the sample are necessary in order to minimize the manipulation of the sample and avoid its modification, to clean-up the sample efficiently, and to quench metabolic reactions that could cause degradation and decomposition. To date, two different types of headspace sampling, static and dynamic, are widely used for volatilomics investigation.
Static headspace sampling is a passive technique for VOCs collection, where no air is circulated for the concentration of the volatiles on a sorbent matrix [18]. As a result, the background noise is drastically reduced due to the absence of a continuous airflow that can contain impurities that could mask compounds released at trace amounts. In static headspace methods, samples are typically sealed inside a container or bag, where the volatiles are released and, in the more traditional version of the technique, the headspace is sampled directly using a gas-tight syringe and transferred to the Gas Chromatography (GC) injection port. When the analytes are present at trace level, it might be necessary to carry out static headspace methods with special techniques to concentrate volatiles during collection and reduce the dilution of the sample during desorption in the GC inlet. In such a context, SPME stands out as the most versatile strategy for volatile capture from the sample headspace in static mode. Nowadays, SPME is the leading technique in the analysis of volatiles of biological origin because it uses a fiber coated with a sorbent phase to combine extraction and pre-concentration compounds. SPME fibers are available in a wide range of coatings that allow the sampling of compounds of different polarities and volatilities. Considering that the goal of volatilomics profiling is to analyze as many metabolites as possible, the use of divinylbenzene/carboxen/polydimethylsiloxane (DVB/CAR/PDMS) fibers is the most suited to increase the number of analytes that can be trapped on the fiber because it can allow capture VOCs in a wide range of polarity and molecular weight [58].
This type of coating contains a layer of CAR particles underneath a layer of DVB particles. Because the ability of adsorbent coatings to extract a particular analyte strongly depends on the size of the pores, larger analytes will be retained in the outer DVB layer, while the smaller analytes will migrate through this layer and are retained by the inner layer of CAR. On the contrary, if the study targeted only on the most volatile fraction, PDMS/CAR would be an appropriate choice of coating, since the micropores of the CAR retain smaller analytes better than other coatings, although introducing a high degree of discrimination towards high-molecular-weight compounds.
On another hand, although other coatings, such as PDMS, polyacrylate (PA), and Carbowax (CW), are also commercially available, their use in volatilomics is quite scarce due to the higher selectivity towards certain classes of polarities [58, 59].
From a practical point of view, SPME is a versatile technique for in-field sampling as a non-destructive strategy for the study of the volatiles emitted ex-vivo, for example, by grapes. In this case, an aluminum wire cage can be used to support a polymeric film to enclose a whole cluster of grapes, and SPME fiber is introduced through a port fitted with a silicone septum (Figure 1a).
Sampling handling techniques of VOC’s fruit. a) Ex-vivo sampling of volatiles from the whole cluster of grapes by SPME; b)Ex-vivo sampling of volatiles from a single grape berry by SPME. Adapted from [
Also, an interesting strategy for speeding up the volatiles’ uptake is vacuum-assisted SPME. For example, in-field sampling of volatiles from a single grape berry, a modified screw top, and a 2 mL glass vial can be used for fiber exposition. A syringe is usually used to create a negative pressure to hold the sampling device with the SPME sealed onto the sample surface (Figure 1b).
This type of coating contains a layer of CAR particles underneath a layer of DVB particles. Because the ability of adsorbent coatings to extract a particular analyte strongly depends on the size of the pores, larger analytes will be retained in the outer DVB layer, while the smaller analytes will migrate through this layer and are retained by the inner layer of Carboxen. Conversely, if the study targeted only on the most volatile fraction, PDMS/CAR would be an appropriate choice of coating, since the micropores of the CAR retain smaller analytes better than other coatings, although introducing a high degree of discrimination towards high-molecular-weight compounds.
Although SPME generally exhibits better extraction efficiency as the polarity of the compound decreases, these three coatings can provide balanced metabolome coverage as long as most polar analytes are present at reasonable concentration levels. Absorbent coatings, such as PDMS, PA, and CW, were rarely employed in profiling studies. These coatings display selectivity based on polarity, resulting in poor metabolomic coverage. The second case is dynamic headspace sampling, which offers a highly concentrated sample that can be desorbed into a solvent at volumes suitable for multiple analyses. To date, it is the most frequently used technique in all areas of plant volatile analysis. Dynamic headspace sampling collects a much larger quantity of compounds at higher concentrations because the continuous stream of air allows the sorbent to act as a filter trapping the volatiles.
Also, push and pull headspace sampling, two examples of dynamic headspace sampling, allow to avoid problems often encountered with the sealed systems used in static headspace and closed-loop stripping methods including heat, water vapor, and, in the case of plants, ethylene accumulation that can affect not only sampling efficiency but also plant physiology. Among the several methods, closed-loop stripping systems have broad utility for the collection of volatiles: volatiles are collected during continuous circulation of HS air inside closed chambers in which air circulation pumps are connected to supporting columns or coated supports [22].
As an example, SPME is a versatile technique for in-field sampling handling as a non-destructive strategy for the study of the volatiles emitted ex-vivo, for example, by the whole cluster of grapes. In this case, an aluminum wire cage can be used to support a polymeric film to enclosing a whole cluster of grapes, and SPME fiber introduced through a port fitted with silicone septa (Figure 1a) [60]. Also, an interesting strategy for speed up the volatile’s uptake is vacuum-assisted SPME. For example, in-field sampling of volatiles from a single grape berry, a modified screw top, and a 2 mL glass vial can be used for fiber exposition. A syringe is usually used to create a negative pressure to hold the sampling device with SPME sealed unto the sample surface (Figure 1b) [60].
Alternatively, to the SPME, some liquid-phase microextractions (LPME), such as the single drop microextraction (SDME) or the hollow fiber liquid-phase microextraction (HF-LPME), can also provide efficient and profitable volatiles recoveries in the headspace static mode. For example, SDME is a technique based on a few microliters of solvent, in which volatiles can be capture in a small drop of extraction solvent-exposed to the headspace of the sample [20, 59]. In the same way, to address the drawbacks of the drop instability, the extraction solvent can be deposited into the lumen of a porous fiber HF-LPME, improving the extraction kinetics by use of a bigger transference surface or by the incorporation of an acceptor solvent into the membrane pores (Supported Liquid Membrane, SLM). Although the use of hazardous organic solvents can be considered a drawback, nowadays those solvent-based extractions can be performed with environmental-friendly alternatives, such as ionic liquids, deep eutectic solvents, or supramolecular solvents, among others.
The second type of headspace sampling is the dynamic headspace (DHS) method. It encompasses strategies in which VOCs are captured in a sorbent-packed trap by passing a continuous flow of inert dry gas through the sample. In this way, the emission of VOCs speeds up by the continuous renovation of the headspace fraction. After extraction, concentrated VOCs can be desorbed from the sorbent-packed trap with a suitable solvent or via thermal desorption. Besides, DHS address some drawbacks of the static modes such as the accumulation of water vapor or highly concentrated compounds, which presence can affect extraction efficiency. Two examples of dynamic headspace sampling which allow avoiding some drawbacks of the static mode, e.g., heat and water vapor accumulation that can affect not only sampling efficiency but also plant physiology, are closed-loop stripping and push and pull methods. These systems collect VOCs in sorbent-packed traps or coated devices, via the continuous circulation of gas inside closed circuits [22].
In addition to headspace sampling techniques, some sui generis approaches can combine two methods from different groups, for example, solvent-assisted flavor evaporation (SAFE). SAFE is an exhaustive extraction technique based on the high volatility rather than the polarity of the target compounds. In this case, a crude-extract from dry sample pieces is prepared with an appropriate solvent, such as dichloromethane, and then added into the dropping funnel and passed through a specific distillation chamber. Extraction takes place at high vacuum, and low-temperature conditions (20–30°C), and VOCs are collected in a cooled extraction vessel [61]. Other techniques including in this group are simultaneous extraction-distillation (SDE) and/or liquid–liquid extraction (LLE). Nevertheless, those can be subjected to some drawbacks, like the use of hazardous solvents, as well as the requirement of high temperatures and long extraction times, with potential formation of artifacts and degradation of some compounds.
Finally, volatile compounds also can be obtained for direct collection of the secretions of odoriferous glands or via non-invasive strategies using PDMS patches or swabs [22]. These techniques are especially useful in the monitoring of VOCs from animals. For example, obtaining the animal skin volatilome on PDMS patches is an excellent option [62]. Patches could be prepared by cutting a Silicone Elastomer Sheet (Goodfellows mfr. No. 942-965-49, Coraopolis, PA) and then carefully fix it on the animal skin with Tegaderm® dressings or water block clear Band-aids®. Alternatively, this procedure could be modified by gently swabbing the skin with or without previous stress-induced secretion. PDMS patches also can be placed into an animal enclosure and used without direct contact for capturing the volatiles that emanates in the headspace.
Currently, gas chromatography coupled to mass spectrometry (GC–MS) is the primary analytical technique for the elucidation of the volatilome profile from natural sources. In gas chromatography analytes elute according to their volatility carried by a gas, usually Helium, through a coated fused silica capillary using a temperature gradient. Separation occurs based on the differential partition between the gas phase and the coating and the eluting peaks will give a response in the detector. The sample is vaporized in the injection system before it enters the column.
Several injection systems can be used to introduce the sample onto the column. Split injection allows transferring to the column only controlled sample amounts and prevent overloading of the column, thanks to a split valve at the base of the hot injector that divides the flow between column and waste in a fixable ratio. High-concentration samples can easily overload the GC column, resulting in all active sites on the column becoming occupied and leading to additional analytes not being retained and therefore to poor chromatographic resolution. For trace analysis, the injector can be used in splitless mode, which allows the entire volume of sample vaporized in the injector to reach the column. An alternative to the split/splitless interface is the programmed temperature vaporizer (PTV). Samples are injected onto a cool (40–60°C) PTV where they are trapped and concentrated on different sorbent materials before the inlet is rapidly heated to desorb the sample onto the column.
Different selectivity and sizes of columns have been used for GC–MS–based metabolomic analysis. The most used phase is 5% phenyl, 95% methyl siloxane, which offers a sufficiently generic selectivity, optimal for metabolomic applications where analytes with a wide range of volatilities have to be separated. Capillary columns of 25 to 30 m will provide the highest resolution and are available in most phases. An important point for all capillary GC–MS work is the need to condition the column prior to running valuable samples. Sangster et al. have recommended that several quality control samples be run at the beginning of a sample batch to condition the column [63]. Care also needs to be taken to randomize the injection sequence in order not to compromise subsequent statistical analysis.
In GC–MS ionization of analytes is mainly produced by electron ionization (EI) or chemical ionization (CI), while ion separation is obtained by mass analyzers operating on different principles. In EI, analytes that elute from the GC column are vaporized into the ion source and collide with an electron beam at 70 eV. As a result of the high energy imparted by electrons to the vaporized molecules, characteristic fragmentation occurs, providing structural information. EI is very robust and highly reproducible between instruments, and spectral libraries are available that can be used to search for the identities of unknown compounds based on m/z and intensity ratios of the observed fragment ions. A disadvantage of EI is that fragmentation is usually so efficient that the intensity of the molecular ion can be extremely low or even lost. For CI, a reagent gas, such as methane or ammonia, is introduced into the source of the mass spectrometer. Protonated gas ions, produced by the collision with electrons originating from an electron beam, ionize the analytes eluting from the column after vaporization into the ion source. Significantly less energy than in EI is transferred to the analytes, and as a result, the dominant ion is usually the molecular ion.
Mass spectrometer based detectors are mainly used in metabolomic analysis and can be grouped according to the spectral information they provide, i.e., low-resolution instruments such as quadrupole mass spectrometer (qMS), ion-trap mass spectrometer (IT-MS), and high-speed time-of-flight mass spectrometer (TOF-MS) give nominal molecular weights and fragmentation of an analyte, while high-resolution instruments (high-resolution TOF-MS and hybrids) give the precise elemental composition of nominal masses. The single quadrupole mass analyzer is widely used and relatively inexpensive. The ions move along the axis of four parallel rods to which a direct current (DC) and an alternating current (AC) voltage are applied. These voltages affect the trajectory of ions traveling down the flight path between the rods in a way that only ions of a given m/z are transmitted at a given point in time. Scan speeds are rather low on quadrupole instruments, therefore considering the very high separation power of GC with peak widths of only a few seconds, it will be difficult to acquire several spectra across the width of a typical peak on a single quadrupole instrument. Time-of-flight (TOF) instruments are the most common mass analyzers in GC–MS–based metabolomics. The ions are accelerated in an electric field in which ions with the same charge will have the same kinetic energy, but different velocity depending on their mass-to-charge ratio (m/z). Successively, the ions enter a field-free region (flight tube) where they separate based on their m/z. TOF instruments are characterized by the fastest scan rate among all mass analyzers: a significant number of spectra can be acquired across each peak, leading to higher sensitivity and better spectral quality.
GC–MS has very high sensitivity and can therefore be used for the analysis of less commonly encountered samples that might only be available in trace amounts. Monodimensional GC–MS analysis provides suitable resolving-power for the analysis of relatively simple mixtures of VOCs. Nevertheless, volatilome samples can be very complex mixtures, involving a diverse plethora of chemical structures in a wide range of polarities, so that the restricted chromatographic resolution commonly limits the identification via MS to the more abundant compounds. Complex mixtures can be better resolved by employing comprehensive two-dimensional gas chromatography–mass spectrometry (GCxGC–MS), which has been defined as “…an orthogonal two-column separation, with complete transfer of a solute from the separation system 1 (column 1) to the separation system 2 (column 2), such that the separation performance from each system (column) is preserved” [64]. In GC × GC, two columns with different polarity—usually a nonpolar column in the first dimension and a moderately polar column for the second one—are run in series. Analytes eluting from the first dimension (1D) column are trapped, focused, and then rapidly injected, as a narrow band of few milliseconds, in the second dimension (2D) column, then the eluting peaks are detected by MS. The transfer process is actuated by a modulator, a thermal or valve-based focusing system. Each single modulator cycle takes a fixed time (4–8 s) and each fraction, injected online into the second column must be analyzed in a time equal to that of the successive modulation. The challenge is to avoid continuously transmitting analyte onto the second column, which would lead to a loss of resolution. A solution to this problem is to make the separation on the second column much faster than the separation on the first column. The volume of data generated is significantly larger than the one obtained in a one-dimensional analysis. However, this approach allows for better separation of the number of components in the sample. Although single qMS instruments are cheaper, can provide very low LODs via selected ion monitoring (SIM), and can provide maximum acquisition rates (20,000 amu/s) suitable for metabolic profiling, TOF has become the preferentially MS analyzers for GCxGC volatilome analysis. TOF-MS instruments are capable of full-spectrum collection rates up to 500 Hz with improved sensitivity. Besides the high-resolution mass spectrometry (HRMS) provide accurate mass data, which increases the identification confidence and allows to annotate molecular formulas for unknown compounds, being especially useful in untargeted metabolomic studies.
Metabolite identification remains a major complication. Although EI generates highly reproducible fragmentation spectra, only a relatively small percentage of metabolites can be identified by searching databases, mainly because these have traditionally been a repository of EI spectra of synthetic organic compounds. Only recently, the number of metabolite spectra started to increase. A more powerful identification method involves comparing both EI/CI spectra and retention indices obtained from analyzing a reference compound under identical analytical conditions. If commercial standards are not available, metabolite identification can be cumbersome.
Retention indexes (RI) were first introduced by Kováts [28] for isothermal analysis and then by Van den Dool [65] for temperature-programmed analysis (linear retention indices, LRIs) and are calculated vs. a homologous series of linear hydrocarbons run in the same GC conditions as samples. RI can also be automatically calculated using the Automated Mass Spectral Deconvolution and Identification System (AMDIS), freely available from the National Institute of Standards and Technology (NIST) at this site (http://www.amdis.net/).
In order to achieve the identification of unknown compounds, their background-subtracted EI spectra are searched against EI libraries (such as the NIST library) to achieve identification. Values of
The high variability of data obtained from the investigated matrix composition makes it hard to indicate a universal approach to quantitatively evaluate the volatilome composition. The most widely used approaches are: (a) relative percentage abundance, (b) internal standard normalized percentage abundance, and (c) “absolute” or true quantitation of one or more target components, with or without a validated method. Relative percentage abundance can be applied only to evaluate relative component ratios within the same sample. Internal standard normalized percentage abundance is the ideal approach when a group of samples is compared: raw data must first be corrected vs. analyte response factors to the detector, then normalized vs. an internal standard. Percentage abundance must be calculated vs. the sum of the areas of a fixed number of selected components, found in all the samples. The quantitation of marker components is obtained from the chromatographic area in SIM mode vs. an internal (or external) standard and calculated via a calibration curve constructed from amounts of pure standards in the selected concentration range.
Some common non-separative techniques used in the study of volatilome using mass spectrometry are selected-ion flow-tube mass spectrometry (SIFT-MS) and proton-transfer-reaction mass spectrometry (PTR-MS). These techniques are focused on the use of soft chemical ionization, allow on-line detection of VOCs with low levels of detection without the need for pre-concentration or sample preparation, which facilitates obtaining reproducible results. For example, Vendel and co-workers [66], used SIFT-MS and HS-SPME-GC–MS for the analysis of strawberry aroma. Although both techniques provided similar results in the study of the fruit ripening, the SIFT-MS analysis was about 11 times faster than HS-SPME-GC–MS. Moreover, SIFT-MS showed low detection limits, so that the postharvest analysis can be easily performed by the analysis of individual fruit. Capellin and collaborators [67] developed a similar study was using PTR-TOF-MS to study the volatilome of clones belonging to three types of apple. They concluded that PTR-TOF-MS is a very useful tool for volatilome studies once this technique allows obtaining a rapid and non-invasive fingerprint of the VOCs profile from single apple fruits.
With an alternative focus, the chromatographic system can be coupled to an olfactometer detector to identify the aroma-active compounds present in a determinate volatilome. This type of analysis allows determining the compounds which generate a positive response to the electronic noise detector, obtaining their identification by comparison of the mass spectrum, retention index, and odor descriptions with reference compounds. Using gas chromatography-olfactometry-mass spectrometry (GC-O-MS), Zhu and co-workers [68] studied the volatile profile of three cultivars of mulberries, establishing benzaldehyde, ethyl butanoate, (E)-2-nonenal, 1-hexanol, hexanal, methional, 3-mercaptohexyl acetate, and 3-mercapto-1-hexanol as the main compounds responsible for the characteristic aroma of mulberry.
Once the raw data have been acquired following chromatographic separation and mass spectrometry analysis, the large amount of data generated needs to be processed following a standardized procedure that includes data conversion, pre-processing, pre-treatment, and metabolite annotation [69]. An additional step, sharing data derived from any metabolomics analysis, currently is optional for researchers but highly recommended.
Data processing starts with a set of raw data files for different samples. Usually, default vendor formats from instruments need a conversion. A useful toolkit compatible with several instruments formats is ProteoWizard (http://proteowizard.sourceforge.net/download.html) [70]. Open-source formats usually supported by many software packages are Network Common Data Form (NetCDF) [71], Extensible Markup Language (mzXML) [72], and Mass Spectrometry Markup Language (mzmL) [73]. Each file is processed to an easily accessible and more informative data table, where rows represent samples and columns represent different features from volatilome. Values from this matrix represent intensity values of peak area/height, standing for relative concentration. The data should be checked for missing values and possible outliers.
Pre-processing involves setting different filters to recognize signals from noise, select masses or intensities to perform feature detection, and finally adjust the retention time shifts parameters needed to align features throughout all samples. The aim of pre-processing is to minimize the number of false positives features and to establish quantitative procedures for discarding less reliable signals with low signal-to-noise ratio, or low prevalence within a similar set of samples [74].
Pre-treatment or data correction is one of the most important steps from data analysis because systematic and technical variation could obscure relevant biological patterns. The variation in the data resulting from a metabolomics experiment is the sum of the induced variation and the total uninduced variation [75]. Some sources of variation could be controlled by researchers through a careful experimental design. In other cases, this variation is very difficult to control. Natural variation in the metabolism of an organism can cause 5000-fold differences in signal intensities for different metabolites, or sampling could not be performed on the exact conditions for all samples, sample work-up varies naturally between batches, and analytical errors are always present. This variation could be accounted for using different classes of corrections that include centering, scaling, transformation, and normalization of raw data and several methods are available to do so (e.g., autoscaling, pareto scaling, range scaling, vast scaling, log transformation, and power transformation, normalization by sum, normalization by a reference sample). The selection of the most appropriate method depends on the hypothesis to be tested and the statistical behavior of the data matrix. Before applying pre-treatment methods, it is required to check if data is fit for analysis. For example, performing the treatment may enhance the results of a clustering method (if the hypothesis is related to comparison of similarities), while obscuring the results of a Principal Component Analysis (PCA) (if in contrast, the hypothesis is related with determining redundancy between metabolites) [75].
The analysis by comparison with pure standards of different family of compounds is advisable, in order to compare the retention rates of the compounds. However, the characterization of a certain metabolite that there are no pure standards, its determination can be done by comparison with homologues of a certain family of compounds, which the detailed analysis of the fragmentation pattern. Metabolite annotation is still challenging despite all efforts made for establishing specialized databases with mass spectral properties of different metabolites. Annotation and identification levels for metabolites were defined by the Chemical Analysis Working Group of the Metabolomics Standards Initiative (MSI). Level 1 indicates compromise identified compounds, level 2 is used for putatively annotated compounds, level 3 is used for putatively characterized compound classes, and level 4 is used for unidentified or unclassified metabolites that still can be differentiated and quantified based upon spectral data. Dark matter, also called “unknown unknowns”, represents the majority of metabolites analyzed on a metabolomics experiment, because instruments collect much more information than it is currently possible to annotate [76]. It is estimated that an average of only 2% of the data can be annotated. This is even a most common problem in metabolomics analysis from animals because many databases are specialized in human-derived metabolites, or some molecular structures from animals have been solved but are absent from the reference databases. Analysis from non-model organisms tends to have a higher number of truly novel compounds, called “unknown unknowns” [77]. As it is impossible to collect spectra for every molecule in the universe, computer-generated (in silico) spectral prediction algorithms are also recommended during metabolite annotation such as CSI:FingerID (https://www.csi-fingerid.uni-jena.de/) and Competitive Fragmentation Modeling-ID (CFM-ID, https://cfmid.wishartlab.com/) for analyzing fragmentation patterns. For volatilome analysis NIST (https://www.mswil.com/software/spectral-libraries-and-databases/nist20/) and Wiley (https://www.mswil.com/software/spectral-libraries-and-databases/wiley-spectral-libraries/wiley-gcms-libraries/) electronic collections are the most used mass spectra databases. The Dictionary of Natural Products (DNP) (http://dnp.chemnetbase.com/faces/chemical/ChemicalSearch.xhtml;jsessionid=DBE98AD72918A1607A7E739064D0DB21), Pherobase (https://www.pherobase.com/), Human Metabolome Database (HMDB) (https://hmdb.ca/), METLIN (https://metlin.scripps.edu/landing_page.php?pgcontent=mainPage), MassBank Japan (http://www.massbank.jp/), MassBank Europe (https://massbank.eu/MassBank/), MassBank North America (https://mona.fiehnlab.ucdavis.edu/), Supernatural II (http://bioinf-applied.charite.de/supernatural_new/index.php), ChEMBL (https://www.ebi.ac.uk/chembl/), Mass Spectral and GC Data of Drugs, Poisons, Pesticides, Pollutants, and Their Metabolites (https://www.wiley.com/en-gb/Mass+Spectral+and+GC+Data+of+Drugs%2C+Poisons%2C+Pesticides%2C+Pollutants%2C+and+Their+Metabolites%2C+5th+Edition-p-9783527342877) and vocBinBase (https://bitbucket.org/fiehnlab/binbase/src/master/) are other useful resources. When compound annotation is not possible and only chemical class could be assigned to a metabolite it is recommended to employ the comprehensive, and computable chemical taxonomy from Classyfire (http://classyfire.wishartlab.com/). See [78] for a review focused on mass spectral databases for LC/MS- and GC/MS-based metabolomics. For the analysis of mVOCs, in 2014 was developed a software that allows the characterization of mass spectra obtained in microorganisms. It was updated in 2018 with more than 2000 compounds from more than 1000 species, which is called mVOC database 2.0 (http://bioinformatics.charite.de/mvoc) [79]. With this tool a more precise characterization of the different volatilome of the microbes studied at present is achieved.
Select the univariate statistics according to the variables of interest. T-test, U-test, and analysis of variance (ANOVA) are the most common univariate statistics employed for data mining in volatilomics. As datasets usually include a large number of features, the significance level should be determined appropriately to reduce the number of false positives and false negatives. For reducing false positive, family wise error rate (FWER) correction, such as a Bonferroni correction, is a conservative approach, in which the p-values are multiplied by the number of comparisons. In contrast, for reducing false negatives, false discovery rate (FDR) correction is a highly sensitive method [80].
Multivariate statistical methods are very powerful at summarizing large and multidimensional data generated from volatilomics. Exactly as for pre-treatment methods, multivariable analysis should be chosen carefully and selected coherently with the hypothesis of interest and methods used for data pretreatment. Unsupervised approaches and supervised approaches differ in how samples are grouped within the multivariate calculations. Unsupervised solely have access to the matrix to find features useful for grouping and categorizing the samples. Clustering methods, such as hierarchical clustering (HCA), K-means clustering, self-organizing maps, principal component analysis (PCA) are among this group. Once the data have been analyzed by unsupervised methods, supervised methods (e.g. partial least squares discriminant analysis (PLD-DA), artificial neural networks, and evolutionary algorithms) should be applied for further evaluation [81]. Supervised methods have access to qualitative or quantitative traits (e.g., specie, location, body size, tissue type) and the matrix of measurements and can classify samples. Volcano plots have also recently been used to identify significantly covarying metabolites in binary comparisons. Volcano plots show each features’ statistical significance, p-value, on the y-axis, and fold change along the x-axis [82].
Correlation networks is a visualization tool that summarizes positive and negative correlations found between samples that represent different biological process [69]. Molecular networking organizes metabolite features from a volatilomics analysis into a connectivity network based on similarities in molecular fragmentation patterns obtained from mass spectrometry [82]. This analysis cluster families of molecules through vector correlations between fragment ions and enhance the interpretation of volatilome differentiation using a chemically informed visualization. Also, it enhances the annotation process with experimental and in silico databases [83]. When it is possible to combine Volatilomic and Genomic analysis, molecular networking can also be useful to prioritize features by linking observed natural products to their cognate biosynthetic gene clusters and gene cluster families [82].
Recently, many researchers have shared raw data files on open repositories, and this has motivated computer scientists to develop modern algorithms for facilitating the comparison of MS spectra obtained in different conditions [78]. This comparison still needs human inspection from experts trained in mass spectrometry fragmentation patterns, because is not an automatic process. Some examples of sites that allow raw experimental data to be shared in public repositories include MetaboLights (http://www.ebi.ac.uk/metabolights/), the Metabolomics Workbench (https://www.metabolomicsworkbench.org/), XCMS Online (https://xcmsonline.scripps.edu/landing_page.php?pgcontent=mainPage), MetabolomeExpress (https://www.metabolome-express.org/), GNPS (https://gnps.ucsd.edu/ProteoSAFe/static/gnps-splash.jsp) and the Metabolomic Repository Bordeaux (http://services.cbib.u-bordeaux.fr/MERYB/).
Current technological advances in sample collection, extraction techniques, volatile profiling, and data processing allow that the analysis of an invisible world where VOCs mediates different ecological processes could recover a more accurate picture of the complex chemical communication that occurs in nature. Different combinations of procedures need to be followed by researchers with the aim to answer specific scientific questions or hypotheses. Microextraction techniques emerge as tools for increasing extraction efficiency and at the same time facilitating faster extraction times without the environmental impact of large volume solvent wastes. Gas chromatography has played a fundamental role to detect volatile compounds often present as trace levels. Mass spectrometry has proved to be the preferred technique for the structure elucidation of new compounds and annotation of known VOCs. Current improvements in data analysis allow to extract of more biologically relevant information from a single study and to standardize procedures for evaluating hypothesis properly. All these steps are of paramount importance to evaluate both the ecological function of these compounds and the economic value in the medical, agricultural, flavor, and fragrance industry.
The authors thank the Department of Chemistry and Vicerrectoria de Investigaciones at Universidad de los Andes, Bogotá, Colombia for financial support. We wish to thank to Ministerio de Ciencia, Tecnología e Innovación (MinCiencias) for Julie Paulin Garcia Rodriguez (No 679), Mabel Gonzalez (No 757) and Gerson-Dirceu López (No 785), as well as the support to No. 44842-058-2018 and No. 80740-532-2019 projects. Also, the Faculty of Sciences of the Universidad de los Andes forgivable loan and research funds (INV-2018-2033-1259, INV-2019-2067-1747, INV-2018-2048-1338, and INV-2019-2086-1843). Scholarship granted by Fulbright to Mabel González as a Visiting Scholar at the Dorrestein Laboratory at Skaggs School of Pharmacy & Pharmaceutical Sciences, University of California, San Diego, United States.
The authors declare no conflict of interest.
1D | First-Dimension |
2D | Second-Dimension |
AC | Alternating Current |
AMDIS | Automated Mass Spectral Deconvolution and Identification System |
ANOVA | Analysis of variance |
ATCC | American Type Culture Collection |
CAR | Carboxen |
CFM-ID | Competitive Fragmentation Modeling-Id |
CI | Chemical Ionization |
CITES | Convention on International Trade in Endangered Species of Wild Fauna and Flora |
CW | Carbowax |
DC | Direct Current |
SDE | Simultaneous Extraction-Distillation |
DHS | Dynamic Headspace |
DNP | Dictionary of Natural Products |
DVB | Divinylbenzene |
EI | Electron Ionization |
EOs | Essential Oils |
FWER | Family Wise Error Rate |
FDR | False Discovery Rate |
GC | Gas Chromatography |
GC–MS | Gas Chromatography–Mass Spectrometry |
GC-O-MS | Gas Chromatography-Olfactometry-Mass Spectrometry |
GNPS | Global Natural Products Social Networking |
GCxGC | Comprehensive Two-Dimensional Gas Chromatography |
HCA | Hierarchical Clustering |
HF-LPME | Hollow Fiber Liquid-Phase Microextraction |
HMDB | Human Metabolome Database |
HRMS | High-Resolution Mass Spectrometry |
HS | Headspace |
IT-MS | Ion-Trap Mass Spectrometer |
LLE | Liquid–Liquid Extraction |
LPME | Liquid-Phase Microextractions |
LRI | Linear Retention Indices |
MS | Mass Spectrometer |
MSI | Metabolomics Standards Initiative |
mVOCs | Microbial Volatile Organic Compounds |
m/z | Mass-To-Charge Ratio |
mzmL | Mass Spectrometry Markup Language |
mzXML | Extensible Markup Language |
NetCDF | Network Common Data Form |
NIST | National Institute of Standards and Technology |
PA | Polyacrylate |
PCA | Principal Component Analysis |
PDMS | Polydimethylsiloxane |
PLD-DA | Partial Least Squares Discriminant Analysis |
PTR-MS | Proton-Transfer-Reaction Mass Spectrometry |
PTV | Programmed Temperature Vaporizer |
RI | Retention indexes |
qMS | Quadrupole Mass Spectrometer |
SAFE | Solvent Assisted Flavor Evaporation |
SBSE | Stir Bar Sorptive Extraction |
SDME | Single Drop Microextraction |
SIFT-MS | Selected-Ion Flow-Tube Mass Spectrometry |
SIM | Selected Ion Monitoring |
SLM | Supported Liquid Membrane |
SPE | Solid-Phase Extraction |
SPME | Solid-Phase Microextraction |
TOF-MS | Time-of-Flight Mass Spectrometer |
VOCs | Volatile Organic Compounds |
Ruthenium is a precious metal that belongs to the platinum-group elements [1]. As ruthenium can adopt various oxidation numbers, its coordination complexes adopt a wide variety of oxidation states from -II to VIII [2]. When nitrogen-based donor ligands are coordinated to a central ruthenium atom, the resulting ruthenium complexes generally prefer the +II and + III oxidation states, but occasionally also adopt the +IV and + V states. Arguably the most studied Ru complexes with nitrogen-based donor ligands are those that contain the hexaammineruthenium dication, [Ru(NH3)6]2+, and the tris(2,2′-bipyridine)ruthenium(II) dication, [Ru(bpy)3]2+(bpy = 2,2′-bipyridine) [3, 4, 5, 6]. [Ru(bpy)3]2+ was first reported by Burstall [7] and is easily obtained from the reaction of RuCl3•nH2O with an excess amount of bpy in aqueous ethanol. [Ru(bpy)3]2+ exhibits a stable low-spin t2g6 electronic configuration as well as a reversible one-electron oxidation at +1.29 V (vs SCE) and successive one-electron reductions at −1.33 V, −1.52 V, −1.76 V, and − 2.4 V vs. SCE; the oxidation is a Ru(II/III) metal-center-based process, while the reductions occur on the bpy ligands. [Ru(bpy)3]2+ exhibits a metal-to-ligand charge transfer (MLCT) band at 452 nm and bright luminescence at 612 nm (lifetime: 600 ns) under MLCT excitation. This luminescence arises from the triplet MLCT photoexcited state, which allows this complex to serve as a photosensitizer for a wide scope of photoenergy conversion processes and as a photocatalyst for organic transformations [8]. Therefore, it is hardly surprising that during the past five decades, numerous studies on photoactive [Ru(bpy)3]2+ complexes have been reported [3]. The tuning of their physical properties, such as their absorption/emission maxima or redox potential, via ligand modification has been achieved by introducing substituents on bpy or by replacing the bpy ligand with other
For example, replacing one of the bpy ligands in [Ru(bpy)3]2+ with an
Coordination modes of pyridine and benzimidazole as ligands.
Chemical structures of bidentate and tridentate ligands that contain pyridine and benzimidazole group(s).
This chapter focuses on the molecular design of ruthenium complexes with
Schematic illustration of molecular devices based on electron/proton-responsive Ru complexes confined to a surface.
Benzimidazole ligands can be synthesized by the Phillips condensation reaction between an organic carboxylic acid or nitrile and
Chemical structures of benzimidazole-containing ligands that bridge two Ru centers in bis-bidentate or bis-tridentate coordination modes.
Surface modification plays an important role in controlling the electron-transfer events and chemical reactivity in photocatalysis, as well as the charge-transport process in heterojunctions. Recently, several reviews of the applications of surface modification toward dye-sensitized solar cells and electrochemical catalysts for hydrogen/oxygen-evolution reactions have been published [21, 29, 30, 31, 32, 33, 34], showing the importance of such interdisciplinary research. In the area of solar-energy conversion, Grätzel-type dye-sensitized solar cells composed of mesoporous TiO2 on fluorine-doped SnO2 (FTO) with immobilized Ru complexes that contain 2,2′-bipyridyl-4,4′-dicarboxylate and other bpy-derived ligands have been developed [35]. Interestingly, the electron-injection efficiency from the photoexcited-state Ru complex to TiO2 was found to strongly dependent on the anchoring group [34, 36, 37].
Given that the adsorption strength of a Ru complex on a surface depends on the combination of the anchoring group and the surface material, judicious selection of both is necessary for effective surface functionalization. Recently, indium-tin oxide (ITO)-coated glass or polymer substrates have been employed in a wide variety of electronic display devices such as organic light-emitting diodes (OLEDs) [38]. Transparent ITO electrodes are also employed as cell windows for spectroelectrochemistry. Therefore, ITO is a suitable substrate for monitoring both the electrochemical and spectrochemical changes in redox-active Ru complexes immobilized on its surface. The phosphonic acid group, which is known to immobilize on ITO electrodes, has been employed to anchor the Ru complexes [39]. Furthermore, organic phosphonic acids are known to bind zirconium(IV) ions to form a solid two-dimensional layer structure, [40]. which demonstrates their suitability for use in a layer-by-layer growth method based on redox-active metal complexes. Therefore, we developed several new tridentate benzimidazole ligands with phosphonic acid or phosphonate ester anchor groups (Figure 5). Alkylation of the imino N–H groups of the benzimidazole moieties using bromoalkyl-diethylphosphonate derivatives furnished chelating benzimidazolyl ligands with ethyl-protected phosphonates, which were used for the synthesis of Ru complexes [41]. After the ethyl-protected phosphonate Ru complexes had been purified, the diethyl phosphonate groups were deprotected to provide the corresponding Ru complexes with phosphonic acid groups. In particular, the tridentate ligand
Chemical structures of benzimidazole-containing ligands with phosphonic acid anchor groups and their abbreviations.
Ru complexes are substitutionally inert, and the octahedral coordination geometry around the Ru ion is maintained throughout the Ru(II/III) redox reaction. Therefore, they can be immobilized on a surface to design redox-active molecular devices. When three bidentate ligands are coordinated to an octahedral Ru complex, the formation of Δ and Λ optical isomers is possible, but in the case of Ru complexes surrounded by two tridentate ligands with C2v symmetry, no optical isomers do not exist. Hence, surface-confined Ru complexes that contain tridentate ligands with C2v symmetry such as 2,6-bis(benzimidazolyl)pyridine with phosphonic acid anchors are often selected for surface immobilization [21, 42]. Furthermore, the molecular orientation of Ru complexes self-assembled on a surface is crucial to the construction of further layered structures. To maintain the vertical orientation of the Ru complexes on a surface, free-standing multipodal anchor groups with phosphonic acid have been developed over the last two decades. Several examples are shown in Figure 6 [21, 43, 44, 45, 46]. together with our multipodal tridentate benzimidazole ligand with phosphonate anchors,
Chemical structures of free-standing multipodal phosphonic acid anchor groups on a surface [
Chemical structures of rod-shaped dinuclear Ru complexes that bear free-standing multipodal anchor groups at both ends.
When Ru complexes bearing phosphonic acid anchors are immobilized on an ITO or mica surface by immersion of the substrate into a solution of the Ru complex, the surface coverage of the Ru complex is dependent on the immersion time and the concentration of the complex in the solution. The temporal evolution of the surface coverage can be analyzed using the kinetic Langmuir equation (Eq. (1)), and curve fitting with a rate constant parameter,
Here, Γ(t
Chemisorption kinetics of the Ru–
Another chemical approach to evaluate the surface coverage is using the thermodynamic Langmuir isotherm based upon the concentration dependence of the adsorption of the Ru complex.
Here,
In recent years, several binding modes for the absorption of phosphonic acid groups on metal oxides have been proposed based on intensive studies using polarization modulation infrared reflection adsorption spectroscopy (PM-IRRAS), X-ray photoelectron spectroscopy (XPS), and density functional theory (DFT) calculations in recent years, and the bidentate or tridentate binding modes are considered to be most probable (Figure 9) [30, 32, 34, 44, 47]. The optimum solution pH value for the adsorption of Ru complexes
Proposed surface binding modes of phosphonic acid groups on a metal oxide (MOx) surface (M = metal) [
Atomic force microscopy (AFM) measurements have been used to provide clear surface images depicting the adsorption of these Ru complexes, particularly the surface morphology (
AFM images of dinuclear Ru complex
One advantage of ITO electrodes is that they enable the use of UV–vis spectroscopy to monitor the surface immobilization process. Ru(II) complexes bearing
Ru complexes with benzimidazole derivative ligands act as Brønsted acids and exhibit proton-coupled electron transfer (PCET) reactions in aqueous solution [49, 50]. For example, [Ru(mbibzim)(bibzimH2)]2+ (
Stepwise proton-transfer equilibria of Ru(II)(LMe)(LH2) complexes (
Square scheme of the electron–proton equilibria of Ru complexes
Pourbaix diagram of Ru complex
In biological systems, protons play a very important role in reactions and energy storage. Proton gradients are the driving force for the synthesis of ATP in biological membranes. Applications of proton gradients in energy storage in materials chemistry have shown that PCET chemical systems can be used for energy storage in redox batteries and capacitors. Ru complexes
Pourbaix diagram for a solution redox battery based on a pair of Ru complexes,
The PCET chemistry of Ru complexes that contain benzimidazole derivatives in solution can be extended to surface-bound systems by attaching surface-anchoring groups to the Ru complexes as described in the previous section.
Dinuclear Ru complexes
Chemical structures of dinuclear Ru complexes bearing both a benzimidazole bridging ligand from which protons can dissociate and free-standing multipodal phosphonic acid anchor groups at both ends [
Cyclic voltammograms of Ru complex
The anodic peak current,
Given that the spectral change due to the redox reactions of a monolayer film of
Surface modification using a molecular monolayer film alone enables only a single set of functionalities to be incorporated, and the measurable physical quantities, such as optical absorption or current value, are very low due to the low molecular density on the surface. On the other hand, multi-layer modification has the advantages of allowing various molecular units to be deposited at the surface, achieving greater increases in physical quantities such as optical density and charge stored, and enables the integration of various functionalities at the interface [31]. Thus, the integration of functional metal complexes on an electrode holds great promise for applications in
The formation of well-ordered zirconium(IV) bisphosphonate multilayer films is a well-known method for LbL assemblies on a solid surface that has been developed by Mallouk and others [40]. This method is based on the reconstitution of a two-dimensional layered compound, Zr(HPO3)2, on a gold surface via self-assembly of molecular units with metal ions. Starting from self-assembled 4-mercaptobutylphosphonic acid on the gold surface as a primer layer, alternate immersion of the modified gold substrate into a zirconium(IV) oxychloride solution and a bisphosphonic acid solution leads to multilayer films composed of a two-dimensional zirconium–phosphonate framework structure via LbL growth [40].
Similarly, the rod-shaped Ru complexes
Illustration of the layer-by-layer (LbL) assembly by successive immersion of a solid substrate such as ITO, mica, or a Si wafer into (i) a solution of a given Ru complex with phosphonate anchors, and (ii) a solution of Zr(IV) ions. After washing, this immersion process was conducted repeated several times.
Illustration of the LbL multilayer film of
In each physical measurement, the physical quantities, such as absorbance, amount of charge, and the height of the scratch increased linearly with increasing number of layers. Two types of growth models have been proposed for LbL growth from the surface-primer points via metal coordination on a solid surface (Figure 19) [59]. The first model involves dendritic divergent growth, which would result in an exponential increase in the physical quantities, while the second model involves linear growth of a layered structure. In the case of Ru complex
Illustration of two-layer-growth models: Dendritic divergent growth (left) and linear growth (right) [
The use of the LbL method on a solid surface makes it possible to accumulate various molecular units with different chemical functionalities by adjusting the number of layers and metals in the multilayer films. Furthermore, the sequential order of the various complex units can be varied; the units can be arranged in order of descending or ascending potential or p
Measuring electron-transfer events in multilayer LbL films composed of redox-active Ru complexes on an ITO electrode is fundamental to determine whether electrons can be transmitted through the multiple layers of Ru complexes as the number of layers is increased.
CV measurements of homo-multilayer films of
In addition, potential-step chronoamperometry (PSCA) measurements furnished a relatively small value for the apparent electron-transfer rate,
Multi-layer films of ruthenium complex
As portable electronic devices continue to proliferate, cost-effective cheap energy storage devices that are small, flexible, and low cost and provide high performance during the charging and discharging cycle are in high demand. Molecular-based supercapacitors are promising candidates in terms of these requirements. Redox-active Ru complexes are suitable for the fabrication of energy storage devices, since multilayer molecular Ru assemblies obtained via the LbL method can be scaled by increasing the number of layers, which leads to enhancement of the electrical capacitance in such films [57].
The charge–discharge properties of a sixty-five-layer film of Ru complex
Galvanostatic charge–discharge curves of ITO|(Ru complex
PCET reactions can be used in energy-storage devices such as redox-flow batteries or two half-cells in unbuffered aqueous solution as described in Section
Schematic illustration of two half-cells composed of multilayer ITO|(
During the charging process, the multilayer
At the same time, the multilayer electrode of
where
On the other hand, when all four imino N–H protons on the benzimidazole moieties were protected by N–Me groups, the capacitance decreased by 77% compared to that of the original PCET-type capacitor. This result strongly suggests that the proton movement plays a more important role than the anion movement in the charge storage. Furthermore, the proton movement accompanying the redox reaction in the Ru multilayer films on the ITO electrode was confirmed using a pH-indicator probe in aqueous solution. In this type of LbL films composed of Ru complexes that exhibit PCET-type redox reactions, the capacitance increases almost linearly with the number of layers (Figure 21) [20].
To obtain proton rocking-chair-type redox capacitors that use protons as the charge carriers, the quinone/hydroquinone couple is often used [52, 64, 65, 66, 67]. However, at neutral pH, the electron–proton transfer rate of the quinone/hydroquinone couple is slower than that of the Ru(II/III) couple. The use of the LbL method to fabricate multilayered structures of redox-active Ru complexes that exhibit PCET is advantageous, as the storage capacity can be enhanced by increasing the number of redox-active modular units on demand.
One advantage of the LbL assembly method using metal coordination at the interface is that a combinatorial approach can be employed to construct sequentially ordered hetero-multilayer films(
Monolayer films of the Ru complexes
Cyclic voltammograms of heterolayer films of Ru complexes
Conversely, for the ITO||(
Rectified ET mechanism for the CV response of the ITO||(
Silicon-based
Switching between the “0” and “1” states by applying potentials of −0.5 V and + 0.7 V in the ITO|(
The idea of molecular devices is based on a next-generation paradigm to overcome the limitations associated with Moore’s law, which states that the number of transistors per silicon chip doubles every year, and the use of individual molecules as active electronic components. The first single molecular device was the theoretical proposal of a molecular diode by Aviram and Ratner; [68] subsequently, the concept of molecular electronic devices was further developed by Carter [69]. Various molecules have demonstrated basic electronic functionality as switches, as diodes for rectification, and as optical devices, storage devices, and sensing devices for future information technologies [54, 70]. The recent experimental development of single-molecular conductance measurements using metal–molecule–metal junctions [71] has opened a new avenue for the realization of molecular electronic devices through the judicious selection of molecules [70, 72, 73, 74, 75, 76]. Ru complexes are substitutionally inert in both the Ru(II) and Ru(III) oxidation states, and also exhibit fast self-exchange ET rates due to the small reorganization energy of the Ru(II/III) couple. Therefore, the use of a mixed-valence Ru(II)–Ru(III) complex as a perturbing motif branching from a conducting molecular wire has been proposed by Carter. Here, two molecular devices based on Ru complexes are discussed; the first is a Ru-complex molecular junction that exhibits rectification switching in response to humidity, and the other is a two-terminal memristor device based on the PCET reactions of Ru complexes.
Conductive-probe atomic force microscopy (C-AFM) was employed to measure the
Under dry (low humidity) conditions, the
Structures of Ru complexes
Conceptual illustration of a humidity-switchable molecular diode [
Several factors need to be considered to explain this behavior. The tip-radius affected the asymmetry of the
Recently, memristors have attracted substantial attention as the fourth passive element after resistors, capacitors, and inductors. The memristor was predicted by Chua in 1971 as a new electronic circuit element linking charge and magnetic flux, [79] and the first example of such a device was demonstrated experimentally in 2008. This first memristor device consisted of TiO2-x sandwiched between two Pt metal terminals, in which the oxygen defects led to filament formation, and the defects acted as mobile charged dopants and drifted in the applied electric field [80]. As a result, the device exhibited a periodic pinched hysteresis loop in its
To elucidate the coupling of the proton-transfer ability of P4VP and the PCET reactions of Ru complexes
Cyclic voltammograms of ITO|(
In the initial stage, the
Schematic illustration of the proton-conduction switching in the two-terminal device ITO|(
Therefore, the large
Further important applications for ruthenium complexes include photoredox catalysts and dye-sensitized solar cells. In particular, Ru(bpy)3 or Ru(tpy)2 derivatives have been used as photosensitizer dyes on mesoporous TiO2 surfaces in Grätzel-type solar cells. Over the past two decades, many Ru complexes with phosphonate anchors have been reported, [33] and many Ru dyes derived from Ru(bpy)3 derivatives that contain phosphonate anchors (Figure 30). Additionally, Ru-2,6-bis(benzimidazole-2-yl)pyridine complexes have been employed as photoredox catalysts [85, 86]. The Ru–benzimidazole bond is known to be more stable than the Ru–pyridine bond in the photoexcited state, rendering such Ru-benzimidazole complexes promising candidates for photoelectrochemical redox catalysts.
Chemical structures of Ru(bpy)3 derivatives that contain phosphonic acid anchors and surface-confined Ru catalyst and chromophore–catalyst assemblies [
Substitutionally inert ruthenium complexes bearing benzimidazole derivatives have unique electrochemical and photochemical properties. In particular, proton-coupled electron-transfer in ruthenium–benzimidazole complexes endows them with rich redox chemistry and makes them useful as a modular unit for redox mediators or reactive sites for switching by external stimuli. In this chapter, the role of PCET reactions on Ru–benzimidazole complexes in energy-storage applications and the tuning of metal–metal interactions in aqueous solution was emphasized first. Based on this knowledge acquired from solution chemistry, the chemistry of Ru complexes confined on an electrode surface via their self-assembling from solution for the fabrication of the surface functional molecular devices on electrodes was discussed. Indium-tin oxide (ITO) is often chosen as the electrode due to its transparency and wide use as a substrate in electronics. To immobilize the redox-active Ru complexes on an ITO electrode, tetrapod phosphonic acid anchor groups are often incorporated into tridentate 2,6-bis(benzimidazole-2-yl)pyridine or benzene ligands, which enables the construction of free-standing self-assembled monolayer structures on an ITO electrode. Starting from this monolayer as a primer layer, multilayer films can be constructed by the LbL layer growth method. The resulting multilayers using redox-active Ru complexes as a modular unit exhibited long-range electron transport even in films with over 60 layers (∼100 nm thick) through the “stepping-stone” mechanism. Furthermore, a combinatorial approach to LbL layer growth can be used to obtain bespoke functional heterolayer films via material design. Using this strategy, blocking of electron transfer or rectification can be made to occur in such Ru complex heterolayer films, which results in charge trapping; the trapped electrons can subsequently be released via photo-irradiation, which leads to the new concept of photo-responsive memory devices. The CV response of multilayer films of Ru complexes with PCET depends strongly on the pH value. By judicious selection of the redox potentials and p
Therefore, surface-confined Ru complexes exhibit highly promising potential for the development of new functional molecular-based devices.
The author gratefully acknowledges financial support from MEXT via Grants-in-Aid for Scientific Research, No. 21108003 (Coordination Programming) and JP17H05383 (Coordination Asymmetry) as well as from the Institute of Science and Engineering at Chuo University. The author would also like to thank Dr. Katsuaki Kobayashi, Prof. Katsuhiko Kanaizuka, Dr. Hiroaki Ozawa, as well as all of his past students and coauthors in my papers for their great help and their contributions.
This chapter is dedicated to my good friend Prof. Wolfgang Kaim on the occasion of his 70th birthday, and to my late wife, Masako Haga, who has supported my research activities for many years.
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Most real-world decision-making situations are subject to bounded rationality; whereby the technical and economic evaluation of all solution alternatives (branches) is bounded by the consideration of dominant subjective constraints. The early definition of DSS introduced it as a system that intended to support decision makers in semi-structured problems that could not be completely supported by algorithms. DSSs were planned to be an accessory for managers to expand their capabilities but not to replace them. Decision support systems could provide the means to complement decision makers by quantitatively supporting managerial decisions that could otherwise be based on personal intuition and experience. In addition to the traditional DSS characteristics (i.e., data and model orientation, interactivity), the inclusion of an intelligent knowledge base would be required to quantify the impacts of both technical (hard) and subjective (soft) constraints.",book:{id:"6259",slug:"management-of-information-systems",title:"Management of Information Systems",fullTitle:"Management of Information Systems"},signatures:"Maria Rashidi, Maryam Ghodrat, Bijan Samali and Masoud\nMohammadi",authors:[{id:"211318",title:"Dr.",name:"Maria",middleName:null,surname:"Rashidi",slug:"maria-rashidi",fullName:"Maria Rashidi"},{id:"212606",title:"Dr.",name:"Maryam",middleName:null,surname:"Ghodrat",slug:"maryam-ghodrat",fullName:"Maryam Ghodrat"},{id:"212607",title:"Prof.",name:"Bijan",middleName:null,surname:"Samali",slug:"bijan-samali",fullName:"Bijan Samali"},{id:"274006",title:"Dr.",name:"Masoud",middleName:null,surname:"Mohammadi",slug:"masoud-mohammadi",fullName:"Masoud Mohammadi"}]}],mostDownloadedChaptersLast30Days:[{id:"62362",title:"The Role of Information Systems in Human Resource Management",slug:"the-role-of-information-systems-in-human-resource-management",totalDownloads:7214,totalCrossrefCites:3,totalDimensionsCites:7,abstract:"Over the last years, human resource management (HRM) has experienced significant transformations. The focus has passed from the administrative management tasks to becoming a strategic partner of the overall organization strategy, largely with the strong support of information technologies’ evolution in this field of knowledge area. The extended use of information systems has a deep effect in the way HRM is managed nowadays. It boosted a major transformation of human resources (HR) processes and practices within organizations, namely on how they collect, store, use, and share information. Several HRM processes have become more efficient and the impact of this service level improvement allowed a greater involvement of HR in the business strategy. This new role in business strategy adds significant changes to HR function and to its professionals. Along this chapter, we discuss the effects of information systems in HRM, considering the existing literature on the topic, and describe the benefits and possible limitations of using them. We also provide an overview of some applications of technology in functional areas of HRM, within organizations.",book:{id:"6259",slug:"management-of-information-systems",title:"Management of Information Systems",fullTitle:"Management of Information Systems"},signatures:"Marlene Sofia Alves e Silva and Carlos Guilherme da Silva Lima",authors:[{id:"211475",title:"M.D.",name:"Marlene",middleName:"Sofia",surname:"Silva",slug:"marlene-silva",fullName:"Marlene Silva"},{id:"211476",title:"Dr.",name:"Carlos",middleName:null,surname:"Lima",slug:"carlos-lima",fullName:"Carlos Lima"}]},{id:"62394",title:"Management Functions of Information System Components as an Integration Model",slug:"management-functions-of-information-system-components-as-an-integration-model",totalDownloads:1477,totalCrossrefCites:3,totalDimensionsCites:3,abstract:"Management functions develop first, as systematic steps to carry out management activities, while information components system follow later as part of management elements, where both must be integrated in order to make its practical implementation more clear. Management Functions and Information System Components as an integration model are (1) to explain Management Functions, Information System Components, Goals and Benefit related to Information System and (2) to explain integration process of Management Functions with Information System Component to get goals and benefits as an integrated model. Research method using expert method has done an integration of management function, which includes the cycle of P, O, A, C, E and I, to run management process, must be step by step, and as a cycle. Information components include S, H, F, B, and T and must have minimum requirement. Management of Information System needs goals and benefits that can be calculated clearly and specifically. To get goals and benefits in excellence performance are needed the integrated process to coordinate management functions and information system components, as an Integrated Model with an example in applications of software in Nosocomial Infection Control for Hospital, as the figure below.",book:{id:"6259",slug:"management-of-information-systems",title:"Management of Information Systems",fullTitle:"Management of Information Systems"},signatures:"Boy Subirosa Sabarguna",authors:[{id:"200387",title:"Ph.D.",name:"Boy Subirosa",middleName:null,surname:"Sabarguna",slug:"boy-subirosa-sabarguna",fullName:"Boy Subirosa Sabarguna"}]},{id:"57870",title:"Information and Information Technologies in Conflict Management",slug:"information-and-information-technologies-in-conflict-management",totalDownloads:1206,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"This paper analyzes information and modern information technologies as applied in different organizational environment and considers the content and peculiarities of conflict management process based on implementation of communicative scenarios. Currently, the need for escalated organizational transformations has become imminent, taking into account the intensifying development of the differentiated information society, which requires properly interactive and transparent policy-making. Correct understanding of information and effective implementation of information technologies is a rational attempt to harmonize the modern organizational environment reducing the level of conflict and improving efficiency indexes.",book:{id:"6259",slug:"management-of-information-systems",title:"Management of Information Systems",fullTitle:"Management of Information Systems"},signatures:"Andrei Aleinikov, Daria Maltseva, Alexander Kurochkin and Tatiana\nKoulakova",authors:[{id:"212005",title:"Dr.",name:"Andrey",middleName:null,surname:"Aleynikov",slug:"andrey-aleynikov",fullName:"Andrey Aleynikov"},{id:"219746",title:"Dr.",name:"Tatiana",middleName:null,surname:"Koulakova",slug:"tatiana-koulakova",fullName:"Tatiana Koulakova"},{id:"219747",title:"Dr.",name:"Daria",middleName:null,surname:"Maltseva",slug:"daria-maltseva",fullName:"Daria Maltseva"},{id:"219748",title:"Dr.",name:"Alexander",middleName:null,surname:"Kurochkin",slug:"alexander-kurochkin",fullName:"Alexander Kurochkin"}]},{id:"59493",title:"Some Methods for Evaluating Performance of Management Information System",slug:"some-methods-for-evaluating-performance-of-management-information-system",totalDownloads:1277,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"Recently, several kinds of information systems are developed for purposes and needs of business and play an important role in business organizations and management operations. Management information system, or MIS for short, is a kind of information system. It is a key factor to facilitate and attain efficient decision-making in an organization. Its performance relates to many other information systems, for instance, DSS or decision support system, SIS or strategic information system, etc. Methods of testing statistical hypotheses concerning the performance of MIS are absolutely essential to support management activities and decision-making.",book:{id:"6259",slug:"management-of-information-systems",title:"Management of Information Systems",fullTitle:"Management of Information Systems"},signatures:"Khu Phi Nguyen and Hong Tuyet Tu",authors:[{id:"150274",title:"Associate Prof.",name:"Khu",middleName:"Phi",surname:"Nguyen",slug:"khu-nguyen",fullName:"Khu Nguyen"}]},{id:"63078",title:"Decision Support Systems",slug:"decision-support-systems",totalDownloads:2326,totalCrossrefCites:7,totalDimensionsCites:13,abstract:"The current decision-making problems is more complex than it was in the past, prompting the need for decision support. Most real-world decision-making situations are subject to bounded rationality; whereby the technical and economic evaluation of all solution alternatives (branches) is bounded by the consideration of dominant subjective constraints. The early definition of DSS introduced it as a system that intended to support decision makers in semi-structured problems that could not be completely supported by algorithms. DSSs were planned to be an accessory for managers to expand their capabilities but not to replace them. Decision support systems could provide the means to complement decision makers by quantitatively supporting managerial decisions that could otherwise be based on personal intuition and experience. In addition to the traditional DSS characteristics (i.e., data and model orientation, interactivity), the inclusion of an intelligent knowledge base would be required to quantify the impacts of both technical (hard) and subjective (soft) constraints.",book:{id:"6259",slug:"management-of-information-systems",title:"Management of Information Systems",fullTitle:"Management of Information Systems"},signatures:"Maria Rashidi, Maryam Ghodrat, Bijan Samali and Masoud\nMohammadi",authors:[{id:"211318",title:"Dr.",name:"Maria",middleName:null,surname:"Rashidi",slug:"maria-rashidi",fullName:"Maria Rashidi"},{id:"212606",title:"Dr.",name:"Maryam",middleName:null,surname:"Ghodrat",slug:"maryam-ghodrat",fullName:"Maryam Ghodrat"},{id:"212607",title:"Prof.",name:"Bijan",middleName:null,surname:"Samali",slug:"bijan-samali",fullName:"Bijan Samali"},{id:"274006",title:"Dr.",name:"Masoud",middleName:null,surname:"Mohammadi",slug:"masoud-mohammadi",fullName:"Masoud Mohammadi"}]}],onlineFirstChaptersFilter:{topicId:"97",limit:6,offset:0},onlineFirstChaptersCollection:[],onlineFirstChaptersTotal:0},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:8,limit:8,total:0},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:8,numberOfPublishedChapters:87,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:98,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:27,numberOfPublishedChapters:286,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:9,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:11,numberOfPublishedChapters:139,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:8,numberOfPublishedChapters:129,numberOfOpenTopics:0,numberOfUpcomingTopics:2,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!1},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:106,numberOfOpenTopics:3,numberOfUpcomingTopics:1,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:9,numberOfPublishedChapters:101,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2632-0517",doi:"10.5772/intechopen.73681",isOpenForSubmission:!0}],sshSeriesList:[{id:"22",title:"Business, Management and Economics",numberOfPublishedBooks:1,numberOfPublishedChapters:11,numberOfOpenTopics:2,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:0,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!1},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:0,numberOfPublishedChapters:9,numberOfOpenTopics:4,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{id:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. The whole process of submitting an article and editing of the submitted article goes extremely smooth and fast, the number of reads and downloads of chapters is high, and the contributions are also frequently cited.",author:{id:"55578",name:"Antonio",surname:"Jurado-Navas",institutionString:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRisIQAS/Profile_Picture_1626166543950",slug:"antonio-jurado-navas",institution:{id:"720",name:"University of Malaga",country:{id:null,name:"Spain"}}}},{id:"6",text:"It is great to work with the IntechOpen to produce a worthwhile collection of research that also becomes a great educational resource and guide for future research endeavors.",author:{id:"259298",name:"Edward",surname:"Narayan",institutionString:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259298/images/system/259298.jpeg",slug:"edward-narayan",institution:{id:"3",name:"University of Queensland",country:{id:null,name:"Australia"}}}}]},series:{item:{id:"14",title:"Artificial Intelligence",doi:"10.5772/intechopen.79920",issn:"2633-1403",scope:"Artificial Intelligence (AI) is a rapidly developing multidisciplinary research area that aims to solve increasingly complex problems. In today's highly integrated world, AI promises to become a robust and powerful means for obtaining solutions to previously unsolvable problems. This Series is intended for researchers and students alike interested in this fascinating field and its many applications.",coverUrl:"https://cdn.intechopen.com/series/covers/14.jpg",latestPublicationDate:"May 14th, 2022",hasOnlineFirst:!0,numberOfPublishedBooks:8,editor:{id:"218714",title:"Prof.",name:"Andries",middleName:null,surname:"Engelbrecht",slug:"andries-engelbrecht",fullName:"Andries Engelbrecht",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRNR8QAO/Profile_Picture_1622640468300",biography:"Andries Engelbrecht received the Masters and PhD degrees in Computer Science from the University of Stellenbosch, South Africa, in 1994 and 1999 respectively. He is currently appointed as the Voigt Chair in Data Science in the Department of Industrial Engineering, with a joint appointment as Professor in the Computer Science Division, Stellenbosch University. Prior to his appointment at Stellenbosch University, he has been at the University of Pretoria, Department of Computer Science (1998-2018), where he was appointed as South Africa Research Chair in Artifical Intelligence (2007-2018), the head of the Department of Computer Science (2008-2017), and Director of the Institute for Big Data and Data Science (2017-2018). 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He is a full professor of signal processing and pattern recognition and is head of the Signals and Communications Department at ULPGC, teaching from 2001 on subjects on signal processing and learning theory. His research lines are biometrics, biomedical signals and images, data mining, classification system, signal and image processing, machine learning, and environmental intelligence. He has researched in 52 international and Spanish research projects, some of them as head researcher. He is co-author of 4 books, co-editor of 27 proceedings books, guest editor for 8 JCR-ISI international journals, and up to 24 book chapters. He has over 450 papers published in international journals and conferences (81 of them indexed on JCR – ISI - Web of Science). He has published seven patents in the Spanish Patent and Trademark Office. He has been a supervisor on 8 Ph.D. theses (11 more are under supervision), and 130 master theses. He is the founder of The IEEE IWOBI conference series and the president of its Steering Committee, as well as the founder of both the InnoEducaTIC and APPIS conference series. He is an evaluator of project proposals for the European Union (H2020), Medical Research Council (MRC, UK), Spanish Government (ANECA, Spain), Research National Agency (ANR, France), DAAD (Germany), Argentinian Government, and the Colombian Institutions. He has been a reviewer in different indexed international journals (<70) and conferences (<250) since 2001. He has been a member of the IASTED Technical Committee on Image Processing from 2007 and a member of the IASTED Technical Committee on Artificial Intelligence and Expert Systems from 2011. \n\nHe has held the general chair position for the following: ACM-APPIS (2020, 2021), IEEE-IWOBI (2019, 2020 and 2020), A PPIS (2018, 2019), IEEE-IWOBI (2014, 2015, 2017, 2018), InnoEducaTIC (2014, 2017), IEEE-INES (2013), NoLISP (2011), JRBP (2012), and IEEE-ICCST (2005)\n\nHe is an associate editor of the Computational Intelligence and Neuroscience Journal (Hindawi – Q2 JCR-ISI). He was vice dean from 2004 to 2010 in the Higher Technical School of Telecommunication Engineers at ULPGC and the vice dean of Graduate and Postgraduate Studies from March 2013 to November 2017. He won the “Catedra Telefonica” Awards in Modality of Knowledge Transfer, 2017, 2018, and 2019 editions, and awards in Modality of COVID Research in 2020.\n\nPublic References:\nResearcher ID http://www.researcherid.com/rid/N-5967-2014\nORCID https://orcid.org/0000-0002-4621-2768 \nScopus Author ID https://www.scopus.com/authid/detail.uri?authorId=6602376272\nScholar Google https://scholar.google.es/citations?user=G1ks9nIAAAAJ&hl=en \nResearchGate https://www.researchgate.net/profile/Carlos_Travieso",institutionString:null,institution:{name:"University of Las Palmas de Gran Canaria",institutionURL:null,country:{name:"Spain"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"13633",title:"Prof.",name:"Abdelhamid",middleName:null,surname:"Mellouk",slug:"abdelhamid-mellouk",fullName:"Abdelhamid Mellouk",profilePictureURL:"https://mts.intechopen.com/storage/users/13633/images/1567_n.jpg",institutionString:null,institution:{name:"Paris 12 Val de Marne 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learning consultant from Sweden. \n\nHe is currently at Malmö University in Sweden, but also held positions at Lund University in Sweden and at Moscow Engineering Physics Institute. \nHe holds editorial positions at several international scientific journals and has served as a scientific editor for books and special journal issues. \nHis research interests are wide and include, but are not limited to, autonomous systems, computer modeling, artificial neural networks, artificial intelligence, cognitive neuroscience, cognitive robotics, cognitive architectures, cognitive aids and the philosophy of mind. \n\nDr. Johnsson has experience from working in the industry and he has a keen interest in the application of neural networks and artificial intelligence to fields like industry, finance, and medicine. \n\nWeb page: www.magnusjohnsson.se",institutionString:null,institution:{name:"Malmö University",institutionURL:null,country:{name:"Sweden"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"13818",title:"Dr.",name:"Asim",middleName:null,surname:"Bhatti",slug:"asim-bhatti",fullName:"Asim Bhatti",profilePictureURL:"https://mts.intechopen.com/storage/users/13818/images/system/13818.jpg",institutionString:null,institution:{name:"Deakin University",institutionURL:null,country:{name:"Australia"}}},{id:"151889",title:"Dr.",name:"Joao Luis Garcia",middleName:null,surname:"Rosa",slug:"joao-luis-garcia-rosa",fullName:"Joao Luis Garcia Rosa",profilePictureURL:"https://mts.intechopen.com/storage/users/151889/images/4861_n.jpg",institutionString:null,institution:{name:"University of Sao Paulo",institutionURL:null,country:{name:"Brazil"}}},{id:"103779",title:"Prof.",name:"Yalcin",middleName:null,surname:"Isler",slug:"yalcin-isler",fullName:"Yalcin Isler",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRyQ8QAK/Profile_Picture_1628834958734",institutionString:null,institution:{name:"Izmir Kâtip Çelebi University",institutionURL:null,country:{name:"Turkey"}}}]},{id:"24",title:"Computer Vision",coverUrl:"https://cdn.intechopen.com/series_topics/covers/24.jpg",editor:{id:"294154",title:"Prof.",name:"George",middleName:null,surname:"Papakostas",slug:"george-papakostas",fullName:"George Papakostas",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002hYaGbQAK/Profile_Picture_1624519712088",biography:"George A. Papakostas has received a diploma in Electrical and Computer Engineering in 1999 and the M.Sc. and Ph.D. degrees in Electrical and Computer Engineering in 2002 and 2007, respectively, from the Democritus University of Thrace (DUTH), Greece. Dr. Papakostas serves as a Tenured Full Professor at the Department of Computer Science, International Hellenic University, Greece. Dr. Papakostas has 10 years of experience in large-scale systems design as a senior software engineer and technical manager, and 20 years of research experience in the field of Artificial Intelligence. Currently, he is the Head of the “Visual Computing” division of HUman-MAchines INteraction Laboratory (HUMAIN-Lab) and the Director of the MPhil program “Advanced Technologies in Informatics and Computers” hosted by the Department of Computer Science, International Hellenic University. 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He has an excellent track record in the herpesvirus field, and his group is engaged in clinical research in the field of Epstein-Barr virus diseases. He is the editor of the online Encyclopedia of Environment and he coordinates the Universal Health Coverage education program for the BioHealth Computing Schools of the European Institute of Science.",institutionString:null,institution:{name:"Grenoble Alpes University",country:{name:"France"}}},{id:"131400",title:"Prof.",name:"Alfonso J.",middleName:null,surname:"Rodriguez-Morales",slug:"alfonso-j.-rodriguez-morales",fullName:"Alfonso J. Rodriguez-Morales",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/131400/images/system/131400.png",biography:"Dr. Rodriguez-Morales is an expert in tropical and emerging diseases, particularly zoonotic and vector-borne diseases (especially arboviral diseases). He is the president of the Travel Medicine Committee of the Pan-American Infectious Diseases Association (API), as well as the president of the Colombian Association of Infectious Diseases (ACIN). He is a member of the Committee on Tropical Medicine, Zoonoses, and Travel Medicine of ACIN. He is a vice-president of the Latin American Society for Travel Medicine (SLAMVI) and a Member of the Council of the International Society for Infectious Diseases (ISID). Since 2014, he has been recognized as a Senior Researcher, at the Ministry of Science of Colombia. He is a professor at the Faculty of Medicine of the Fundacion Universitaria Autonoma de las Americas, in Pereira, Risaralda, Colombia. He is an External Professor, Master in Research on Tropical Medicine and International Health, Universitat de Barcelona, Spain. He is also a professor at the Master in Clinical Epidemiology and Biostatistics, Universidad Científica del Sur, Lima, Peru. In 2021 he has been awarded the “Raul Isturiz Award” Medal of the API. Also, in 2021, he was awarded with the “Jose Felix Patiño” Asclepius Staff Medal of the Colombian Medical College, due to his scientific contributions to COVID-19 during the pandemic. He is currently the Editor in Chief of the journal Travel Medicine and Infectious Diseases. His Scopus H index is 47 (Google Scholar H index, 68).",institutionString:"Institución Universitaria Visión de las Américas, Colombia",institution:null},{id:"332819",title:"Dr.",name:"Chukwudi Michael",middleName:"Michael",surname:"Egbuche",slug:"chukwudi-michael-egbuche",fullName:"Chukwudi Michael Egbuche",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/332819/images/14624_n.jpg",biography:"I an Dr. Chukwudi Michael Egbuche. I am a Senior Lecturer in the Department of Parasitology and Entomology, Nnamdi Azikiwe University, Awka.",institutionString:null,institution:{name:"Nnamdi Azikiwe University",country:{name:"Nigeria"}}},{id:"284232",title:"Mr.",name:"Nikunj",middleName:"U",surname:"Tandel",slug:"nikunj-tandel",fullName:"Nikunj Tandel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/284232/images/8275_n.jpg",biography:'Mr. Nikunj Tandel has completed his Master\'s degree in Biotechnology from VIT University, India in the year of 2012. He is having 8 years of research experience especially in the field of malaria epidemiology, immunology, and nanoparticle-based drug delivery system against the infectious diseases, autoimmune disorders and cancer. He has worked for the NIH funded-International Center of Excellence in Malaria Research project "Center for the study of complex malaria in India (CSCMi)" in collaboration with New York University. The preliminary objectives of the study are to understand and develop the evidence-based tools and interventions for the control and prevention of malaria in different sites of the INDIA. Alongside, with the help of next-generation genomics study, the team has studied the antimalarial drug resistance in India. Further, he has extended his research in the development of Humanized mice for the study of liver-stage malaria and identification of molecular marker(s) for the Artemisinin resistance. At present, his research focuses on understanding the role of B cells in the activation of CD8+ T cells in malaria. Received the CSIR-SRF (Senior Research Fellow) award-2018, FIMSA (Federation of Immunological Societies of Asia-Oceania) Travel Bursary award to attend the IUIS-IIS-FIMSA Immunology course-2019',institutionString:"Nirma University",institution:{name:"Nirma University",country:{name:"India"}}},{id:"334383",title:"Ph.D.",name:"Simone",middleName:"Ulrich",surname:"Ulrich Picoli",slug:"simone-ulrich-picoli",fullName:"Simone Ulrich Picoli",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/334383/images/15919_n.jpg",biography:"Graduated in Pharmacy from Universidade Luterana do Brasil (1999), Master in Agricultural and Environmental Microbiology from Federal University of Rio Grande do Sul (2002), Specialization in Clinical Microbiology from Universidade de São Paulo, USP (2007) and PhD in Sciences in Gastroenterology and Hepatology (2012). She is currently an Adjunct Professor at Feevale University in Medicine and Biomedicine courses and a permanent professor of the Academic Master\\'s Degree in Virology. She has experience in the field of Microbiology, with an emphasis on Bacteriology, working mainly on the following topics: bacteriophages, bacterial resistance, clinical microbiology and food microbiology.",institutionString:null,institution:{name:"Universidade Feevale",country:{name:"Brazil"}}},{id:"229220",title:"Dr.",name:"Amjad",middleName:"Islam",surname:"Aqib",slug:"amjad-aqib",fullName:"Amjad Aqib",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/229220/images/system/229220.png",biography:"Dr. Amjad Islam Aqib obtained a DVM and MSc (Hons) from University of Agriculture Faisalabad (UAF), Pakistan, and a PhD from the University of Veterinary and Animal Sciences Lahore, Pakistan. Dr. Aqib joined the Department of Clinical Medicine and Surgery at UAF for one year as an assistant professor where he developed a research laboratory designated for pathogenic bacteria. Since 2018, he has been Assistant Professor/Officer in-charge, Department of Medicine, Manager Research Operations and Development-ORIC, and President One Health Club at Cholistan University of Veterinary and Animal Sciences, Bahawalpur, Pakistan. He has nearly 100 publications to his credit. His research interests include epidemiological patterns and molecular analysis of antimicrobial resistance and modulation and vaccine development against animal pathogens of public health concern.",institutionString:"Cholistan University of Veterinary and Animal Sciences",institution:null},{id:"62900",title:"Prof.",name:"Fethi",middleName:null,surname:"Derbel",slug:"fethi-derbel",fullName:"Fethi Derbel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/62900/images/system/62900.jpeg",biography:"Professor Fethi Derbel was born in 1960 in Tunisia. He received his medical degree from the Sousse Faculty of Medicine at Sousse, University of Sousse, Tunisia. He completed his surgical residency in General Surgery at the University Hospital Farhat Hached of Sousse and was a member of the Unit of Liver Transplantation in the University of Rennes, France. He then worked in the Department of Surgery at the Sahloul University Hospital in Sousse. Professor Derbel is presently working at the Clinique les Oliviers, Sousse, Tunisia. His hospital activities are mostly concerned with laparoscopic, colorectal, pancreatic, hepatobiliary, and gastric surgery. He is also very interested in hernia surgery and performs ventral hernia repairs and inguinal hernia repairs. He has been a member of the GREPA and Tunisian Hernia Society (THS). During his residency, he managed patients suffering from diabetic foot, and he was very interested in this pathology. For this reason, he decided to coordinate a book project dealing with the diabetic foot. Professor Derbel has published many articles in journals and collaborates intensively with IntechOpen Access Publisher as an editor.",institutionString:"Clinique les Oliviers",institution:null},{id:"300144",title:"Dr.",name:"Meriem",middleName:null,surname:"Braiki",slug:"meriem-braiki",fullName:"Meriem Braiki",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/300144/images/system/300144.jpg",biography:"Dr. Meriem Braiki is a specialist in pediatric surgeon from Tunisia. She was born in 1985. She received her medical degree from the University of Medicine at Sousse, Tunisia. She achieved her surgical residency training periods in Pediatric Surgery departments at University Hospitals in Monastir, Tunis and France.\r\nShe is currently working at the Pediatric surgery department, Sidi Bouzid Hospital, Tunisia. Her hospital activities are mostly concerned with laparoscopic, parietal, urological and digestive surgery. She has published several articles in diffrent journals.",institutionString:"Sidi Bouzid Regional Hospital",institution:null},{id:"229481",title:"Dr.",name:"Erika M.",middleName:"Martins",surname:"de Carvalho",slug:"erika-m.-de-carvalho",fullName:"Erika M. de Carvalho",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/229481/images/6397_n.jpg",biography:null,institutionString:null,institution:{name:"Oswaldo Cruz Foundation",country:{name:"Brazil"}}},{id:"186537",title:"Prof.",name:"Tonay",middleName:null,surname:"Inceboz",slug:"tonay-inceboz",fullName:"Tonay Inceboz",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/186537/images/system/186537.jfif",biography:"I was graduated from Ege University of Medical Faculty (Turkey) in 1988 and completed his Med. PhD degree in Medical Parasitology at the same university. I became an Associate Professor in 2008 and Professor in 2014. I am currently working as a Professor at the Department of Medical Parasitology at Dokuz Eylul University, Izmir, Turkey.\n\nI have given many lectures, presentations in different academic meetings. I have more than 60 articles in peer-reviewed journals, 18 book chapters, 1 book editorship.\n\nMy research interests are Echinococcus granulosus, Echinococcus multilocularis (diagnosis, life cycle, in vitro and in vivo cultivation), and Trichomonas vaginalis (diagnosis, PCR, and in vitro cultivation).",institutionString:"Dokuz Eylül University",institution:{name:"Dokuz Eylül University",country:{name:"Turkey"}}},{id:"71812",title:"Prof.",name:"Hanem Fathy",middleName:"Fathy",surname:"Khater",slug:"hanem-fathy-khater",fullName:"Hanem Fathy Khater",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/71812/images/1167_n.jpg",biography:"Prof. Khater is a Professor of Parasitology at Benha University, Egypt. She studied for her doctoral degree, at the Department of Entomology, College of Agriculture, Food and Natural Resources, University of Missouri, Columbia, USA. She has completed her Ph.D. degrees in Parasitology in Egypt, from where she got the award for “the best scientific Ph.D. dissertation”. She worked at the School of Biological Sciences, Bristol, England, the UK in controlling insects of medical and veterinary importance as a grant from Newton Mosharafa, the British Council. Her research is focused on searching of pesticides against mosquitoes, house flies, lice, green bottle fly, camel nasal botfly, soft and hard ticks, mites, and the diamondback moth as well as control of several parasites using safe and natural materials to avoid drug resistances and environmental contamination.",institutionString:null,institution:{name:"Banha University",country:{name:"Egypt"}}},{id:"99780",title:"Prof.",name:"Omolade",middleName:"Olayinka",surname:"Okwa",slug:"omolade-okwa",fullName:"Omolade Okwa",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/99780/images/system/99780.jpg",biography:"Omolade Olayinka Okwa is presently a Professor of Parasitology at Lagos State University, Nigeria. She has a PhD in Parasitology (1997), an MSc in Cellular Parasitology (1992), and a BSc (Hons) Zoology (1990) all from the University of Ibadan, Nigeria. She teaches parasitology at the undergraduate and postgraduate levels. She was a recipient of a Commonwealth fellowship supported by British Council tenable at the Centre for Entomology and Parasitology (CAEP), Keele University, United Kingdom between 2004 and 2005. She was awarded an Honorary Visiting Research Fellow at the same university from 2005 to 2007. \nShe has been an external examiner to the Department of Veterinary Microbiology and Parasitology, University of Ibadan, MSc programme between 2010 and 2012. She is a member of the Nigerian Society of Experimental Biology (NISEB), Parasitology and Public Health Society of Nigeria (PPSN), Science Association of Nigeria (SAN), Zoological Society of Nigeria (ZSN), and is Vice Chairperson of the Organisation of Women in Science (OWSG), LASU chapter. She served as Head of Department of Zoology and Environmental Biology, Lagos State University from 2007 to 2010 and 2014 to 2016. She is a reviewer for several local and international journals such as Unilag Journal of Science, Libyan Journal of Medicine, Journal of Medicine and Medical Sciences, and Annual Research and Review in Science. \nShe has authored 45 scientific research publications in local and international journals, 8 scientific reviews, 4 books, and 3 book chapters, which includes the books “Malaria Parasites” and “Malaria” which are IntechOpen access publications.",institutionString:"Lagos State University",institution:{name:"Lagos State University",country:{name:"Nigeria"}}},{id:"273100",title:"Dr.",name:"Vijay",middleName:null,surname:"Gayam",slug:"vijay-gayam",fullName:"Vijay Gayam",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/273100/images/system/273100.jpeg",biography:"Dr. Vijay Bhaskar Reddy Gayam is currently practicing as an internist at Interfaith Medical Center in Brooklyn, New York, USA. He is also a Clinical Assistant Professor at the SUNY Downstate University Hospital and Adjunct Professor of Medicine at the American University of Antigua. He is a holder of an M.B.B.S. degree bestowed to him by Osmania Medical College and received his M.D. at Interfaith Medical Center. His career goals thus far have heavily focused on direct patient care, medical education, and clinical research. He currently serves in two leadership capacities; Assistant Program Director of Medicine at Interfaith Medical Center and as a Councilor for the American\r\nFederation for Medical Research. As a true academician and researcher, he has more than 50 papers indexed in international peer-reviewed journals. He has also presented numerous papers in multiple national and international scientific conferences. His areas of research interest include general internal medicine, gastroenterology and hepatology. He serves as an editor, editorial board member and reviewer for multiple international journals. His research on Hepatitis C has been very successful and has led to multiple research awards, including the 'Equity in Prevention and Treatment Award” from the New York Department of Health Viral Hepatitis Symposium (2018) and the 'Presidential Poster Award” awarded to him by the American College of Gastroenterology (2018). He was also awarded 'Outstanding Clinician in General Medicine” by Venus International Foundation for his extensive research expertise and services, perform over and above the standard expected in the advancement of healthcare, patient safety and quality of care.",institutionString:"Interfaith Medical Center",institution:{name:"Interfaith Medical Center",country:{name:"United States of America"}}},{id:"93517",title:"Dr.",name:"Clement",middleName:"Adebajo",surname:"Meseko",slug:"clement-meseko",fullName:"Clement Meseko",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/93517/images/system/93517.jpg",biography:"Dr. Clement Meseko obtained DVM and PhD degree in Veterinary Medicine and Virology respectively. He has worked for over 20 years in both private and public sectors including the academia, contributing to knowledge and control of infectious disease. Through the application of epidemiological skill, classical and molecular virological skills, he investigates viruses of economic and public health importance for the mitigation of the negative impact on people, animal and the environment in the context of Onehealth. \r\nDr. Meseko’s field experience on animal and zoonotic diseases and pathogen dynamics at the human-animal interface over the years shaped his carrier in research and scientific inquiries. He has been part of the investigation of Highly Pathogenic Avian Influenza incursions in sub Saharan Africa and monitors swine Influenza (Pandemic influenza Virus) agro-ecology and potential for interspecies transmission. He has authored and reviewed a number of journal articles and book chapters.",institutionString:"National Veterinary Research Institute",institution:{name:"National Veterinary Research Institute",country:{name:"Nigeria"}}},{id:"158026",title:"Prof.",name:"Shailendra K.",middleName:null,surname:"Saxena",slug:"shailendra-k.-saxena",fullName:"Shailendra K. Saxena",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRET3QAO/Profile_Picture_2022-05-10T10:10:26.jpeg",biography:"Professor Dr. Shailendra K. Saxena is a vice dean and professor at King George's Medical University, Lucknow, India. His research interests involve understanding the molecular mechanisms of host defense during human viral infections and developing new predictive, preventive, and therapeutic strategies for them using Japanese encephalitis virus (JEV), HIV, and emerging viruses as a model via stem cell and cell culture technologies. His research work has been published in various high-impact factor journals (Science, PNAS, Nature Medicine) with a high number of citations. He has received many awards and honors in India and abroad including various Young Scientist Awards, BBSRC India Partnering Award, and Dr. JC Bose National Award of Department of Biotechnology, Min. of Science and Technology, Govt. of India. Dr. Saxena is a fellow of various international societies/academies including the Royal College of Pathologists, United Kingdom; Royal Society of Medicine, London; Royal Society of Biology, United Kingdom; Royal Society of Chemistry, London; and Academy of Translational Medicine Professionals, Austria. He was named a Global Leader in Science by The Scientist. He is also an international opinion leader/expert in vaccination for Japanese encephalitis by IPIC (UK).",institutionString:"King George's Medical University",institution:{name:"King George's Medical University",country:{name:"India"}}},{id:"94928",title:"Dr.",name:"Takuo",middleName:null,surname:"Mizukami",slug:"takuo-mizukami",fullName:"Takuo Mizukami",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/94928/images/6402_n.jpg",biography:null,institutionString:null,institution:{name:"National Institute of Infectious Diseases",country:{name:"Japan"}}},{id:"233433",title:"Dr.",name:"Yulia",middleName:null,surname:"Desheva",slug:"yulia-desheva",fullName:"Yulia Desheva",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/233433/images/system/233433.png",biography:"Dr. Yulia Desheva is a leading researcher at the Institute of Experimental Medicine, St. Petersburg, Russia. She is a professor in the Stomatology Faculty, St. Petersburg State University. She has expertise in the development and evaluation of a wide range of live mucosal vaccines against influenza and bacterial complications. Her research interests include immunity against influenza and COVID-19 and the development of immunization schemes for high-risk individuals.",institutionString:'Federal State Budgetary Scientific Institution "Institute of Experimental Medicine"',institution:null},{id:"238958",title:"Mr.",name:"Atamjit",middleName:null,surname:"Singh",slug:"atamjit-singh",fullName:"Atamjit Singh",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/238958/images/6575_n.jpg",biography:null,institutionString:null,institution:null},{id:"333753",title:"Dr.",name:"Rais",middleName:null,surname:"Ahmed",slug:"rais-ahmed",fullName:"Rais Ahmed",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/333753/images/20168_n.jpg",biography:null,institutionString:null,institution:null},{id:"252058",title:"M.Sc.",name:"Juan",middleName:null,surname:"Sulca",slug:"juan-sulca",fullName:"Juan Sulca",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/252058/images/12834_n.jpg",biography:null,institutionString:null,institution:null},{id:"191392",title:"Dr.",name:"Marimuthu",middleName:null,surname:"Govindarajan",slug:"marimuthu-govindarajan",fullName:"Marimuthu Govindarajan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/191392/images/5828_n.jpg",biography:"Dr. M. Govindarajan completed his BSc degree in Zoology at Government Arts College (Autonomous), Kumbakonam, and MSc, MPhil, and PhD degrees at Annamalai University, Annamalai Nagar, Tamil Nadu, India. He is serving as an assistant professor at the Department of Zoology, Annamalai University. His research interests include isolation, identification, and characterization of biologically active molecules from plants and microbes. He has identified more than 20 pure compounds with high mosquitocidal activity and also conducted high-quality research on photochemistry and nanosynthesis. He has published more than 150 studies in journals with impact factor and 2 books in Lambert Academic Publishing, Germany. He serves as an editorial board member in various national and international scientific journals.",institutionString:null,institution:null},{id:"274660",title:"Dr.",name:"Damodar",middleName:null,surname:"Paudel",slug:"damodar-paudel",fullName:"Damodar Paudel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/274660/images/8176_n.jpg",biography:"I am DrDamodar Paudel,currently working as consultant Physician in Nepal police Hospital.",institutionString:null,institution:null},{id:"241562",title:"Dr.",name:"Melvin",middleName:null,surname:"Sanicas",slug:"melvin-sanicas",fullName:"Melvin Sanicas",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/241562/images/6699_n.jpg",biography:null,institutionString:null,institution:null},{id:"337446",title:"Dr.",name:"Maria",middleName:null,surname:"Zavala-Colon",slug:"maria-zavala-colon",fullName:"Maria Zavala-Colon",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Puerto Rico, Medical Sciences Campus",country:{name:"United States of America"}}},{id:"338856",title:"Mrs.",name:"Nur Alvira",middleName:null,surname:"Pascawati",slug:"nur-alvira-pascawati",fullName:"Nur Alvira Pascawati",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Universitas Respati Yogyakarta",country:{name:"Indonesia"}}},{id:"441116",title:"Dr.",name:"Jovanka M.",middleName:null,surname:"Voyich",slug:"jovanka-m.-voyich",fullName:"Jovanka M. 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This topic is dedicated to biologically plausible descriptions and computational models - at various abstraction levels - of neurons and neural systems. This includes, but is not limited to: single-neuron modeling, sensory processing, motor control, memory, and synaptic plasticity, attention, identification, categorization, discrimination, learning, development, axonal patterning, guidance, neural architecture, behaviors, and dynamics of networks, cognition and the neuroscientific basis of consciousness. Particularly interesting are models of various types of more compound functions and abilities, various and more general fundamental principles (e.g., regarding architecture, organization, learning, development, etc.) found at various spatial and temporal levels.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/23.jpg",hasOnlineFirst:!0,hasPublishedBooks:!1,annualVolume:11419,editor:{id:"14004",title:"Dr.",name:"Magnus",middleName:null,surname:"Johnsson",slug:"magnus-johnsson",fullName:"Magnus Johnsson",profilePictureURL:"https://mts.intechopen.com/storage/users/14004/images/system/14004.png",biography:"Dr Magnus Johnsson is a cross-disciplinary scientist, lecturer, scientific editor and AI/machine learning consultant from Sweden. \n\nHe is currently at Malmö University in Sweden, but also held positions at Lund University in Sweden and at Moscow Engineering Physics Institute. \nHe holds editorial positions at several international scientific journals and has served as a scientific editor for books and special journal issues. \nHis research interests are wide and include, but are not limited to, autonomous systems, computer modeling, artificial neural networks, artificial intelligence, cognitive neuroscience, cognitive robotics, cognitive architectures, cognitive aids and the philosophy of mind. \n\nDr. Johnsson has experience from working in the industry and he has a keen interest in the application of neural networks and artificial intelligence to fields like industry, finance, and medicine. \n\nWeb page: www.magnusjohnsson.se",institutionString:null,institution:{name:"Malmö University",institutionURL:null,country:{name:"Sweden"}}},editorTwo:null,editorThree:null,series:{id:"14",title:"Artificial Intelligence",doi:"10.5772/intechopen.79920",issn:"2633-1403"},editorialBoard:[{id:"13818",title:"Dr.",name:"Asim",middleName:null,surname:"Bhatti",slug:"asim-bhatti",fullName:"Asim Bhatti",profilePictureURL:"https://mts.intechopen.com/storage/users/13818/images/system/13818.jpg",institutionString:null,institution:{name:"Deakin University",institutionURL:null,country:{name:"Australia"}}},{id:"151889",title:"Dr.",name:"Joao Luis Garcia",middleName:null,surname:"Rosa",slug:"joao-luis-garcia-rosa",fullName:"Joao Luis Garcia Rosa",profilePictureURL:"https://mts.intechopen.com/storage/users/151889/images/4861_n.jpg",institutionString:null,institution:{name:"University of Sao Paulo",institutionURL:null,country:{name:"Brazil"}}},{id:"103779",title:"Prof.",name:"Yalcin",middleName:null,surname:"Isler",slug:"yalcin-isler",fullName:"Yalcin Isler",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRyQ8QAK/Profile_Picture_1628834958734",institutionString:null,institution:{name:"Izmir Kâtip Çelebi University",institutionURL:null,country:{name:"Turkey"}}}]},onlineFirstChapters:{paginationCount:8,paginationItems:[{id:"81791",title:"Self-Supervised Contrastive Representation Learning in Computer Vision",doi:"10.5772/intechopen.104785",signatures:"Yalin Bastanlar and Semih Orhan",slug:"self-supervised-contrastive-representation-learning-in-computer-vision",totalDownloads:3,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Pattern Recognition - 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A viral disease can be defined as an infectious disease that has recently appeared within a population or exists in nature with the rapid expansion of incident or geographic range. 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The applications of this research cover many related fields, such as biotechnology and medicine, where, for example, Bioinformatics contributes to faster drug design, DNA analysis in forensics, and DNA sequence analysis in the field of personalized medicine. Personalized medicine is a type of medical care in which treatment is customized individually for each patient. Personalized medicine enables more effective therapy, reduces the costs of therapy and clinical trials, and also minimizes the risk of side effects. Nevertheless, advances in personalized medicine would not have been possible without bioinformatics, which can analyze the human genome and other vast amounts of biomedical data, especially in genetics. The rapid growth of information technology enabled the development of new tools to decode human genomes, large-scale studies of genetic variations and medical informatics. 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Recently, bioinspired systems have been successfully employing biomechanics to develop and improve assistive technology and rehabilitation devices. The research topic "Bioinspired Technology and Biomechanics" welcomes studies reporting recent advances in bioinspired technologies that contribute to individuals\' health, inclusion, and rehabilitation. 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We encourage the submission of manuscripts that provide novel and mechanistic insights that report significant advances in the fields. Topics can include but are not limited to: Biotechnology such as biotechnological products and process engineering; Biotechnologically relevant enzymes and proteins; Bioenergy and biofuels; Applied genetics and molecular biotechnology; Genomics, transcriptomics, proteomics; Applied microbial and cell physiology; Environmental biotechnology; Methods and protocols. Moreover, topics in biosensor technology, like sensors that incorporate enzymes, antibodies, nucleic acids, whole cells, tissues and organelles, and other biological or biologically inspired components will be considered, and topics exploring transducers, including those based on electrochemical and optical piezoelectric, thermal, magnetic, and micromechanical elements. Chapters exploring biomaterial approaches such as polymer synthesis and characterization, drug and gene vector design, biocompatibility, immunology and toxicology, and self-assembly at the nanoscale, are welcome. 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