Selected MRP2 substrates.
\\n\\n
Released this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\\n\\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
\\n"}]',published:!0,mainMedia:{caption:"Highly Cited",originalUrl:"/media/original/117"}},components:[{type:"htmlEditorComponent",content:'IntechOpen is proud to announce that 191 of our authors have made the Clarivate™ Highly Cited Researchers List for 2020, ranking them among the top 1% most-cited.
\n\nThroughout the years, the list has named a total of 261 IntechOpen authors as Highly Cited. Of those researchers, 69 have been featured on the list multiple times.
\n\n\n\nReleased this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\n\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
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The contents of the book will be written by multiple authors and edited by experts in the field.",isbn:"978-1-80355-439-6",printIsbn:"978-1-80355-438-9",pdfIsbn:"978-1-80355-440-2",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,isSalesforceBook:!1,isNomenclature:!1,hash:"43443244d8385c57f1424d5d37c91788",bookSignature:"Prof. Elsadig Musa Ahmed",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/12239.jpg",keywords:null,numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"April 22nd 2022",dateEndSecondStepPublish:"May 13th 2022",dateEndThirdStepPublish:"July 12th 2022",dateEndFourthStepPublish:"September 30th 2022",dateEndFifthStepPublish:"November 29th 2022",dateConfirmationOfParticipation:null,remainingDaysToSecondStep:"2 months",secondStepPassed:!0,areRegistrationsClosed:!1,currentStepOfPublishingProcess:3,editedByType:null,kuFlag:!1,biosketch:null,coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"268621",title:"Prof.",name:"Elsadig",middleName:"Musa",surname:"Ahmed",slug:"elsadig-ahmed",fullName:"Elsadig Ahmed",profilePictureURL:"https://mts.intechopen.com/storage/users/268621/images/17940_n.jpg",biography:"Dr. Elsadig Musa Ahmed is Professor of Economics and Technology Management at Multimedia University (MMU), MMU Senate member, Students’ disciplinary committee and Board of Postgraduates. Coordinator for Post Graduate programs of the Faculty of Business (March 2006-April 2014), Chairperson of Center for Globalization and Sustainability Research (CGSR) (March2009-April2014), Multimedia University (MMU), Melaka Campus, Malaysia, member of Research and Development, research grants panel and the Institute of Postgraduate Studies (IPS) Coordination Committee (ICC) MMU. He is currently teaching Advanced Research Methodology, Entrepreneurship and Commercialization, and Economics for Managers at the postgraduate level and economic subjects at the undergraduate level.\nHis research interests include development economics, productivity analysis, knowledge-based economy, productivity and environment (green productivity), Bioeconomy, Islamic finance and microfinance, economic growth, (environment, tourism) and Entrepreneurship. He is the book\\'s author (Green Productivity: Applications in Malaysia’s Manufacturing) in 2012. He has published more than 100 publications in international refereed journals and presented several papers at conferences. He supervised and produced 14 PhD, 4 DBA, 3 Masters, and 8 MBA Theses. Currently, supervises several students at Doctor of Philosophy (PhD.), Master of Philosophy (MPhil) and MBA project, undergraduate final levels. In terms of research grants he received 5 external projects in ICT and Economic Growth, Foreign Direct Investment Spillover Effects from the Malaysian government, and Mobile Banking for Microfinance from the Islamic Development Bank (IsDB), Jeddah KSA. He examined several PhD theses from Malaysian Universities, Indian Universities, and other countries. I have been appointed as auditor, assessor, and editorial board member for several programmes, journals, conferences, and professorial positions. He has been appointed as a panel review of the Malaysian Ministry of Education research grants and reviewer for the IsDB proposals for postdoctoral and PhD scholarships. In terms and training, he conducted several workshops and public lectures not limited to writing research grants proposals, postgraduate thesis writing, Writing scientific papers for publishing in Scopus and WoS indexed journals, leadership, and performance analysis appraisal in Malaysia, KSA, and Sudan. \nHe is the leader of the Economic Planning Forum and Research skills Workshops of Sudanese researchers’ initiatives. A member of The Council for Sudanese Experts and Scientists Abroad, World Economics Association, World Assembly of Youth (WAY), Arab Science and Technology Foundation (ASTF), World Academy of Sciences, Engineering and Technology (WASET), Scientific and Technical Committee on Humanities and Social Sciences, World Association for Sustainable Development (WASD), Sudan Knowledge and several associations. He is an editorial board member and reviewer for various international journals and conferences such as (Economic Modelling, Journal of Productivity Analysis, Applied Economics, Journal of Information and Knowledge Management, Telecommunications Policy). He was awarded the best paper award at XXth Conference of CEDIMS, Laval University, Quebec, Canada in November 2010, and the academic staff and excellent research awards of Multimedia University several times.",institutionString:"Multimedia University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"0",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"Multimedia University",institutionURL:null,country:{name:"Malaysia"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"7",title:"Business, Management and Economics",slug:"business-management-and-economics"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"429339",firstName:"Jelena",lastName:"Vrdoljak",middleName:null,title:"Ms.",imageUrl:"https://mts.intechopen.com/storage/users/429339/images/20012_n.jpg",email:"jelena.v@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:"1591",title:"Infrared Spectroscopy",subtitle:"Materials Science, Engineering and Technology",isOpenForSubmission:!1,hash:"99b4b7b71a8caeb693ed762b40b017f4",slug:"infrared-spectroscopy-materials-science-engineering-and-technology",bookSignature:"Theophile Theophanides",coverURL:"https://cdn.intechopen.com/books/images_new/1591.jpg",editedByType:"Edited by",editors:[{id:"37194",title:"Dr.",name:"Theophile",surname:"Theophanides",slug:"theophile-theophanides",fullName:"Theophile Theophanides"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3161",title:"Frontiers in Guided Wave Optics and Optoelectronics",subtitle:null,isOpenForSubmission:!1,hash:"deb44e9c99f82bbce1083abea743146c",slug:"frontiers-in-guided-wave-optics-and-optoelectronics",bookSignature:"Bishnu Pal",coverURL:"https://cdn.intechopen.com/books/images_new/3161.jpg",editedByType:"Edited by",editors:[{id:"4782",title:"Prof.",name:"Bishnu",surname:"Pal",slug:"bishnu-pal",fullName:"Bishnu Pal"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"371",title:"Abiotic Stress in Plants",subtitle:"Mechanisms and Adaptations",isOpenForSubmission:!1,hash:"588466f487e307619849d72389178a74",slug:"abiotic-stress-in-plants-mechanisms-and-adaptations",bookSignature:"Arun Shanker and B. 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The major routes of exposure to these chemicals comprise incorporation with the diet, inhalation or absorption through the skin. Preservation of health depends largely on the body\'s ability to eliminate these harmful substances. In this regard, the organism possesses a sophisticated system of detoxification mainly expressed in organs such as the liver, intestine, and kidney. The detoxification process consists of intracellular biotransformation enzymes that neutralize the toxins and membrane transporters for their subsequent elimination from the cell. The biotransformation process is carried out by the same biochemical machinery that metabolizes endogenous compounds, often of similar chemical structure. Even though a compound can be excreted without undergoing any change, it is usually converted by biotransformation enzymes into a more hydrophilic derivative prior to elimination. The biotransformation reactions are carried out by phase I enzymes such as cytochrome P450 (CYP) members and by phase II conjugating enzymes such as glutathione S-transferase (GST; EC 2.5.1.18), UDP-glucuronosyltransferase (UGT; EC 2.4.1.17), and sulfotransferase (SULT; EC 2.8.2.) [1, 2]. Phase I enzymes usually act in tandem with phase II enzymes, which ultimately results in incorporation of anionic groups into the xenobiotic molecule. The hydrophilic derivatives can be excreted from the cells by phase III or membrane transport systems, with the anionic groups acting as
What follows is a description of the role of the multidrug resistance-associated protein 2 (MRP2, ABCC2) as an important component of the ABC family involved in xenobiotic disposition by liver and intestine.
\nMRP2 structure consists of a large core segment, containing two cytosolic nucleotide-binding domains (NBDs), two membrane-spanning domains (MSDs), and a linker segment L1, shared by other ABC members. Additionally, MRP2 contains a third NH2-terminal membrane-spanning domain MSD0, also called terminal transmembrane domain, with five transmembrane helices resulting in an extracellular NH2-terminus and an intracellular linker segment 0 (L0) (Figure 1) [4]. MRP2 is characteristically expressed at the apical membrane of polarized cells such as hepatocytes, enterocytes, and renal tubular cells [4–6], where it plays a primary role in the elimination of specific compounds. Particularly, the highest concentration of this transporter is found in the liver and intestine [7], two organs playing a prominent role in xenobiotic detoxification commonly known as “first-pass metabolism and clearance”. Protein expression of MRP2 is highest in enterocytes of the proximal small intestine, decreasing in direction to the terminal ileum [8], gradient shared with the expression of phase II metabolizing enzymes such as GST and UGT [9, 10], thus suggesting that metabolism and transport processes may act coordinately. In the liver, the major biotransformation organ, MRP2 is abundantly expressed in the bile canalicular membranes of the hepatocyte [11], where it plays a role in bile formation through secretion of endogenous substrates such as glutathione (GSH) and glutathione conjugates. Canalicular MRP2 also constitutes the main route of elimination of xenobiotics conjugated with GSH, sulfate or glucuronic acid [12]. Similarly, immunohistochemical analysis in normal rat liver demonstrated that UGTs and rMrp2 are localized in the same regions [13, 14], also indicating that they may work in cooperation. MRP2 in either localization contributes significantly to disposition of potentially harmful compounds thus decreasing their toxicity.
\n(A) Molecular structure of MRP2/ABCC2. MSDs: membrane-spanning domains; NBDs: nucleotide-binding domains; L0: linker segment 0. (B) Coordinated action between phase II metabolizing enzymes and MRP2 in the enterocyte. Hydrophobic xenobiotics (X) may enter the cell by diffusion through the apical membrane of the enterocyte. After that, they may suffer metabolic phase I reaction by cytochrome P450 and/or subsequent conjugation by phase II enzymes, such as UDP-glucuronosyltransferase (UGT) localized in the endoplasmic reticulum or glutathione S-transferase (GST) or sulfotransferase (SUL) localized in the cytosol. In the phase III, the more hydrophilic metabolites (Y) may be actively secreted into the intestinal lumen by MRP2. (C) Coordinated action between phase II metabolizing enzymes and MRP2 in the hepatocyte. Here, hydrophobic xenobiotics (X) enter the cell through the basolateral pole of the membrane in the hepatocyte. After conjugation by phase II metabolizing enzymes, the final product (
Selected substrates of MRP2 are included in Table 1. Studies using Groningen Yellow (GY)/
TR- Wistar [15, 16] or Eisai hyperbilirubinemic rats (EHBR) [17] that are rMrp2 deficient as a result of mutations leading to premature stop codons have helped to identify transporter substrates initially. Interestingly, ingredients of our daily diet are substrates for MRP2. That is the case of the tea component epicatechin, the dietary supplement chrysin [18, 19], and the meat-derived dietary carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) [20]. Finally, it is important to emphasize that there are MRP2 substrates which influence transporter expression thus influencing its own bioavailability. That is the case, for example, of tamoxifen [21].
Endogenous compounds | \nExogenous compounds | \n
---|---|
Glutathione Bilirubin glucuronides Conjugated bile salts Leukotrienes C4, D4, E4 Steroids (17β-glucuronosyl estradiol) Triiodo-L-thyronine ethinylestradiol-3-O-glucuronide | \n
Selected MRP2 substrates.
Expression of MRP2 can be regulated at different levels [22], which can be grouped in two main categories: (i) transcriptional level, implying changes in mRNA synthesis rate, or (ii) post-transcriptional level, comprising complex processes involving or not changes in MRP2 mRNA levels. Regarding the transcriptional regulation, the MRP2 promoter contains a number of binding sites recognizing a variety of transcription factors, which in turn can be activated by either endo- or xenobiotics [23, 24]. Thus, a wide variety of drugs, environmental pollutants, and natural toxins behave as ligands of transcription factors/nuclear receptors such as farnesoid X-activated receptor (FXR), pregnane X receptor (PXR), liver X receptor α (LXRα), and constitutive androstane receptor (CAR), to ultimately induce the synthesis of MRP2 mRNA [25]. They modulate MRP2 transcriptionally through binding to the response element ER-8, which extends from −401 to −376 bp of the MRP2 promoter [25]. Additionally, the study of MRP2 promoter identified binding sites for other transcription factors such as the nuclear factor-erythroid 2-related factor-2 (Nrf2), the peroxisome proliferator-activated receptor alpha (PPARα), CCAAT/enhancer-binding protein-β (C/EBPβ), and hepatic nuclear factors (HNFs), which can also influence the MRP2 expression at the transcriptional level. Finally, a particular transcriptional regulation involves the intracellular nucleotide cyclic adenosine monophosphate (cAMP) pathway, likely triggered by xenobiotics acting predominantly through binding to plasma membrane receptors. This was so far demonstrated in the intestine [26], where the treatment of Caco-2 human intestinal cells with the membrane-permeable analogue dibutyryl cAMP or the adenylyl cyclase activator forskolin led to a significant induction in hMRP2 protein and mRNA expression. Reporter gene and chromatin immunoprecipitation assays performed in this same study showed an increased binding of the transcription factors c-JUN and activating transcription factor-2 (ATF2) to a regulatory region containing activator protein-1 (AP-1) and cAMP response element (CRE) binding sites within the MRP2 promoter.
\nOn the other hand, post-transcriptional MRP2 regulation can involve the dynamic endocytic retrieval and exocytic insertion of this transporter between the canalicular membrane and an intracellular pool of vesicles [27]. A variety of signal transduction pathways involving the activation of the mitogen-activated protein kinases (MAPK) A and C take part in these events [27–29]. Also, mRNA splicing may account for post-transcriptional regulation. As an example, alternative splicing of hMRP2 mRNA has been shown to be a cause underlying Dubin–Johnson syndrome as a consequence of synthesis of nonfunctional protein [30, 31]. Additionally, MRP2 can be translationally modulated. In this regard, Jones et al. [32] observed that under certain situations rMrp2 protein in rats is modified without changes in mRNA levels. This is not just attributed to a modified rate of protein degradation but to the presence of several rMrp2 transcription initiation sites in the 5\' untranslated region [7, 33]. The alternative use of these sites leads to the production of different rMrp2 mRNAs with differential translational efficiency.
\nWhat follows is a description of the regulatory properties of MRP2 as an important component of the ABC family in liver and intestine. The effects of xenobiotics on MRP2 expression and activity were particularly considered. Transcriptional and post-transcriptional regulations were described separately.
\nSeveral xenobiotics including therapeutic drugs, environmental pollutants, and natural toxins have shown to activate different transcription factors and nuclear receptors thus exhibiting the potential of increasing MRP2 expression [34]. However, not all xenobiotics induce the expression of MRP2. Indomethacin, a nonsteroidal anti-inflammatory drug, reduced the expression of rat rMrp2 at the mRNA and protein levels in the liver [35]. This reduction was associated with a diminished mRNA expression of the hepatic nuclear receptors CAR, FXR, PXR, retinoic acid receptor α (RARα), and retinoid X receptor α (RXRα). This down-regulation of nuclear receptors is consistent with observations in endotoxin-treated rats that also proved to cause rMrp2 down-regulation at the transcriptional level [36, 37]. Intestinal injury caused by indomethacin can increase endotoxin levels in portal blood [38], which in turn induces several immune responses and oxidative stress, as shown by the reduced levels of hepatic GSH and increased levels of nitric oxide (NO) and nitrosothiols in portal blood [35]. In this regard, El Kasmi et al. demonstrated that dextran sulfate sodium-induced intestinal injury also down-regulates hepatic mMrp2 expression in mice liver and that the intestinal microbiota and TLR4 (Toll-like receptor 4) are involved in this effect [39]. In addition, it was shown that mice with intestinal injury that received soy oil-based parenteral nutrition containing phytosterols exhibited an exacerbated decrease in mMrp2 mRNA levels. The phytosterol stigmasterol was at least partially involved and associated with increased levels of interleukin 6 (IL-6) mRNA and reduced levels of FXR mRNA in liver [39].
\nIn contrast to indomethacin, several drugs are able to induce the expression of MRP2. For example, spironolactone (SL), a drug used to treat patients with edema and ascites, has been shown to increase bile flow in rats due to the up-regulation of rMrp2 at the transcriptional level, probably in response to increased PXR levels [40]. This up-regulation in rMrp2 resulted in increased efflux activity of the model substrate of rMrp2 dinitrophenyl-S-glutathione (DNP-SG)
Acetaminophen (APAP) represents one of the most common over-the-counter drugs, used as an effective and safe analgesic and antipyretic. Nevertheless, APAP overdose is very frequent and associated with severe liver injury. Although the mechanism underlying APAP toxicity is not completely understood, the CYP-biotransformation product N-acetyl-p-benzoquinone imine (NAPQI) was described as a mediator of APAP toxic effects since it promotes GSH depletion and binds itself to cellular proteins [46]. APAP phase II metabolites resulting from conjugation with glucuronic acid and sulfate are known MRP2 substrates. Similarly, MRP2 transports the GSH conjugate of NAPQI, thus contributing to reduce the toxic burden exerted by APAP. In this regard, the administration of a single hepatotoxic dose of APAP to Wistar rats resulted in an increase in rMrp2 expression in liver plasma membranes [47]. In a similar study, an induction hepatic mMrp2 following Nrf2 activation was demonstrated in mice, clearly suggesting the presence of an adaptive mechanism to the APAP-triggered injury [48, 49]. In line with these observations, therapeutic activation of Nrf2 has been proposed as a possible strategy to ameliorate APAP-associated hepatotoxicity [50–52]. Nrf2 bears a special toxicological relevance due to its activation by pro-oxidant compounds and reactive metabolites usually associated with situations of drug overdose or exposure to environmental toxicants. Under homeostatic conditions, Nrf2 is sequestered in the cytosol by the Kelch-like ECH-associated protein 1 (Keap1) which promotes Nrf2 ubiquitination and proteosomal degradation. Upon an oxidative stimulus, it takes place a modification in the oxidation status of particular cysteine residues in the Keap1 molecule leading to Nrf2 dissociation and migration to the nucleus where it binds to antioxidant response elements (ARE) within the promoters and activates the transcription of target genes [53] including antioxidant and GSH synthesis enzymes and also drug transporters like MRP2 [54]. Management of Nrf2 activation could be applied to other cases of oxidative stress-associated hepatic injury. For instance, the Nrf2 activator N-acetylcysteine was described to ameliorate the rMrp2 down-regulation exerted by the pro-oxidant phytochemical timosaponin A3 [55]. Similarly, other Nrf2 activators are being tested in clinical trials for the treatment of hepatic and extrahepatic diseases [53].
\nEnvironmental pollutants such as arsenite significantly increased rMrp2 protein expression in rat liver after 2 weeks of exposure. Longer exposure treatment (4 or 6 weeks) also increased rMrp2 expression but to a lesser extent [56]. Arsenite not only regulates Mrp2 but is also an MRP2 substrate, so transporter induction may help to counteract the toxic effects of arsenite in the liver. In agreement with this, arsenite content in bile decreased with the exposure time in the same manner as rMrp2 protein induction. Lipid peroxidation was increased and GSH peroxidase activity was reduced in the liver at 4 and 6 weeks of arsenite exposure, indicating a probable effect of oxidative stress in attenuating hepatic rMrp2 induction. This regulation of Mrp2 may explain the dual effects reported for arsenite exposure [57].
\nThe T-2 mycotoxin is commonly found in different crops. Prolonged exposure (3 weeks) of poultry to T-2 reduced cMrp2 mRNA expression in the liver of broiler chickens [58]. Although the authors suggest that PXR may be involved in the down-regulation observed, no studies were conducted to prove that. The organochlorine pesticides 2,4\'-dichlorodiphenyltrichloroethane (DDT), 4,4\'-DDT, chlordane, heptachlor, dieldrin, and lindane, highly resistant to degradation, were shown to increase hMRP2 mRNA in HepaRG cells after a 48-h exposure [59]. This regulation could be mediated by PXR, since this nuclear receptor expression was increased in human hepatocytes after treatment with chlordane, dieldrin, and endosulfan [60].
\nBisphenol A (BPA) is a typical contaminant of food, water, and air. A study evaluating the association between the expression of drug transporters in fetal liver and BPA exposure showed a positive correlation between BPA levels and hMRP2 expression. A similar correlation was described between BPA levels and Nrf2 expression, suggesting also a mediation of this transcription factor in the hMRP2 regulation by BPA and agreeing well with a previous report showing Nrf2 activation by BPA
Transcriptional regulation of MRP2 by xenobiotics was also demonstrated in extrahepatic tissues like the small intestine. An example of therapeutic drugs affecting MRP2 gene expression is rifampicin, a well-known PXR agonist which has been demonstrated to increase hMRP2 expression and activity in healthy volunteers. Fromm et al. reported an up-regulation of hMRP2 mRNA and protein in duodenal biopsies [63]. Later, Oswald et al. showed the impact of this regulation on oral availability and efficacy of the coadministered drug ezetimibe [64]. The same inducing effect was reported using the human-derived cell line LS180 [65]. Similarly, carbamazepine is another PXR agonist [66] shown to increase hMRP2 mRNA and protein levels in human healthy volunteers and also to reduce intestinal absorption of the co-administered MRP2 substrate talinolol [67].
\nEven though there are only few reports on drug–drug interactions associated with PXR-dependent modulation of intestinal MRP2, many other agents have been shown to regulate its expression via PXR. Pregnenolone-16α-carbonitrile, a synthetic steroid, induced mMrp2 mRNA expression in jejunum of C57BL/6 mice (200 mg/kg, i.p., 4 days). A concomitant up-regulation of PXR mRNA was observed and the involvement of this nuclear receptor was confirmed using PXR knockout mice [68]. The antiviral agents and PXR agonists efavirenz and saquinavir [69] also up-regulated hMRP2 expression in LS180 cells [65, 70]. Since these drugs are usually involved in long-term treatments, coadministration with MRP2 substrates could result in unwanted drug–drug interactions. In the same human intestinal cell line, the effect of the endothelin receptor antagonist bosentan [71] and the antineoplastic mitotane [72] was demonstrated. They both exerted a significant hMRP2 induction concomitantly with PXR activation at pharmacologically relevant concentrations.
\nIn some studies, the increases in MRP2 expression were correlated experimentally with increased transport activity. Examples of these drugs are BZL and SL, both PXR agonists. Perdomo et al. reported an induction of rMrp2 protein in jejunum of BZL-treated rats (100 mg/kg, i.p., 3 days) [43]. This change was accompanied with an increased efflux of DNP-SG to the intestinal lumen. These results not only demonstrate higher secretion of rMrp2 substrates but also strongly suggest a restriction in the absorption of xenobiotics incorporated luminally in BZL-treated rats. Similarly, SL was demonstrated to increase serosal to mucosal transport of DNP-SG well correlating with increased rMrp2 mRNA and protein expression in rat proximal jejunum. The PXR antagonist ketoconazole was able to prevent this induction, suggesting mediation by this nuclear receptor [73].
\nCimetidine and quinidine have been shown to increase both hMRP2 and PXR expressions in T84 cells [74]. Similarly, the anticonvulsant phenobarbital induced PXR mRNA and hMRP2 mRNA and protein at the same time in Caco-2 cells [75]. On the contrary, MRP2 expression is down-regulated by drugs that decrease PXR expression. Haslam et al. reported such an effect in T84 cells for the cholesterol-lowering drug atorvastatin and the anticancer agents topotecan and irinotecan [74].
\nXenobiotics can regulate expression of intestinal MRP2 interacting with nuclear receptors other than PXR. That is the case of the bcl-2 inhibitor obatoclax, which at nanomolar concentrations induced hMRP2 mRNA in LS180 cells through activation of the aryl hydrocarbon receptor [76]. Another example is the proteasome inhibitor bortezomib, which also increases hMRP2 mRNA expression in SW-480 human cells [77]. Even though the mediator has still to be identified, the transcription factor Nrf2 appears to be the main candidate considering its simultaneous up-regulation and also the well-demonstrated relationship between MRP2 induction and Nrf2 activation in tissues like liver [49], kidney [78], and brain [79].
\nAmong the natural compounds modulating intestinal MRP2, the isothiocyanates sulforaphane (SF) and erucin (ER) were well studied. Derived from cruciferous vegetables, they have drawn the attention of the researchers due to their anticancer properties [80]. After microarray studies, Traka et al. reported hMRP2 up-regulation in Caco-2 cells treated with SF (50 μM, 24 h) [81]. They confirmed this finding by RT-PCR analysis. Using the same model, Jakubíková et al. showed a similar hMRP2 mRNA increase after treatment with SF and with ER (20 μM, 24 h) [82]. This effect appears to be partly mediated by phosphoinositide 3-kinase (PI3K)/AKT, considering the inhibition exhibited by the PI3K/AKT inhibitor LY294002. Later, in analogous experimental conditions, Harris and Jeffery demonstrated an induction also at protein level [83]. Considering that Nrf2 is activated by SF [84], this transcription factor may play a role in MRP2 up-regulation.
\nOther naturally occurring xenobiotics found to modulate intestinal MRP2 are the polyphenols quercetin and resveratrol (RES). The first one was demonstrated to up-regulate hMRP2 at protein level in Caco-2 cells (50 and 100 μM, 72 h). A coordinated induction of the phase II enzyme UGT1A6 was also observed, suggesting reduced absorption and enhanced secretion of glucuronides at intestinal level [85]. Studies using RES have become of strong interest after the increasing evidence regarding its beneficial health effects. A short time ago, RES ability to down-regulate MRP2 at mRNA and protein levels has been proven in rat intestine and Caco-2 cells [86]. The functional impact was evaluated in the latter model by determination of intracellular retention of the MRP2 substrate methotrexate (MTX). Treatment with RES increased the accumulation of MTX, suggesting a suppressed efflux activity. Moreover, in an attempt to clarify the mechanism, the authors found a concomitant inhibition of the insulin-like growth factor receptor 1 (IGF-1R)/AKT/ERK signaling pathway.
\nAs anticipated, post-transcriptional regulation of MRP2 activity may also occur in response to exposition to xenobiotics. Faldaprevir is a drug used to treat patients with hepatitis C in spite that it causes hyperbilirubinemia. Acute treatment of human and rat hepatocytes with faldaprevir inhibited hMRP2-/rMrp2-mediated efflux of bilirubin glucuronides into bile [87]. This may partially explain the impaired bilirubin disposition by faldaprevir. However, toxicology studies in monkeys and patients showed that the bilirubin accumulated during faldaprevir treatment was mainly unconjugated, suggesting that the main cause is probably inhibition of glucuronidation ather than excretion of the conjugated metabolites. Simeprevir, another drug used to treat hepatitis, causes hyperbilirubinemia composed by conjugated and unconjugated bilirubin, which supports an impaired hMRP2 efflux activity [88].
\nEthynylestradiol (EE) and genistein (GNT) are estrogenic compounds of particular relevance considering their oral incorporation as components of contraceptives formulations and soy-derived food, respectively. Interestingly, they were demonstrated to regulate intestinal MRP2 at post-transcriptional level, although showing a noticeable dose and model dependence. Thus, it was initially found that EE at a cholestatic dose (5 mg/kg b.w. day, for 5 consecutive days, s.c.) down-regulates rMrp2 expression and function in rat proximal jejunum, without changes in mRNA levels [89]. However, at pharmacological concentrations (0.5–5 pM) EE up-regulates hMRP2 expression and activity in Caco-2 cells. This hMRP2 induction was estrogen receptor β (ERβ)-mediated but not associated with changes at the mRNA level, thus suggesting a post-transcriptional regulation [90]. The implication of ERβ in such kind of regulation is possible since it was reported to regulate miRNAs expression [91] which, in turn, can alter hMRP2 expression [92]. Similarly, Caco-2 cells exposed to GNT (1 μM, 48 h) exhibited an ERβ-mediated hMRP2 induction at protein level without changes in expression at the mRNA level. This was associated with increased transporter activity and enhanced protection against 1-chloro-2,4-dinitrobenzene, an MRP2 substrate precursor [90]. GNT can also modulate MRP2 activity in an acute fashion, i.e., without changes in transporter expression. Some years ago, it was reported that this isoflavone competitively inhibits hepatic rMrp2 in isolated and perfused rat liver model [93]. In line with this result, Yokooji et al. demonstrated that GNT administered intravenously reduced rMrp2-mediated secretion of irinotecan hydrochloride and its metabolites in rat liver and intestine [94].
\nThe uricosuric drug probenecid represents another example of xenobiotics affecting intestinal MRP2 activity without modifying MRP2 expression. Probenecid is a classical competitive inhibitor of organic anions transport also used in the clinical practice to enhance plasma levels of antibiotics. Although nonspecific, its inhibitory effect on intestinal MRP2 was clearly demonstrated in rats [95] and in Caco-2 cells [90]. Nowadays, more potent and specific MRP inhibitors like MK571 are preferred for characterization of transport specificity. Finally, various members of the large family of nonsteroidal anti-inflammatory drugs are recognized MRP2 modulators [96]. In intestine, indomethacin was shown to inhibit MRP2 and to increase sulfasalazine transepithelial permeability, both in rat small intestine and in Caco-2 cell monolayers [97]. In agreement with these findings, Caco-2 cells coincubated with indomethacin exhibited an increased permeability to the hMRP2 substrates fluvastatin [98] and colchicine [99].
\nAlthough the organisms are permanently exposed to a wide range of xenobiotics such as therapeutic drugs, environmental pollutants, and natural toxins, they possess a sophisticate system of detoxification in which metabolizing enzymes and transport proteins play an essential role. Evidence from
Expression and activity of MRP2 can be modulated at both transcriptional and post-transcriptional levels. The nuclear receptor PXR plays a major role in transcriptional regulations. PXR functions as sensor for many agents and its activation leads to a coordinated response on biotransformation enzymes and transport systems. Examples of these agents are rifampicin, carbamazepine, pregnenolone-16α-carbonitrile, efavirenz, saquinavir, BZL, SL, etc. Other xenobiotics such as bortezomib, BPA, and sulforaphane regulate MRP2 as a result of the interaction with Nrf2. Alternatively, regulation of MRP2 activity by xenobiotics can occur without changes in transporter expression, as it was demonstrated to GNT. Finally, it is important to note that regulation of MRP2 activity by therapeutic agents can result in changes in their therapeutic efficacy or safety, or alternative in drug–drug interactions if other drugs, substrates of MRP2, are simultaneously administered.
\nThe theory [1], simply stated, is that what we currently refer to as “cold dark matter” is, in actuality, slow-moving interstellar and intergalactic neutral atomic hydrogen in its lower 1 s ground state. Its exceedingly low density within the vacuum of space can be quantified by measuring the intensity of its signature spectral hyperfine 21-cm
Following a brief review of the historical evidence for the existence of dark matter, its key observations reported in 2018 and 2019 will be summarized and its current constraints elaborated. The author’s calculations, in the context of these observations, will then be presented in the Results section, and a Discussion section with a table based upon these findings will follow.
It is generally agreed that astronomer Fritz Zwicky, in 1933, was the first scientist to apply the virial theorem to infer the existence of dark matter. He referred to it as “dunkle materie” (i.e., “dark matter”) [2, 3]. Unfortunately, Zwicky’s dark matter proposal was largely ignored at that time.
Beginning in 1970, this problem of “missing matter” was further elucidated and essentially proven by the detailed studies of galactic rotation by Vera Rubin and William Ford [4, 5], although it took considerable time for them to receive due recognition for this achievement.
With gradual acceptance of the observational implications, what has followed in the ensuing decades has been a stepwise progression of tightening constraints on the nature and quantity of dark matter. As a consequence, much like a horse race with changing leads, various creative and exotic theories of the nature of dark matter (WIMPs, MACHOs, axions, sterile neutrinos, supersymmetry partners, SIMPs, GIMPs, etc.) have fallen in and out of favor [6]. Given the difficulty of its detection, there have even been attempts to discard the idea of dark matter altogether in favor of modifying Newtonian celestial mechanics (Modified Newtonian Dynamics (MOND)) [7, 8].
A review of these various theories, and a discussion of their current plausibility, is beyond the scope of this chapter. Whole books have been written about them. Suffice it to say, in view of the many continuing exotic dark matter detector failures, there is room for a new theory such as the one presented herein. The following section will summarize key constraints on dark matter as of 2020.
Upon establishing the likelihood of an abundance of cosmic matter which,
Although relatively few in number, MW halo stars at various known distances beyond the galactic disk can provide for line-of-site spectral analysis and a rough MW halo vacuum density determination of interstellar neutral atomic hydrogen in its lower ground state. Specifically, the intensity of the hyperfine 21-cm absorption line gives us some idea of the number of these particular atoms per unit volume of the column of intervening interstellar space. Best estimates of this sort, made over a number of decades, have indicated an average density within the MW interstellar vacuum of roughly one of these atoms per cubic centimeter [11, 12, 13].
Making use of some initial
Posti and Helmi 20 kpc halo sphere of the MW galaxy.
The total virial mass of their sphere was reported by Posti and Helmi to be 1.91 × 1011 Mʘ (solar masses), of which the mass of dark matter was reported to be 1.37 × 1011 Mʘ. This would imply that the MW 20 kpc sphere ratio of dark matter-to-visible matter is about 2.54:1. Therefore, if we normalize the MW visible mass to the 250 billion Mʘ value given in the 2019
Aside from the inability of dark matter to emit light, observations have confirmed that it is nearly collisionless. It appears to be composed of particles with a low scattering cross section. This can be deduced from Tucker’s early observations of the bullet cluster [15] and subsequent observations of other colliding galaxies.
Dark matter, at present, is also believed to be cold (i.e., slow-moving). A predicted Maxwell-Boltzmann particle velocity distribution ranging from roughly 0 to 600 km/sec, and peaking at roughly 220–230 km/sec, is the theoretical basis for optimizing a variety of cold dark matter particle detectors [16]. Unfortunately, none of these experiments to date has produced a positive result of an exotic (i.e., non-baryonic) dark matter particle. Intriguingly, however, the 2018 EDGES study [17] of the hyperfine 21-cm
Figure 3 on page 9 of Barkana’s review [18] related to the EDGES study findings summarizes the new cosmic dawn dark matter constraints with a log graph of the implied baryon-dark matter (b-DM) cross-sectional σ1 and the minimum possible 21-cm brightness temperature (T21) on the two vertical axes and the corresponding implied dark matter particle mass MX on the horizontal axis. All constraint values indicated in the graph correspond to the strong signal measured at
Without specifically naming any particular non-excluded baryons, physicist Stacy McGaugh published a brief note [19] at the time of the EDGES publication (March 2018) which strongly supports the idea that the cosmic dawn observations are to be, in his words, “expected for a purely baryonic universe.” He begins the note with the observation that the strength of the redshifted hyperfine 21-cm absorption line at
An additional constraint on dark matter has to do with the “cusp-core problem,” specifically why some galaxies have a distinctly cuspy distribution of dark matter and others do not. A 2019 report on dark matter distribution within dwarf galaxies, by Read et al. [20], offers a clue. It shows that galaxies which stopped forming stars over 6 billion years ago tend to be cuspier than those with more extended star formation. This is equivalent to saying that the extended star formation dwarf galaxies have shallower dark matter cores. Thus, their findings agree well with models where dark matter is presumably heated up by bursty star formation. This means that any plausible theory of dark matter must explain why extended and bursty star formation is correlated with a so-called “cored” dark matter distribution.
One obvious possible interpretation of the Read observations is simply that bursts of highly energetic particles and photons, produced by a concentration of new stars in and around active galactic centers, would tend to heat up and eject cold dark matter from their vicinity. If this is the correct interpretation, then a self-interacting dark matter (SIDM) model becomes unnecessary to explain the “cusp-core problem.” In fact, all sorts of bizarre non-baryonic properties of dark matter then become unnecessary.
Given the new dark matter theory as briefly summarized in the Introduction section, a simple calculation can be made on the Posti and Helmi 20 kpc MW halo sphere, as a test of this theory. If we start with the current best estimate of an average of only one atom of atomic hydrogen in the lower ground state per cubic centimeter of the Posti and Helmi 20 kpc halo sphere, that assumes a vacuum hydrogen density of 1.67 × 10−21 kg m−3. If we then multiply that number by the volume of the 20 kpc sphere (9.85 × 1062 m3), the total mass of atomic hydrogen in the bottom ground state is 1.645 × 1042 kg. That is the equivalent of 827 billion Mʘ. This is 3.3 times the 2019
Observations of the CMB anisotropy map suggest the following cosmic evolution scenario since the CMB emission epoch:
Denser regions of the primordial hydrogen distribution, already subject to the positive feedback of gravity, further aggregated into the hot stars, warm gas clouds, galaxies, quasars, and filaments. In contrast, due to adiabatic cosmic expansion, the primordial hydrogen within the low gravity interstices of the CMP map progressively became exceedingly sparse and cold (i.e., CMB-equilibrated). These interstices we know today as the vast interstellar and intergalactic space, including the voids.
The expanding and cooling universe, after CMB emission, was completely dark before the first dense clusters of primordial hydrogen underwent nuclear fusion. This period, known as the cosmic “dark age,” merged into the “cosmic dawn” reionization epoch at around 100 million years after the big bang. The “cosmic dawn” epoch is named as such because this is when the first stars are thought to have formed.
As documented by the EDGES study, a strange phenomenon occurred during the period of cosmic dawn. For about 150 million years, corresponding roughly to the cosmological redshift range of 15 <
Cosmic dawn CMB decoupling of primordial hydrogen.
This phenomenon of “cosmic dawn CMB decoupling” is most commonly attributed to a b-DM scattering interaction, whereby dark matter is presumed to have chilled faster than primordial hydrogen during the cosmic dark age, to the point where it could then interact with and chill the CMB-equilibrated interstitial hydrogen and decouple it from the CMB radiation temperature.
The problem with this particular explanation of the EDGES study observations is to explain why the beginning of the CMB decoupling phenomenon
Fully in keeping with McGaugh’s bold assertion of a purely baryonic mechanism, this cosmic dawn coincidence may have been
The key dark matter features, including observational constraints achieved over the last few years, and the correlating features of interstitial atomic hydrogen in the lower HI ground state, can now be brought together into a table (Table 1) for comparison.
Dark matter features | Interstitial HI cold hydrogen | References |
---|---|---|
Cold (0–600 km/sec) | Cold (0–600 km/sec) | [16] |
Dark (no emissions) | Lower ground state (cannot emit) | [2, 3, 4, 5] |
Cross-section σ1 > 1.5 × 10−21 cm | σ1 > 1.5 × 10−21 cm (at low velocity) | [15, 17, 18] |
Baryon (strongest 21-cm signal) | Baryon for XHI = 1 and TS = TK | [19] |
Mass-Energy less than 3 GeV | Mass-Energy = 0.938 GeV | [17, 18] |
Mass 20 kpc Halo = 635 Billion Mʘ | Mass 20 kpc Halo = 827 Billion Mʘ | [14, 10] |
Central DM heating (“coring”) | Ejected and loses ground state | [20] |
CMB decoupling at cosmic dawn | Wouthuysen-Field Effect | [21, 22] |
Structural scaffold | Most abundant atom | [9] |
Existence at CMB emission | Most abundant atom | [9] |
Dark matter features vs. interstitial HI cold hydrogen.
These correlations are striking and
It has long been assumed that the average atomic density of the “nearly empty” vacuum of interstellar space beyond the visible stars, gas clouds, and cosmic dust can be ignored in galactic mass calculations. While this might be true for the confines of the galactic disk and bulge, where visible matter is particularly concentrated, it is definitely not true for the galactic halo in close proximity to the disk. The sheer vastness of space belies the assumption mentioned above. It appears that this mistaken assumption has been a key foundational error behind the long-standing mystery of dark matter. The simple calculation in the Results section supports this conclusion. Even a single stray baryonic atom per cubic centimeter of interstellar space within the 20 kpc MW halo of Posti and Helmi can dwarf the combined mass of all visible stars, clouds of gas, and cosmic dust!
The fact that the particular atom in question appears now not to be in the least bit exotic but, instead, the most common structural element in the universe is indeed ironic. In a sense, because of the many distractions and obscurations provided by the highly visible warm and hot hydrogen atoms, cold interstitial hydrogen, because of its remote location, extremely low density, low velocity, and prolonged lower ground state, has been
Any useful physical theory should be falsifiable and predictive. The falsifiability of this particular theory is obvious. This theory would be falsified if a particle MX of 0.938 GeV becomes excluded from dark matter constraints, or current best estimates of the average MW halo vacuum density of cold atomic hydrogen are subsequently proven to be
There will be tightening dark matter constraints around a particle MX value of 0.938 GeV (i.e., the mass energy of neutral atomic hydrogen).
Computer simulations of galaxy formation and evolution which incorporate this theory will show excellent correlations with observations, including the coring effect of heating and ejecting cold interstellar hydrogen from active galactic centers with bursty star formation.
No exotic non-baryonic particles fitting the observed qualitative and quantitative constraints will ever be discovered.
To summarize, this chapter has introduced the reader to a plausible new theory of dark matter which appears to match current observational constraints. The theory, simply stated, is that what we currently refer to as “cold dark matter” is, in actuality, slow-moving interstellar and intergalactic neutral atomic hydrogen in its lower 1 s ground state. So long as it stays in this lower ground state, it cannot emit light. Furthermore, it is currently so sparse as to be nearly collisionless. Whenever and wherever hydrogen is mostly above this ground state, and significantly more concentrated, it is readily visible and we call it something else (a cold, warm, or hot gas cloud, for instance).
Dark matter observations corresponding to the cosmic dawn epoch, which were reported in 2018 and 2019, have provided the necessary constraints on dark matter to favor this theory above all others at the present time. In particular, the Bowman (i.e., EDGES) and Barkana references point to a cold dark matter particle with features quite consistent with cold atomic hydrogen. Furthermore, a convincing case has been made by McGaugh that the strong hydrogen absorption signal at cosmic dawn is the
We conclude by asking the following question:
If interstitial cold atomic hydrogen in its lower ground state is qualitatively and quantitatively sufficient to explain dark matter observations to date, do we really need to spend more of our time and money continuing to look for anything else?
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All published Book Chapters are licensed under a Creative Commons Attribution 3.0 Unported License. Monographs are licensed under the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) license granted to all others. Our Copyright Policy aims to guarantee that original material is published while at the same time giving significant freedom to our Authors. IntechOpen upholds a flexible Copyright Policy meaning that there is no copyright transfer to the publisher and Authors hold exclusive copyright to their work.
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Utkin",authors:[{id:"16132",title:"Dr.",name:"Andrei",middleName:"B.",surname:"Utkin",slug:"andrei-utkin",fullName:"Andrei Utkin"}]},{id:"73811",doi:"10.5772/intechopen.94103",title:"Introduction to Quantum Computing",slug:"introduction-to-quantum-computing",totalDownloads:1211,totalCrossrefCites:3,totalDimensionsCites:4,abstract:"Quantum computing is a modern way of computing that is based on the science of quantum mechanics and its unbelievable phenomena. It is a beautiful combination of physics, mathematics, computer science and information theory. It provides high computational power, less energy consumption and exponential speed over classical computers by controlling the behavior of small physical objects i.e. microscopic particles like atoms, electrons, photons, etc. Here, we present an introduction to the fundamental concepts and some ideas of quantum computing. This paper starts with the origin of traditional computing and discusses all the improvements and transformations that have been done due to their limitations until now. Then it moves on to the basic working of quantum computing and the quantum properties it follows like superposition, entanglement and interference. To understand the full potentials and challenges of a practical quantum computer that can be launched commercially, the paper covers the architecture, hardware, software, design, types and algorithms that are specifically required by the quantum computers. It uncovers the capability of quantum computers that can impact our lives in various viewpoints like cyber security, traffic optimization, medicines, artificial intelligence and many more. At last, we concluded all the importance, advantages and disadvantages of quantum computers. Small-scale quantum computers are being developed recently. This development is heading towards a great future due to their high potential capabilities and advancements in ongoing research. Before focusing on the significances of a general-purpose quantum computer and exploring the power of the new arising technology, it is better to review the origin, potentials, and limitations of the existing traditional computing. This information helps us in understanding the possible challenges in developing exotic and competitive technology. It will also give us an insight into the ongoing progress in this field.",book:{id:"10209",slug:"quantum-computing-and-communications",title:"Quantum Computing and Communications",fullTitle:"Quantum Computing and Communications"},signatures:"Surya Teja Marella and Hemanth Sai Kumar Parisa",authors:[{id:"297632",title:"Mr.",name:"Surya Teja",middleName:null,surname:"Marella",slug:"surya-teja-marella",fullName:"Surya Teja Marella"},{id:"336267",title:"Mr.",name:"Hemanth Sai Kumar",middleName:null,surname:"Parisa",slug:"hemanth-sai-kumar-parisa",fullName:"Hemanth Sai Kumar Parisa"}]}],mostDownloadedChaptersLast30Days:[{id:"73811",title:"Introduction to Quantum Computing",slug:"introduction-to-quantum-computing",totalDownloads:1206,totalCrossrefCites:3,totalDimensionsCites:4,abstract:"Quantum computing is a modern way of computing that is based on the science of quantum mechanics and its unbelievable phenomena. It is a beautiful combination of physics, mathematics, computer science and information theory. It provides high computational power, less energy consumption and exponential speed over classical computers by controlling the behavior of small physical objects i.e. microscopic particles like atoms, electrons, photons, etc. Here, we present an introduction to the fundamental concepts and some ideas of quantum computing. This paper starts with the origin of traditional computing and discusses all the improvements and transformations that have been done due to their limitations until now. Then it moves on to the basic working of quantum computing and the quantum properties it follows like superposition, entanglement and interference. To understand the full potentials and challenges of a practical quantum computer that can be launched commercially, the paper covers the architecture, hardware, software, design, types and algorithms that are specifically required by the quantum computers. It uncovers the capability of quantum computers that can impact our lives in various viewpoints like cyber security, traffic optimization, medicines, artificial intelligence and many more. At last, we concluded all the importance, advantages and disadvantages of quantum computers. Small-scale quantum computers are being developed recently. This development is heading towards a great future due to their high potential capabilities and advancements in ongoing research. Before focusing on the significances of a general-purpose quantum computer and exploring the power of the new arising technology, it is better to review the origin, potentials, and limitations of the existing traditional computing. This information helps us in understanding the possible challenges in developing exotic and competitive technology. It will also give us an insight into the ongoing progress in this field.",book:{id:"10209",slug:"quantum-computing-and-communications",title:"Quantum Computing and Communications",fullTitle:"Quantum Computing and Communications"},signatures:"Surya Teja Marella and Hemanth Sai Kumar Parisa",authors:[{id:"297632",title:"Mr.",name:"Surya Teja",middleName:null,surname:"Marella",slug:"surya-teja-marella",fullName:"Surya Teja Marella"},{id:"336267",title:"Mr.",name:"Hemanth Sai Kumar",middleName:null,surname:"Parisa",slug:"hemanth-sai-kumar-parisa",fullName:"Hemanth Sai Kumar Parisa"}]},{id:"71370",title:"Complex Space Nature of the Quantum World: Return Causality to Quantum Mechanics",slug:"complex-space-nature-of-the-quantum-world-return-causality-to-quantum-mechanics",totalDownloads:1001,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"As one chapter, we about to begin a journey with exploring the limitation of the causality that rules the whole universe. Quantum mechanics is established on the basis of the phenomenology and the lack of ontology builds the wall which blocks the causality. It is very difficult to reconcile the probability and the causality in such a platform. A higher dimension consideration may leverage this dilemma by expanding the vision. Information may seem to be discontinuous or even so weird if only be viewed from a part of the degree of freedoms. Based on this premise, we reexamined the microscopic world within a complex space. Significantly, some knowledge beyond the empirical findings is revealed and paves the way for a more detailed exploration of the quantum world. The random quantum motion is essential for atomic particle and exhibits a wave-related property with a bulk of trajectories. It seems we can break down the wall which forbids the causality entering the quantum kingdom and connect quantum mechanics with classical mechanics. The causality returns to the quantum world without any assumption in terms of the quantum random motion under the optimal guidance law in complex space. Thereby hangs a tale, we briefly introduce this new formulation from the fundamental theoretical description to the practical technology applications.",book:{id:"10076",slug:"quantum-mechanics",title:"Quantum Mechanics",fullTitle:"Quantum Mechanics"},signatures:"Ciann-Dong Yang and Shiang-Yi Han",authors:[{id:"158670",title:"Prof.",name:"Ciann-Dong",middleName:null,surname:"Yang",slug:"ciann-dong-yang",fullName:"Ciann-Dong Yang"},{id:"315900",title:"Dr.",name:"Shiang-Yi",middleName:null,surname:"Han",slug:"shiang-yi-han",fullName:"Shiang-Yi Han"}]},{id:"72922",title:"Analysis of Quantum Confinement and Carrier Transport of Nano-Transistor in Quantum Mechanics",slug:"analysis-of-quantum-confinement-and-carrier-transport-of-nano-transistor-in-quantum-mechanics",totalDownloads:622,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"Quantum mechanics is the branch of physics that consists of laws explaining the physical properties of the nature of nano-particles and their characteristics on an atomic scale. The study of nano-particles significantly challenges our current perception of the universe and the fabric of reality itself. Quantum particles have both wave-like and particle-like characteristics. The fundamental equation that predicts the physical behaviour of a quantum system is the Schrödinger equation and the Poisson equation using Monte Carlo simulations. This gives rise to the wavefunction, electron and hole densities, energy levels and band structure of the system which contains all the measurable information about the particle such as time and position, where position is represented using probabilities. This is because particles do not have one definite position during the time before measurement. In fact, they exist as a fuzzy distribution of all possible states where the likelihood of finding the particle in some states is more probable than others. This is known as being in a superposition of all states. When the quantum system is observed, however, its wavefunction collapses so it consequently falls into one specific position. Moreover, in this chapter we present the simulation results of conduction band profile, electron density (classical and quantum mechanical), eigenstate and eigenfunctions for Si, SOI and III-V MOSFET structures at bias voltage 1.0 V using 1D Poisson-Schrödinger solver.",book:{id:"10076",slug:"quantum-mechanics",title:"Quantum Mechanics",fullTitle:"Quantum Mechanics"},signatures:"Aynul Islam and Anika Tasnim Aynul",authors:[{id:"316001",title:"Dr.",name:"Islam",middleName:null,surname:"Aynul",slug:"islam-aynul",fullName:"Islam Aynul"},{id:"325161",title:"BSc.",name:"Anika Tasnim",middleName:null,surname:"Aynul",slug:"anika-tasnim-aynul",fullName:"Anika Tasnim Aynul"}]},{id:"71547",title:"Dipolar Interactions: Hyperfine Structure Interaction and Fine Structure Interactions",slug:"dipolar-interactions-hyperfine-structure-interaction-and-fine-structure-interactions",totalDownloads:636,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"The interaction between the nuclear spin and the electron spin creates a hyperfine structure. Hyperfine structure interaction occurs in paramagnetic structures with unpaired electrons. Therefore, hyperfine structure interaction is the most important of the fundamental parameters investigated by electron paramagnetic resonance (EPR) spectroscopy. For EPR spectroscopy the two effective Hamiltonian terms are the hyperfine structure interaction and the electronic Zeeman interaction. The hyperfine structure interaction has two types as isotropic and anisotropic hyperfine structure interactions. The zero-field splitting term (electronic quadrupole fine structure), the nuclear Zeeman term, and the nuclear quadrupole interaction term are among the Hamiltonian terms used in EPR. However, their effects are not as much as the term of the hyperfine structure interaction. The zero-field splitting term and the nuclear quadrupole interaction term are the fine structure terms. The interaction of two electron spins create a zero-field splitting, the interaction between the two nucleus spins form the nuclear quadrupole interaction. Hyperfine structure interaction, zero-field interaction, and nuclear quadrupole interaction are subclasses of dipolar interaction. Interaction tensors are available for all three interactions.",book:{id:"10076",slug:"quantum-mechanics",title:"Quantum Mechanics",fullTitle:"Quantum Mechanics"},signatures:"Betül Çalişkan and Ali Cengiz Çalişkan",authors:[{id:"199110",title:"Dr.",name:"Betül",middleName:null,surname:"Çalişkan",slug:"betul-caliskan",fullName:"Betül Çalişkan"},{id:"208732",title:"Dr.",name:"Ali Cengiz",middleName:null,surname:"Çalişkan",slug:"ali-cengiz-caliskan",fullName:"Ali Cengiz Çalişkan"}]},{id:"73016",title:"Exactly Solvable Problems in Quantum Mechanics",slug:"exactly-solvable-problems-in-quantum-mechanics",totalDownloads:708,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"Some of the problems in quantum mechanics can be exactly solved without any approximation. Some of the exactly solvable problems are discussed in this chapter. Broadly there are two main approaches to solve such problems. They are (i) based on the solution of the Schrödinger equation and (ii) based on operators. The normalized eigen function, eigen values, and the physical significance of some of the selected problems are discussed.",book:{id:"10076",slug:"quantum-mechanics",title:"Quantum Mechanics",fullTitle:"Quantum Mechanics"},signatures:"Lourdhu Bruno Chandrasekar, Kanagasabapathi Gnanasekar and Marimuthu Karunakaran",authors:[{id:"239576",title:"Dr.",name:"Marimuthu",middleName:null,surname:"Karunakaran",slug:"marimuthu-karunakaran",fullName:"Marimuthu Karunakaran"},{id:"252354",title:"Dr.",name:"Bruno Chandrasekar",middleName:null,surname:"L",slug:"bruno-chandrasekar-l",fullName:"Bruno Chandrasekar L"},{id:"325784",title:"Dr.",name:"K",middleName:null,surname:"Gnanasekar",slug:"k-gnanasekar",fullName:"K Gnanasekar"}]}],onlineFirstChaptersFilter:{topicId:"230",limit:6,offset:0},onlineFirstChaptersCollection:[],onlineFirstChaptersTotal:0},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:8,limit:8,total:0},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:9,numberOfPublishedChapters:90,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:104,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:32,numberOfPublishedChapters:320,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:12,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:11,numberOfPublishedChapters:141,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:8,numberOfPublishedChapters:133,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!0},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:113,numberOfOpenTopics:3,numberOfUpcomingTopics:1,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:11,numberOfPublishedChapters:107,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:19,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2753-894X",doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:5,numberOfOpenTopics:1,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!0},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:0,numberOfPublishedChapters:16,numberOfOpenTopics:5,numberOfUpcomingTopics:0,issn:null,doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{id:"6",text:"It is great to work with the IntechOpen to produce a worthwhile collection of research that also becomes a great educational resource and guide for future research endeavors.",author:{id:"259298",name:"Edward",surname:"Narayan",institutionString:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259298/images/system/259298.jpeg",slug:"edward-narayan",institution:{id:"3",name:"University of Queensland",country:{id:null,name:"Australia"}}}},{id:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. 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Dr. Koprowski has authored more than a hundred research papers with dozens in impact factor (IF) journals and has authored or co-authored six books. Additionally, he is the author of several national and international patents in the field of biomedical devices and imaging. 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His research interests are focused on modern imaging methods used in medicine and pharmacy, including in particular hyperspectral imaging, dynamic thermovision analysis, high-resolution ultrasound, as well as other techniques such as EPR, NMR and hemispheric directional reflectance. Author of over 100 scientific works, patents and industrial designs. Expert of the Polish National Center for Research and Development, Member of the Investment Committee in the Bridge Alfa NCBiR program, expert of the Polish Ministry of Funds and Regional Policy, Polish Medical Research Agency. Editor-in-chief of the journal in the field of aesthetic medicine and dermatology - Aesthetica.",institutionString:null,institution:{name:"Medical University of Silesia",institutionURL:null,country:{name:"Poland"}}},editorTwo:null,editorThree:null},{id:"8",title:"Bioinspired Technology and Biomechanics",coverUrl:"https://cdn.intechopen.com/series_topics/covers/8.jpg",isOpenForSubmission:!0,editor:{id:"144937",title:"Prof.",name:"Adriano",middleName:"De Oliveira",surname:"Andrade",slug:"adriano-andrade",fullName:"Adriano Andrade",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRC8QQAW/Profile_Picture_1625219101815",biography:"Dr. Adriano de Oliveira Andrade graduated in Electrical Engineering at the Federal University of Goiás (Brazil) in 1997. He received his MSc and PhD in Biomedical Engineering respectively from the Federal University of Uberlândia (UFU, Brazil) in 2000 and from the University of Reading (UK) in 2005. He completed a one-year Post-Doctoral Fellowship awarded by the DFAIT (Foreign Affairs and International Trade Canada) at the Institute of Biomedical Engineering of the University of New Brunswick (Canada) in 2010. Currently, he is Professor in the Faculty of Electrical Engineering (UFU). He has authored and co-authored more than 200 peer-reviewed publications in Biomedical Engineering. He has been a researcher of The National Council for Scientific and Technological Development (CNPq-Brazil) since 2009. He has served as an ad-hoc consultant for CNPq, CAPES (Coordination for the Improvement of Higher Education Personnel), FINEP (Brazilian Innovation Agency), and other funding bodies on several occasions. He was the Secretary of the Brazilian Society of Biomedical Engineering (SBEB) from 2015 to 2016, President of SBEB (2017-2018) and Vice-President of SBEB (2019-2020). He was the head of the undergraduate program in Biomedical Engineering of the Federal University of Uberlândia (2015 - June/2019) and the head of the Centre for Innovation and Technology Assessment in Health (NIATS/UFU) since 2010. He is the head of the Postgraduate Program in Biomedical Engineering (UFU, July/2019 - to date). He was the secretary of the Parkinson's Disease Association of Uberlândia (2018-2019). Dr. Andrade's primary area of research is focused towards getting information from the neuromuscular system to understand its strategies of organization, adaptation and controlling in the context of motor neuron diseases. His research interests include Biomedical Signal Processing and Modelling, Assistive Technology, Rehabilitation Engineering, Neuroengineering and Parkinson's Disease.",institutionString:null,institution:{name:"Federal University of Uberlândia",institutionURL:null,country:{name:"Brazil"}}},editorTwo:null,editorThree:null},{id:"9",title:"Biotechnology - Biosensors, Biomaterials and Tissue Engineering",coverUrl:"https://cdn.intechopen.com/series_topics/covers/9.jpg",isOpenForSubmission:!0,editor:{id:"126286",title:"Dr.",name:"Luis",middleName:"Jesús",surname:"Villarreal-Gómez",slug:"luis-villarreal-gomez",fullName:"Luis Villarreal-Gómez",profilePictureURL:"https://mts.intechopen.com/storage/users/126286/images/system/126286.jpg",biography:"Dr. Luis Villarreal is a research professor from the Facultad de Ciencias de la Ingeniería y Tecnología, Universidad Autónoma de Baja California, Tijuana, Baja California, México. 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Much of biochemistry is devoted to enzymes, proteins that catalyze chemical reactions, enzyme structures, mechanisms of action and their roles within cells. Biochemistry also studies small signaling molecules, coenzymes, inhibitors, vitamins, and hormones, which play roles in life processes. Biochemical experimentation, besides coopting classical chemistry methods, e.g., chromatography, adopted new techniques, e.g., X-ray diffraction, electron microscopy, NMR, radioisotopes, and developed sophisticated microbial genetic tools, e.g., auxotroph mutants and their revertants, fermentation, etc. More recently, biochemistry embraced the ‘big data’ omics systems. Initial biochemical studies have been exclusively analytic: dissecting, purifying, and examining individual components of a biological system; in the apt words of Efraim Racker (1913 –1991), “Don’t waste clean thinking on dirty enzymes.” Today, however, biochemistry is becoming more agglomerative and comprehensive, setting out to integrate and describe entirely particular biological systems. The ‘big data’ metabolomics can define the complement of small molecules, e.g., in a soil or biofilm sample; proteomics can distinguish all the comprising proteins, e.g., serum; metagenomics can identify all the genes in a complex environment, e.g., the bovine rumen. 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Dr. Blumenberg’s research is focused on the epidermis, expression of keratin genes, transcription profiling, keratinocyte differentiation, inflammatory diseases and cancers, and most recently the effects of the microbiome on the skin. 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In recent years, the application of chemistry to biological molecules has gained significant interest in medicinal and pharmacological studies. This topic will be devoted to understanding the interplay between biomolecules and chemical compounds, their structure and function, and their potential applications in related fields. Being a part of the biochemistry discipline, the ideas and concepts that have emerged from Chemical Biology have affected other related areas. 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Behind these definitions are hidden all the aspects of normal and pathological functioning of all processes that the topic ‘Metabolism’ will cover within the Biochemistry Series. 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Thus proteomics, an area of research that detects all protein forms expressed in an organism, including splice isoforms and post-translational modifications, is more suitable than genomics for a comprehensive understanding of the biochemical processes that govern life. The most common proteomics applications are currently in the clinical field for the identification, in a variety of biological matrices, of biomarkers for diagnosis and therapeutic intervention of disorders. From the comparison of proteomic profiles of control and disease or different physiological states, which may emerge, changes in protein expression can provide new insights into the roles played by some proteins in human pathologies. Understanding how proteins function and interact with each other is another goal of proteomics that makes this approach even more intriguing. Specialized technology and expertise are required to assess the proteome of any biological sample. Currently, proteomics relies mainly on mass spectrometry (MS) combined with electrophoretic (1 or 2-DE-MS) and/or chromatographic techniques (LC-MS/MS). MS is an excellent tool that has gained popularity in proteomics because of its ability to gather a complex body of information such as cataloging protein expression, identifying protein modification sites, and defining protein interactions. 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