Feedback phosphorylation events in MAPK ERK1/2 pathway.
\r\n\tFrom the definition of Massive MIMO, the Book covers the important aspects of channel estimation, different efficiency parameters, and various practical deployment considerations. From the beginning, a very general, yet tractable, canonical system model with spatial channel correlation is required. This model is used to realistically assess the Spectral Efficiency and Energy Efficiency and is later extended to also include the impact of hardware impairments.
\r\n\r\n\tAs an overall framework, the authors and researchers who are working in the Area of Massive MIMO and 5G are expected to submit chapters covering these areas to give insight into research about MIMO.
",isbn:null,printIsbn:"979-953-307-X-X",pdfIsbn:null,doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,isSalesforceBook:!1,isNomenclature:!1,hash:"f6e96802bc79d6b8b0bab9ad24980cbc",bookSignature:"Dr. Sudhakar Radhakrishnan",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/7638.jpg",keywords:"Multi Antenna Systems, Diversity, Space-time Codes, Rake Receiver, MIMO Wireless Communication, SVD, Equalising MIMO Systems, Predistortion, Beam Forming Principles, Increased Spectrum Efficiency, Interference Cancellation, Beam Former",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:0,numberOfDimensionsCitations:0,numberOfTotalCitations:0,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"October 18th 2019",dateEndSecondStepPublish:"March 6th 2020",dateEndThirdStepPublish:"May 5th 2020",dateEndFourthStepPublish:"July 24th 2020",dateEndFifthStepPublish:"September 22nd 2020",dateConfirmationOfParticipation:null,remainingDaysToSecondStep:"2 years",secondStepPassed:!0,areRegistrationsClosed:!0,currentStepOfPublishingProcess:5,editedByType:null,kuFlag:!1,biosketch:null,coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"26327",title:"Dr.",name:"Sudhakar",middleName:null,surname:"Radhakrishnan",slug:"sudhakar-radhakrishnan",fullName:"Sudhakar Radhakrishnan",profilePictureURL:"https://mts.intechopen.com/storage/users/26327/images/system/26327.png",biography:"Dr. R. Sudhakar is a professor and head of the Department of Electronics and Communication Engineering, Dr. Mahalingam College of Engineering and Technology, Pollachi, India. He is also an associate editor for IEEE Access, from which he received the Outstanding Associate Editor Award in 2019. He is a reviewer of sixteen international journals, including IEEE Transactions on Systems, Man, and Cybernetics: Systems, International Arab Journal of Information Technology, and International Journal of Computer and Electrical Engineering, among others. He has published 110 papers in international, and national journals and conference proceedings. 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From chapter submission and review, to approval and revision, copy-editing 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. 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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:"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"}}]},chapter:{item:{type:"chapter",id:"76089",title:"Regulation of MAPK ERK1/2 Signaling by Phosphorylation: Implications in Physiological and Pathological Contexts",doi:"10.5772/intechopen.97061",slug:"regulation-of-mapk-erk1-2-signaling-by-phosphorylation-implications-in-physiological-and-pathologica",body:'Among post-translational modifications, protein phosphorylation is the most common. Vitellin was the first protein which phosphorylation was discovered, by Phoebus Levene in 1906 [1, 2]. In 1954, Burnett and Kennedy reported the process of enzymatic phosphorylation. Then, Edwin Krebs and Edmond Fischer described how phosphorylation and dephosphorylation can take place and they demonstrated how the process is governed by enzymes [3, 4]. In 1992, the Nobel Prize in Physiology or Medicine was awarded jointly to Edmond H. Fischer and Edwin G. Krebs for their discoveries concerning reversible protein phosphorylation as a biological regulatory mechanism.
Phosphorylation is a reversible protein modification and results from the addition of a phosphate group (PO4) to the polar group of amino acids. The most common amino acids that are phosphorylated are serine (Ser), threonine (Thr) and tyrosine (Tyr). Although phosphorylation of histidine and aspartate residues can also occur, they are less stable than others. Phosphorylation of a protein can change binding to other proteins: because each phosphate group has two negative charges, phosphorylation can cause a conformational change in the protein by attracting a cluster of positively charged amino acid side chains. This can change the binding of ligands on the protein surface and therefore its activity. On the other hand, the addition of a phosphate group to a protein can be recognized by other proteins having for instance SH2 and PTB domains, that then can attach to phosphorylated proteins such as the cytoplasmatic tail of receptor tyrosine kinases (RTK). Finally, phosphorylation can mask a binding site that otherwise holds two proteins together and then can disrupt this interaction.
Enzymes that catalyze the addition of a phosphate group to a protein are kinases; the reaction is unidirectional because of the large amount of free energy released when the phosphates bonds are broken in ATP to produce ADP. The human genome includes more than 500 protein kinases, and it is estimated that more than one-third of the 10,000 proteins in a typical mammalian cell are phosphorylated at any given time, many with more than one phosphate. Conversely, phosphatases are enzymes that remove a phosphate group from a protein, having the opposite function of kinases. Dephosphorylation has more rapid kinetics than phosphorylation by kinases. The human genome contains more than 200 phosphatases, classified into different families including protein tyrosine phosphatases (PTP), the metal-dependent protein phosphatase PPM, the phosphoprotein phosphatase (PPP) that are pSer/pThr- specific, the dual specificity phosphatase (DUSP) family and the PTEN family of lipid phosphatases [5].
Protein phosphorylation may occur at a single site that primes location for subsequent phosphorylations or directly at multiples sites. Thus, a single protein kinase or multiple kinases may act on the target protein, creating a synchronized cascade of phosphorylations. These events participate in dynamic intracellular signaling that enable cells to respond to extracellular stimuli and to adapt to internal changes. Mitogen-protein activated kinases (MAPK) are conserved kinases in eukaryotes, integrating cell signaling pathways that regulate processes such as cell proliferation, cell differentiation and cell death, from yeast to humans. There are four independent MAPK pathways: MAPK ERK1/2, ERK-5 (also referred to as BMK-1), c-Jun N- terminal kinase (JNK), and p38 signaling families. MAPK modules contain 3-tier kinases that are sequentially activated by phosphorylation. MAPK proteins are designated from upstream to downstream signaling pathway: MAPK kinase kinase (MAPKKK) phosphorylates MAPK kinase (MAPKK); MAPKK phosphorylates and thus activates MAPK. We will focus on MAPK ERK1/2 signaling to illustrate how a particular post-translational modification such as phosphorylation can regulate a signaling pathway and how its dysregulation can be implicated in pathological processes such as tumorigenesis.
The Extracellular Signal-Regulated Kinases (ERK) have key roles in processes like cell growth, cell proliferation and cell survival. In humans, there are three isoforms of ERK: ERK-1, ERK-2 and ERK-5. Hereon we will concentrate on classical MAPK ERK1/2 to comprehend how this signaling is regulated by phosphorylation.
In the canonical human MAPK ERK1/2 pathway there are three types of MAPKKK (A-Raf, B-Raf and Raf-1 or C-Raf kinases), two MAPKK (MEK1, MEK2) and two MAPK ERK-1, ERK-2. Interestingly, MAPK ERK1/2 signaling is basically regulated by phosphorylations. On the first level, Raf are serine/threonine-protein kinases that phosphorylate human MEK on Ser-218 and Ser-222, producing their activation. The Raf family of kinases includes three isoforms with high homology and a similar domain organization. On the second level, MEK1/2 are dual specificity protein kinases that phosphorylate a threonine and a tyrosine residue in a Thr-Glu-Tyr sequence located in ERK1/2, rendering them active. While human ERK-1 is phosphorylated on Thr-202 and Tyr-204, ERK-2 is phosphorylated on Thr-185 and Tyr-187 residues for activation. Phosphorylation of ERK1/2 by MEK1/2 leads to the rearrangement of several polar contacts, which results in conformational changes in neighboring structural elements (reviewed on [6]). Finally, ERK1/2 are serine/threonine kinases that phosphorylate a wide variety of substrates in different subcellular compartments including the Golgi apparatus, the mitochondrial membrane, the cytoplasm and the nucleus.
MAPK ERK1/2 phosphorylate substrates in a short Pro-X- Ser/Thr-Pro consensus motif (X representing any residue) and interactions with docking sites are important for specificity. Two motifs have been described, the D- and F-motifs, that can cooperate to enhance the substrate affinity of ERK and to set phosphorylation kinetics [7]. ERK1/2 phosphorylate more than 600 proteins, leading to responses such as cell cycle progression, proliferation, cytokinesis, transcription, differentiation, senescence, cell death, migration, formation of GAP junctions, actin and microtubule networks, neurite extension, cell adhesion and motility, survival and apoptosis [8]. To ensure that these cell responses are adaptive to stimuli in space and time, a fine regulation of MAPK signaling is thus necessary. Remarkably, control of ERK1/2 signaling is in part ensured by phosphorylations and dephosphorylations.
The MAPK ERK1/2 has at least 3 tiers of regulation: the control of the phosphorylation and thus of the activity of Raf, MEK1/2 and ERK1/2. Additionally, upstream signals from cell receptors to Raf and downstream targets of ERK1/2 play an active role in regulating the MAPK ERK1/2 pathway. Interestingly, mechanisms of MAPK regulation are based partly on the same mechanisms that activate this pathway: phosphorylation events. In this section we specify how phosphorylation can regulate MAPK ERK1/2 signaling from Raf to ERK1/2 by the activity of kinases in feedback signals, and through dephosphorylation by phosphatases.
When RTK are activated by growth factors, their phosphorylated tyrosines enable the coupling of adaptor proteins such as GRB2. This latter binds with SOS, a guanine exchange factor that promotes the activation of Ras. From this level, MAPK ERK1/2 signaling axis exerts feedback regulations through phosphorylations. Growth factor stimulation (like epidermal growth factor EGF) of the cell induces the phosphorylation of four serine residues in a region encompassing three proline-rich SH3-binding sites in the C-terminal domain of SOS1 [9]. These phosphorylation events are realized by ERK1/2 and constitute a negative feedback regulation that leads to a reduction in Ras activation. Kinetic simulation model using parameters collected in living cells found that possibly more than four phosphorylation sites decisively suppress SOS activity [10]. Indeed, SOS1 is also phosphorylated by the ERK1/2 effector ribosomal S6 kinase 2 (RSK-2) on Ser1134 and Ser1161, leading to the recruitment of 14-3-3 and is thus a negative regulation of ERK1/2 activity [11] (Figure 1 and Table 1).
Representative phosphorylation events leading to activation and feedback signaling in the MAPK ERK1/2 pathway. Phosphorylation constitutes activation (red arrows) or inhibition (black arrows) of proteins of MAPK ERK1/2 signaling. Specific details are provided in
Number in figure | Protein phosphorylated | Phosphorylation site | Kinase | Type of feedback | Consequence | References |
---|---|---|---|---|---|---|
1 | SOS1 | Ser1132, Ser1167, Ser 1178, Ser 1193 | ERK1/2 | Negative | Decreased binding affinity of Grb2 to human Sos1 | [9] |
2 | SOS1 | Ser1134, Ser1161 | RSK | Negative | Facilitates 14-3-3 binding, decreasing MAPK activation | [10] |
3 | RasGRP2 | Ser394 | ERK1/2 | Negative | Inhibits RasGRP2 ability to activate Rap1, leading to decreased activation of ERK1/2 | [12] |
4 | MEK1/2 | Proline-rich sequence (PRS) | PAK1 | Positive | Enhances MEK1/2 interaction with C-Raf | [13, 14, 15] |
5 | KSR1 | Thr260, Thr274, Ser443 | ERK1/2 | Negative | Interrupts association of KSR1 with B-Raf and MEK1/2, driving the release of KSR1 from the plasma membrane | [16, 17] |
6 | MEK1 | Thr292 | ERK1/2 | Negative | Inhibits MEK1 kinase activity towards ERK1/2, interferes with the binding of MEK1 to ERK2 and reduces the ability of PAK to phosphorylate MEK1 on S298 (required for the activation of MEK1 by cell adhesion) | [18, 19] |
7 | C-Raf | Ser29, Ser43, Ser642, Ser289, Ser296, Ser301 | ERK1/2 | Negative | Desensitized C-Raf, do not localize to the plasma membrane and do not engage with activated Ras | [20] |
8 | DUSP6 | Ser159, Ser174, Ser197 | ERK1/2 | Negative | Induces degradation of DUSP6 | [21, 22] |
9 | B-Raf | Ser445 | Rap1 | Positive | Activation of B-Raf | [23] |
Feedback phosphorylation events in MAPK ERK1/2 pathway.
In platelets and nexus ERK1/2 is also activated downstream of the small GTPase Rap1. RasGRP2 is the predominant guanine exchange factor that specifically activates Rap1. RasGRP2, playing a similar role to SOS for Ras, is phosphorylated by ERK1/2 on Ser394 located in the linker region implicated in its autoinhibition. In this case, RasGRP2 phosphorylation results also in a negative feedback loop that determines the amplitude and duration of active ERK1/2 [12]. Moreover, Rap1 is able to phosphorylate and activate B-Raf (but not C-Raf) [23]. Upon cell adhesion and downstream of the small GTPase Rac, the serine/threonine-protein kinase PAK1 phosphorylates the MEK proline-rich sequence (PRS), enhancing its interaction with C-Raf [13] (Figure 1 and Table 1).
Regarding Raf, it has been shown that mitogenic stimuli induce the phosphorylation of C-Raf by ERK1/2 on six residues, needing MEK signaling. Hyperphosphorylation of these sites promotes the subsequent dephosphorylation of C-Raf by PP2A and the return to the inactive state [20]. On the other side, Raf interaction with MEK is also regulated by the inhibitor protein RKIP, which binds to both proteins preventing their physical association. RKIP interferes with the phosphorylation of MEK when bound to C-Raf. Association of RKIP with C-Raf is regulated partly by phosphorylation: phosphorylation of RKIP on serine 153 by PKC or putatively by ERK induces its dissociation from C-Raf [24, 25]. RKIP has then an important role in generating a switch-like behavior of MEK1/2 activity [26].
MEK1/2 is also the target of feedback regulation in the ERK1/2 pathway. Indeed, ERK1/2 phosphorylates MEK1 on Thr292, Thr286 and Thr386, resulting in reduced MEK activity and thus constitutes a negative feedback for MAPK ERK1/2 signaling [18, 19]. Moreover, MEK1 phosphorylation on Thr292 by ERK1/2 interferes with MEK1 binding to ERK2 and reduces MEK1 phosphorylation on S298 by PAK, required for the activation of MEK1 by cell adhesion [13, 14, 15] (Figure 1 and Table 1).
Another example of feedback regulation of MAPK ERK1/2 signaling by phosphorylation is the case of the protein scaffold KSR1. In fact, KSR1 can be phosphorylated in Thr256, Thr260, Thr274, Ser320, Ser443, Ser463 by ERK1/2
Another regulation of MAPK activity is accomplished by phosphatases that modulate later phases of ERK1/2 signaling. Ser/Thr phosphatases, protein tyrosine phosphatase and dual-specificity Thr/Tyr phosphatases (DUSP) dephosphorylate and thus inactivate ERK1/2. MAP Kinase Phosphatases (MKP) belong to DUSP and represent specific phosphatases that principally regulate MAPK activity in mammalian cells and tissues. While some DUSP dephosphorylate p38, JNK and ERK1/2, others are specific for p38/JNK or for ERK1/2. In this latter case are found cytoplasmic DUSP that inactivate ERK1/2 in the cytoplasm and include DUSP6/MKP-3, a specific phosphatase that binds to ERK1 and ERK2, inactivating them. This specificity is ensured by the fact that the interaction of DUSP6 with ERK1/2 is a requirement for the catalytic activation of the phosphatase through conformational changes [27, 28]. Interestingly, whilst inactivating ERK1/2, DUSP6 is in turn regulated by ERK1/2. Indeed, stimulation with serum or PDGF-B alone can induce a MEK-dependent phosphorylation of DUSP6 on Ser159, Ser174, and Ser197, which is followed by the degradation of the phosphatase by the proteasome [21, 22]. We have shown that another pathway involved in growth factor signaling, the PI3K/mTOR signaling pathway, accounts for a part of the phosphorylation and degradation of DUSP6 induced by serum growth factors. Furthermore, specific agonists of the mTOR pathway, such as amino acids or insulin/IGF-1 are also able to induce the phosphorylation and degradation of DUSP6. Mutagenesis studies identified Ser159 within DUSP6 as the target of the mTOR pathway [29]. Thus, DUSP6 is a point for double MAPK control: the phosphatase exerts a negative regulation for ERK1/2 activity but at the same time, ERK1/2 is able to phosphorylate DUSP6 and then induces its degradation. DUSP6 appears therefore as a spot for fine ERK1/2 signaling regulation in time. Moreover, DUSP6 is a branch-point for the crosstalk between two major signaling pathways induced by growth factors, the MEK/ERK1/2 pathway and the PI3K/mTOR pathway. Notably, both pathways are frequently overactivated in cancer cells. Thus, a regulation of MAPK ERK1/2 signaling in time and space is necessary to warrant cell physiological responses and to avoid aberrant signaling activation that facilitates pathological conditions.
MAPK ERK1/2 signaling can determine excluding cell responses such as proliferation and differentiation. Differences in cell responses upon MAPK ERK signaling depend on the regulation of the pathway through protein interactions by scaffolds and through inhibitory and adaptor proteins that enhance, decrease, or redirect the flow of phosphorylation cascades. In this section, we will describe how phosphorylation can be implicated in this type of MAPK ERK1/2 signaling regulation. Scaffold proteins bind to multiple interacting proteins by interconnecting them into a stable complex. This allows the rapid transmission of the signal. Another role of scaffolds is to sequester sets of interacting proteins to limit interactions with other proteins and minimize crosstalk between pathways that some components may share. Scaffold proteins such as KSR1, β-Arrestin, paxillin and IQGAP1 regulate the kinetics, amplitude, and localization of ERK1/2 signaling [30]. Ras-1 suppressor kinase (KSR1) is one of the best characterized scaffold proteins in the ERK1/2 cascade. It has several different domains through which it can interact with C-Raf, MEK1/2, and ERK1/2. In response to growth factors, KSR1 translocates to the plasma membrane where it promotes the activation of MEK1/2 by presenting it to activated Raf. In the absence of stimulus, the ubiquitin-protein isopeptide ligase family member IMP and the 14.3.3 protein prevent the function of KSR1. Mitogens induce the dephosphorylation of IMP at S392 by protein phosphatase-2A (PP2A) and the degradation of the protein, which is sufficient to allow KSR1 to translocate to the cell membrane [31]. Activated Ras also induces phosphorylation of KSR1 at residues Thr260, Thr274, and Ser443 [16]. Then, while activated Ras prevents the effects of 14.3.3 and IMP that inhibit KSR1 function, it also induces its phosphorylation at Thr274, preparing KSR1 for degradation. KSR1 can then regulate ERK1/2 activation kinetics and influence the biological fate of the cell. The interaction and in particular the synchronization between these processes generates a combinatorial control to modulate both the amplitude and the duration of ERK1/2 activity.
If scaffold proteins play a key role in regulating ERK1/2 signaling in subcellular locations, different factors modulate the strength and the duration of ERK signaling in time: the density of cell surface receptor and its different internalization patterns, the surrounding extracellular matrix and the interaction between kinases and phosphatases. The duration of the signal is critical in determining cell response to ERK1/2 signaling. For instance, long-term ERK1/2 activation can cause differentiation while short-term ERK1/2 activation can lead to cell division. This was initially demonstrated in rat pheochromocytoma PC-12 cells, in which transient activation of ERK1/2 by epidermal growth factor (EGF) or insulin peaks at 5 min and fells back to near-background levels within 15 minutes, and results in cell proliferation. On the other hand, sustained activation of ERK1/2 by nerve growth factor (NGF) persists for more than 60 minutes and induces cell differentiation [32]. This type of cell response according to duration of ERK1/2 signaling has been also reported in fibroblasts, macrophages and T lymphocytes [33, 34, 35]. As this type of studies has been made using mainly immunoblotting techniques to monitor ERK1/2 activation dynamics, the use of new approaches gaining spatio-temporal resolution will be of great interest to advance in the understanding of ERK1/2 signaling in time and in subcellular localizations. For example, using Förster Resonance Energy Transfer (FRET)-based ERK biosensors, Keyes et al. showed that EGF induces sustained ERK1/2 activity near the plasma membrane in contrast to the transient activity observed in the cytoplasm and in the nucleus. This supports the concept that the spatial and temporal regulation of ERK1/2 activity is integrated by the cell to control the specificity of signaling [36].
Studies on RTK receptors have shown that their activation kinetics and regulatory mechanisms also play a key role in the activation of the MAPK ERK1/2 pathway. For example, PC-12 cells that express few NGF receptors do not undergo differentiation in response to NGF [37]. Moreover, changing the amount of receptor occupation by decreasing the concentration of agonists alters the duration of ERK1/2 signaling. The rate and degree of receptor internalization also contribute to ERK signaling, not only as a checkpoint for signal termination, but may exhibit additional signaling by the receptor-ligand complex from an internalized cellular location [38].
The MAPK/ERK signaling module is considered the most important oncogenic driver of human malignancies [39]. Mutational oncogenic activation of the Ras/Raf/MEK/ERK pathway occurs in a wide variety of cancers concerning approximately 34% of all human cancers. Activation of the ERK1/2 signaling pathway promotes proliferation and has anti-apoptotic effects, increasing tumor invasion and metastasis. The overexpression of the pathway can lead to cell transformation, tumor proliferation, invasion, metastasis, extracellular matrix degradation and tumor angiogenesis. VEGF is an important pro-angiogenic factor and the most powerful pro-vascular endothelial growth cytokine that promotes cell division and vascular construction. The MAPK ERK1/2 signaling pathway can activate transcription factors to enhance the transcription of VEGF, promoting the formation of blood vessels and tumor angiogenesis [40, 41].
Aberrant activation of the Ras/Raf/MEK/ERK pathway may be driven by abnormal receptor kinase activation or by oncogenic mutations of pathway components, leading to tumorigenesis. Overactivation of Ras is observed in approximately 30% of all human cancers but can be higher in some cancers like pancreas cancer (90%), colon cancer (50%) and thyroid cancer (50%) [42, 43]. Mutations in Ras occurs in codons 12, 13, 59 and 61, leading to its constitutive activation. Indeed, mutant oncogenic Ras proteins are insensitive to GTP-catalyzed GTPase hydrolysis activator protein, resulting in a constitutively active GTP-bound Ras. K-Ras and N-Ras are the most common mutated isoforms in human cancer, although H-Ras can also be involved. K-Ras is involved in up to 96% of pancreatic ductal adenocarcinomas, 52% of colorectal carcinomas and 32% of lung adenocarcinomas [44].
Downstream of Ras, Raf can be activated by mutations that mainly affect B-Raf isoform, the most potent activator of MEK1/2 compared with the other Raf isoforms (A-Raf and C-Raf). B-Raf can be mutated in 70% of melanomas, in 36-53% of papillary thyroid cancer, in 30% of ovarian cancer and in 22% of colorectal cancer [45]. The most common mutation of B-Raf is the change of a valine to a glutamic acid in position 600 (V600E). Other B-Raf mutations in cancer are mainly clustered in the activation segment or the so-called glycine-rich loop in B-Raf [46]. Oncogenic mutations of B-Raf lead to hyperactivity of its downstream effectors MEK1/2 and ERK1/2. For cellular transformation to occur, two mutations in Ras/Raf/MEK/ERK1/2 pathway can be needed: for instance, B-Raf and Ras mutations can drive tumorigenesis for colorectal cancer (K-ras G13D; B-Raf G463V), for ovarian cancer (K-ras G13D; B-Raf G463E), and for non-small cell lung cancer (N-Ras Q61K; B-Raf L596V) [45].
Downstream of Raf, MEK1/2 can be highly phosphorylated in colorectal cancer, gliomas, prostate cancer, breast cancer and head and neck cancer [47, 48, 49, 50, 51]. Constitutively active mutants of MEK-1 have higher basal activity than the wildtype unphosphorylated MEK. Expression of these mutants in mammalian cells lead to ERK1/2 activation in growth factor-deprived cells, cellular transformation and solid tumor growth in nude mice [33, 52, 53]. If mutant MEK can act as oncogene, its frequency in human cancers appears to be rare [54]. Finally, MAPK ERK1/2 are not frequently mutated. However, some mutations in ERK have been described: ERK2 mutants were identified as rare cancer-associated gain- and loss-of-function gene products: ERK2 D321N, ERK2 E322K, ERK2 L73P, ERK2 S151D and ERK2 D319N [55, 56, 57, 58, 59, 60]. While ERK2 D319N has not an increased basal kinase activity, it shows an elevated sensitivity to low levels of signaling
Hyperactivation of Ras/Raf/MEK/ERK signaling pathway in human cancers prompted the development of small molecule inhibitors that target its components for use in cancer therapeutics (Table 2). Pharmacological inhibition of Ras has been a major challenge. For instance, the affinity of Ras protein for GTP is extraordinarily high and it is then very difficult to develop a competitive binding strategy. Over the past few years, several groups discovered and developed small molecule Ras modulators using protein structure-guided design approaches [80, 81, 82] and exploring SOS as a target for Ras activation [83]. Cysteine-reactive inhibitors that bind to the mutant K-Ras G12C, which is commonly found in cancer, have been developed: SML-8-73-1 and SML-10-70-1 can selectively inhibit K-Ras G12C, changing the nucleotide preference to favor GDP over GTP and thus blocking Ras signaling [69, 84]. These compounds may be used in the future for additional K-Ras mutations.
Protein | Mutation | Cancer | Inhibitor | Test/effect/approval | Reference |
---|---|---|---|---|---|
B-Raf | V600E V600K V226M | Melanoma (66%) Ovarian cancer (35-70%) Thyroid cancer (70%) | Vemurafenib | Approved by the FDA for metastatic and unresectable melanoma with B-Raf V600K mutation | FDA |
Dabrafenib and Trametinib | Approved by the FDA and EMA for melanoma cancer, anaplastic thyroid cancer, NSCLC | FDA, EMA [64] | |||
LGX818 | Approved by the FDA for the treatment of patients with unresectable or metastatic melanoma with B-Raf mutations | FDA [65] | |||
TAK-632 | TAK-632 demonstrates potent antiproliferative effects both on NRAS-mutated melanoma cells and B-Raf-mutated melanoma cells; the combination of TAK-632 and the MAPK kinase (MEK) inhibitor TAK-733 exhibits synergistic antiproliferative effects on these cells | [66] | |||
MLN2480 | In vitro analysis of MLN2480 and TAK-733 (allosteric MEK kinase inhibitor) demonstrates synergistic activity in cell proliferation. In vivo, MLN2480 shows antitumor activity in melanoma, colon, lung, and pancreatic cancer xenograft models | [67, 68] | |||
Sorafenib | Approved by the FDA for renal and hepatocellular carcinoma | FDA | |||
N-Ras | Q61RQ61LG12D | Melanoma (15- 20%) Myeloid leukemia (30%) Lung cancer (35%) | Ribociclib and Binimetinib | Phase Ib/II trials in patients with locally advanced or metastatic N-Ras mutant melanoma | Clinical trial NCT01781572 |
G12V | Thyroid carcinoma (27%) | Trametinib and Palbociclib | Phase I/II trial in patients with solid tumors and with a specific cohort for N-Ras-mutant melanoma | Clinical trial NCT02065063 | |
K-Ras | G12DG12CG13D | Lung cancer (30%) Colorectal cancer (45%) Pancreatic cancer (90%) Blandder cancer (50%) | SML-8-73-1, SML-10-70-1 | SML-10-70-1, a prodrug of SML-8-73-1, inhibits lung cancer A549, H23, and H358 cells | [69] |
MEK | S217ES221E | Melanoma (3-8%) Breast cancer (7-9%) | Selumetinib | Approved by the FDA for treatment of pediatric patients aged 2 years and older with neurofibromatosis type 1 (NF1) who have symptomatic, inoperable plexiform neurofibromas; approved by the EMA for the treatment of neurofibromatosis | FDA, EMA |
Trametinib | Approved by the FDA and EMA for treatment of patients with unresectable or metastatic melanoma with B-Raf V600E or V600K mutations | FDA, EMA | |||
Pimasertib | Has demonstrated potent antitumour activity in human lung, colorectal, melanoma cancer cells and xenograft models; phase I/II clinical trial in patients with locally advanced or metastatic solid tumors | [70, 71, 72] | |||
Cobimetinib | Approved by the FDA and EMA for use in combination with vemurafenib for the treatment of metastatic melanoma | FDA, EMA | |||
G-573, GDC-0623 | In vitro GDC-0623 inhibits cellular proliferation of mutant cancer cells A375 (B-Raf V600E), HCT116 (KRAS G13D), COLO 205 (BRAF V600E), HT- 29 (BRAF V600E), and HCT116 (KRAS G13D). In vivo GDC-0623 causes potent tumor growth inhibition in mouse MiaPaCa-2, A375 and HCT116 xenografts | [73] | |||
TAK-733 | In vitro TAK-733 demonstrates broad activity in most melanoma cell lines; in vivo TAK-733 demonstrates broad antitumor activity in mouse xenograft models of human cancer including melanoma, colorectal, NSCLC, pancreatic and breast cancer | [74] | |||
Binimetinib(Mek 162) | Approved by the FDA for treatment in combination with LGX818 for patients with unresectable or metastatic melanoma with a B-Raf V600E or V600K mutation; approved by the EMA for the treatment of colorectal carcinoma | FDA, EMA | |||
ERK 1/2 | NA | Melanoma (67%) | Ulixertinib(BVD-523) | In vitro combined Ulixertinib (BVD-523) and VS-5584 treatment causes significant induction of cell death in human pancreatic cancer (HPAC) cells, in pancreatic ductal adenocarcinoma cell lines BxPC-3, MIAPaCa-2, and CFPAC-1. Clinical trials in phase I for tumor advanced pancreatic and other solid tumors cancer and phase II for advanced malignancies harboring MEK or atypical B-Raf alterations. | [75] Clinical trial NCT03454035 and NCT04488003 |
GDC-0994 | In vitro Ravoxertinib (GDC0994) decreases the viability of lung adenocarcinoma cell lines (A549, HCC827, HCC4006). In vivo GDC0994 results in significant single-agent activity in multiple cancer models, including K-Ras-mutant and B-Raf-mutant human xenograft tumors in mice. Clinical trials phase I for locally advanced or metastatic solid tumors, NSCLC, metastatic colorectal cancer, metastatic NSCLC, metastatic cancers and melanoma | [76] Clinical trials NCT01875705 and NCT02457793 | |||
SCH772984 | In vitro SCH772984 results in a G1 arrest in SCH772984-sensitive melanoma cells. In vivo antitumor activity is observed in the K-Ras-mutant pancreatic MiaPaCa model | [77] | |||
AEZS-134 | Synergistic effect of triptorelin, ERK inhibitor AEZS-134 and dual PI3K/ERK inhibitor AEZS-136 in MDA-MB-231 triple-negative breast cancer cells | [78] | |||
(S)-14 K | In vivo (S)-14 k inhibited tumor growth in mouse xenograft models | [79] |
Available inhibitors for MAPK ERK1/2 proteins.
NA: not available; FDA: food and drug administration of USA; EMA: European medicines agency; NSCLC: non-small cell lung cancer.
Sorafenib is an orally available compound that was initially developed as a C-Raf inhibitor and was then identified as a multikinase inhibitor for B-Raf, VEGFR1/2/3, Kit, PDGFR, RET, and Flt3. Sorafenib is currently approved by the FDA for renal and hepatocellular carcinoma for its anti-angiogenic effects [84, 85]. For other cancers like melanoma, sorafenib produced favorable responses in less than 5% of patients in clinical trials [85, 86]. This low response rate can be due to the fact that its activity against B-Raf V600E mutants and wild-type enzymes is low. Subsequent efforts have focused on targeting B-Raf for the treatment of B-Raf mutant melanoma. Vemurafenib and dabrafenib, two B-Raf V600E inhibitors, have achieved benefits in clinical trials [87, 88]. Currently, vemurafenib is approved by the FDA for metastatic and unresectable melanoma with B-Raf V600K mutation [89] and dabrafenib for metastatic melanoma with B-Raf V600K-mutated [84, 88]. Although B-Raf inhibitors have achieved clinical benefit in the treatment of cancer, all ATP-competitive Raf inhibitors including vemurafenib, dabrabenib, and sorafenib can lead to paradoxical activation of the MAPK pathway in wild-type B-Raf cells [90, 91]. Some reports suggest that insensitivity to Raf inhibitors might be due to EGFR-mediated reactivation of MAPK signaling in B-Raf mutant colorectal cancer [92]. Indeed, the combination of EGFR and B-Raf inhibitors block the reactivation of MAPK signaling of B-Raf mutant in colorectal cancer cells and
Even though MEK1/2 mutations are rare in human cancers, MEK1/2 have become an attractive drug target because these proteins are downstream of Ras and Raf in the signaling pathway [95]. The first MEK1/2 inhibitor, PD098059, is an allosteric inhibitor that acts on the not-phosphorylated form of MEK1 and mutant MEK1 S217 and S221E [96]. The allosteric MEK inhibitor CI-1040 was the first small molecule to enter clinical trials. Although it had antitumor effects, the development of this compound was stopped due to poor bioavailability and lack of efficacy in phase II clinical trials [97]. Other highly selective inhibitors of MEK1 and MEK2 include selumetinib and trametinib [98, 99, 100]. This latter prevents Raf-dependent MEK phosphorylation and activation. Other MEK inhibitors in development include pimasertib [101], cobimetinib [102], rafametinib [103], G-573, GDC-0623 [73], TAK-733 [104], RO5126766, RO4987655 [105, 106] and MEK162 [107].
Because there are few ERK1/2 mutations in human cancers, this MAPK has been only considered as a target in 35 clinical trials, compared with more than 300 clinical trials for the inhibition of Raf and MEK. Nonetheless, due to drug resistance resulting from Raf and MEK1/2 inhibitors, ERK1/2 have become an interesting target for inhibiting MAPK ERK1/2 signaling in cancer [46]. ERK1/2 inhibitors can reverse overactivation of the MAPK pathway induced by upstream mutations, including Ras mutations [84, 92, 108]. For instance, MAPK inhibition in B-Raf V600E mutant metastatic melanoma provokes drug resistance and recovery of ERK activity [109, 110]. Interestingly, selective removal of ERK1 or ERK2
One of the challenges in cancer treatment is developing drug resistance. The mechanisms involved in resistance are complicated and include genetic mutations that occur in target proteins like in MAPK signaling, loss of functions in the control of MAPK signaling feedback, and abnormal tumor suppressor gene alterations [112]. Yet, MAPK inhibitors represent good options for targeting cancer cells with MAPK overactivation or MAPK ERK1/2 mutations. In the future, cell-specific deliverance of MAPK inhibitors to tumoral cells should enhance their efficiency and decrease side effects in patients.
MAPK are conserved kinases in eukaryotes, containing 3-tier kinases that are sequentially activated by phosphorylation. This post-translational modification plays an essential role in MAPK ERK1/2 signaling. Not only the activation but also the regulation of this pathway is achieved through the actions of kinases and phosphatases, establishing positive and negative signaling feedbacks. Control of MAPK ERK1/2 signaling in time and space is ensured by proteins such as scaffolds that are themselves regulated by phosphorylation events. Changes in duration of ERK1/2 phosphorylation and thus activity, can result in different cell responses, can result in different cell responses. Thus, a tight regulation of MAPK ERK1/2 signaling is needed to guarantee adaptive cell responses. Aberrant activation of Ras/Raf/MEK/ERK pathway can lead to tumorigenesis and MAPK inhibitors, already in clinical use, represent good options for targeting cancer cells with MAPK overactivation or MAPK ERK1/2 mutations.
We thank Helden Natalia Vélez González for assistance in figure design.
The authors declare no conflict of interest.
DUSP | dual specificity phosphatase |
EGF | epidermal growth factor |
EMA | European medicines agency |
ERK | extracellular signal-regulated kinases |
FDA | food and drug administration |
FRET | Förster resonance energy transfer |
GRB2 | growth factor receptor-bound protein 2 |
KSR1 | Ras-1 suppressor kinase |
MAPK | mitogen-protein activated kinases |
MAPKK | MAPK kinase |
MAPKKK | MAPK kinase kinase |
MKP | map kinase phosphatase |
mTOR | mechanistic target of rapamycin |
NGF | nerve growth factor |
NSCLC | non-small cell lung cancer |
PDGF-B | platelet-derived growth factor subunit B |
PDGFR | platelet-derived growth factor |
PI3K | phosphatidylinositol 4,5-bisphosphate 3-kinase |
PPM | metal-dependent protein phosphatase |
PPP | phosphoprotein phosphatase |
PRS | proline-rich sequence |
PTEN | phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase |
PTP | protein tyrosine phosphatases |
RTK | receptor tyrosine kinase |
RSK-2 | ribosomal S6 kinase 2 |
SOS1 | son of sevenless homolog 1 |
The development of a terahertz (THz) source has obtained much interest over the last three decades due to their widespread scientific and military applications [1, 2, 3]. Photoconductive antennas (PCAs) illuminated by a femtosecond (fs) laser have been becoming the dominant methods for intense THz radiations [3] since the pioneering demonstration of picosecond photoconducting Hertzian dipoles in 1984 [4]. Historically, commercial semi-insulating (SI)-GaAs grown by liquid-encapsulated Czochralski has been the cost-effective choice as the substrate for PCAs, due to its high resistivity (>107 Ω cm) and high electron mobility (μ > 7000 cm2/Vs) [5]. Afterward, about 1 μm-thick film of low-temperature (LT) grown GaAs (LT-GaAs) by molecular beam epitaxy (MBE) on the surface of SI-GaAs substrate is extensively used to reduce carrier lifetime to below 1 ps with high resistivity (107 Ω cm) and relatively reasonable mobility μ (100–300 cm2/Vs) [6, 7], in order to efficiently generate broadband THz radiations of over 1 THz and reduce the carrier lifetime of PCAs on SI-GaAs (τ > 100 ps). An alternative approach for short lifetime is to create point defects in SI-GaAs by ion-implantation technique. Arsenic, oxygen, nitrogen, carbon, hydrogen (proton), etc., have been implanted into SI-GaAs and the obtained GaAs PCAs are similar to those on LT-GaAs [8, 9, 10, 11]. However, the process conditions for either LT-GaAs or ion-implanted GaAs are not easy to reproduce in mass production, because of the difficult control of low-temperature process for MBE [12, 13], extremely high implantation energies (∼MeV) for heavy ions [11] and the challenging control for post annealing at relatively low temperatures [8, 14].
\nFundamentally, the THz radiation power and optical-to-THz conversion efficiency for GaAs PCAs illuminated by femtosecond laser pulses are proportional to the photoconductive material factor μτ2 of PCAs [15]. The reduced electron mobility and carrier lifetime as mentioned earlier will seriously affect the THz power and conversion efficiency [3, 16, 17]. The radiation mechanism is attributed to a time-varying current, a result of photo carriers accelerating across photoconductive gap in the presence of applied electrical field [18]. The emitted THz pulse energy is derived from that stored in the static bias field [19]. Grischkowsky has reported that an extremely strong field exists near the anode of electrically biased PCAs [20], and Salem also demonstrated that THz amplitude can be multiplied by many times when the focused laser beam moved to the anode of an ion-implanted GaAs antenna at the same bias voltage [9]. Recently, plasmonic contact electrodes were used to enhance light absorption within distances of ∼100 nm from the anode and 7.5% optical-to-THz conversion efficiency was recorded at very low pump densities of <10 μJ/cm2 [21]. However, a tightly focused laser beam will cause a high screening effect [22] and the THz power from PCA becomes lower and lower as optical pump saturates [23, 24], which principally sets an upper limit for the conversion efficiency of THz radiations. Thus, it is critical to find out a strategy of creating sufficient defects to reduce the carrier lifetime without affecting mobility detrimentally. High-energy and low-dosage ion-implantation has been verified to be an efficient method of creating proper profiles of defects, in order to obtain both excellent carrier acceleration at the shallow region and fast carrier trapping at the deep layer for THz generations [11, 25]. Also, hydrogen implantation is extensively used to separate high-power active devices (IGBT, laser diodes, LED, etc.) from their mother substrate and get superior performance of high frequency and high efficiency.
\nIn this work, the photoconductive antenna substrate was a commercial high-resistivity (5 × 107 Ω cm), liquid-encapsulated Czochralski-grown, (100)-oriented, semi-insulating (SI)-GaAs wafer. A 10/200 nm-thick Ti/Au metal layer stack was deposited on GaAs substrate by e-beam evaporation, functioning as metal electrodes for PCAs. The PCA has a bow-tie antenna structure with a photoconductive gap of 0.4 mm, 90° bow angle, and antenna length of 2 mm, as shown in Figure 1(a). Afterward, ion beam for hydrogen, helium, or oxygen was implanted into such SI GaAs PCAs with penetration depth of 2.5 μm and the acceleration energies are 300 keV, 800 keV, 3 MeV for H, He, O respectively. Implantation energies were selected so that the peak of ion concentration profile is situated deeper than the thickness of THz-relevant layer within SI-GaAs antenna, which is ∼2 μm. The implantation dosage varied from 1 × 1012 to 1 × 1015 cm−2, where lower dose and higher energies were used for heavier ions whereas higher dose and lower energies were suitable for lighter ions. The process details for all samples with different implantation conditions are shown in Table 1.
\n(a) Schematic structure for bow-tie photoconductive antenna (the inset is its photograph). (b) Cross-section of H-implanted GaAs PCAs with acceleration and trapping of photo carriers.
Implantation dose (cm−2) | \nImplantation energy | \nIon beam | \n
---|---|---|
1 × 1015 | \n300 KeV | \nHydrogen | \n
5 × 1014 | \n300 KeV | \nHydrogen | \n
1 × 1014 | \n300 KeV | \nHydrogen | \n
1 × 1013 | \n800 KeV | \nHelium | \n
5 × 1012 | \n800 KeV | \nHelium | \n
5 × 1012 | \n3 MeV | \nOxygen | \n
1 × 1012 | \n3 MeV | \nOxygen | \n
Process details for all samples with different implantation conditions.
As discussed in our previous work [25], 300 keV H implantation was an easily reproducible condition for fabricating SI-GaAs PCAs with ion penetration depth of 2.5 μm, effectively defining the active region for THz generations. The implantation dosage of H ions varied from 1 × 1014 to 1 × 1015 cm−2, to find out optimum conditions for ion-implanted GaAs PCAs. Density profiles of the generated defects and the implanted ions were optimized by the stopping and range of ions in matter (SRIM) program [26], and the peak distribution situates as deep as 2.5 μm distance from PCA surface. The defects concentration in shallow regions (<1 μm deep) are over three orders of magnitude lower than the peak concentration at 2.5 μm distance, where most photo carriers are generated under femtosecond laser excitation and accelerated at local electrical fields for THz generations. As carriers transit into defects-rich regions underneath the acceleration layer, they will be efficiently trapped and the carrier acceleration for THz generations is successfully separated from defects by implantation without obvious decrease of transient mobility in shallow regions. Moreover, the accumulation of photo carriers against the electrical bias was significantly suppressed, avoiding the screen effects by the pump laser (Figure 1(b)). Two more sets of samples fabricated on a bare SI-GaAs substrate and 1-μm-thick LT-GaAs grown on an SI-GaAs substrate (“LT-GaAs” hereafter) were prepared for reference.
\nAs shown in Figure 2, density profiles of the generated defects and the implanted ions were simulated with the stopping and range of ions in matter (SRIM) program [26]. The implantation conditions for H, He and O are 300 keV, 1 × 1015 cm−2; 800 keV, 1 × 1013 cm−2; and 3 MeV, 1 × 1012 cm−2 respectively. At such implantation energies, most ions for all three kinds of samples are implanted far below a surface layer of about 2.5 μm deep where most laser power is absorbed within 1 μm-deep distance and most terahertz power is generated within 2 μm-deep distance. The ion concentration in this region is over three orders of magnitude lower than the peak concentration, whereas the vacancy density profile for all ion beams (H, He, or O) is nearly the same within THz generation distance (∼2 μm below the surface). Another reason to use such implantation energies is to reduce the lifetime and therefore strongly reduce the density of photo carriers produced at a depth of ∼2 μm, which are not only useless for terahertz generation but also cause the saturation for optical pump.
\nIon implantation and corresponding vacancy profiles for samples with H dosage of 1 × 1015 cm−2, He dosage of 1 × 1013 cm−2, and O dosage of 1 × 1012 cm−2, calculated by Stopping and Range of Ions in Matter (SRIM), where a Monte-Carlo simulation of 5 × 105 ions was performed for hydrogen, helium, and oxygen. Also, the implantation angle of 7° was used to avoid possible channeling to the crystal axis.
Figure 3 shows the dark currents versus bias voltage (I-V) characteristics for H-implanted and SI-GaAs PCAs without light illumination, measured by a Keysight B1500A semiconductor device analyzer. Currents passing through the SI-GaAs sample quickly exceed the space-charge limited (SCL) electron flows at low voltage of ∼20 V, and then significantly increase by a polynomial V3 response dominated by a double carrier injection current, as demonstrated in Ref. [21]. It is observed that currents in SI-GaAs antenna under 140 V go up to 10 mA even without any light illumination. This means a considerable temperature increase in active region due to huge heat dissipations, which would affect the efficiency of SI-GaAs antenna and result in electrical breakdown of the device. On the contrary, H-implanted samples follow almost linear dependence of currents on bias voltages in broad range of over 100 V and did not show obvious currents increase of V3 response even as the bias voltages go up over 200 V. It can be seen that H ions in GaAs extend the linear range of currents dependence on voltages, compared to that for bare SI-GaAs samples. The carrier accumulation near the high electrical field region along anode is significantly suppressed by the corresponding trapping sites and the double carrier injection is eliminated effectively.
\nCurrent-voltage characteristics for SI-GaAs THz antenna and H-implanted one.
The setup for characterization of the THz waves is based on a conventional time-domain spectroscopy system (TDS) triggered by a femtosecond laser as shown in Figure 4. A mode-locked Ti: Sapphire laser generates 80 fs light pulses at a wavelength of ∼780 nm and a repetition rate of 80 MHz. The femtosecond pump pulses were focused by an objective lens with 10 μm-diameter illumination spot on the proximity of anode for a biased photoconductive antenna, which was mounted on the flat side of a Si hemispherical lens with a diameter of 15 mm. The emitted THz radiation was collimated and focused by two pairs of gold-coated off-axis parabolic mirrors onto a photoconductive sampling detector, which was also a photoconductive antenna with bow-tie shape and gap of 20 μm mounted on the back of a Si hemispherical lens with the same diameter. The photoconductive detector was gated by femtosecond probe beam pulses that were separated from the pump beam pulses by a beam splitter.
\nSchematic diagram of THz TDS setup used for measuring electric field of THz pulse.
\n\n
(a) Normalized THz pulses emitted from GaAs antennas of 1 × 1014, 5 × 1014, 1 × 1015 cm−2, SI-GaAs, and LT-GaAs. (b) Fast Fourier transformed spectra of THz signals for different GaAs emitters.
In order to interpret the THz radiation waveform, we analyze the THz radiation assuming that the emitted field \n
where the integration is taken over the whole device including carrier acceleration layer and carrier trapping layer (Figure 1(b)). The transient current depends on the free-carrier concentration \n
the contribution of the holes which have a much smaller mobility is neglected. We analyze the carrier transport based on a set of kinetic equations [27] which can be written as follows:
\nwhere \n
Based on this theoretical model, the main positive peak observed in the waveforms of Figure 5(a) is attributed to the rises of surge current by photo-carrier injection and the subsequent carrier acceleration under bias fields (tacc. in Figure 5(a)), while the second negative peak after the main peak is related to the decay of current governed by the carrier trapping (ttrap in Figure 5(a)). For the ion-implanted GaAs PCAs, we have to consider the carrier dynamics of acceleration process in shallow layer (<2 μm) and trapping process in the underneath layer (∼2.5 μm deep), as shown in Figure 1(b). After laser is absorbed within 1 μm depth, photo carriers are created accordingly and accelerated within 2 μm depth for efficient THz generations. The main peak distribution of implanted ions and related defects at ∼2.5 μm depth enables efficient carrier trapping and significantly reduce carrier concentration in the trapping layer (Figure 1(b)). If the pump pulse laser width (δt) is larger than the carrier momentum relaxation time (τm), and if the carrier lifetime (τc) is larger than the pump laser pulse width (τm < δt < τc), the carrier acceleration and resultant current rise are determined by the pump laser pulse width, which is related to tacc.. This is exactly the situation in the shallow laser absorption layer (1 μm deep) for ion-implanted GaAs PCAs; where the momentum relaxation time was estimated to be about 10 fs; the laser pulse width was 80 fs, and the carrier lifetime was over 10 ps (similar to lifetime in bare SI GaAs), respectively. Assuming the transition time for photo carriers from absorption region (1 μm) to the trapping layer (2.5 μm) is shorter than the carrier trapping time, the carrier trapping and corresponding current decay depends on peak concentrations of H ions and implantation-related defects at 2.5 μm depth; considering that carrier transition time is about 100 fs, and the carrier trapping time (ttrap) is estimated to be ∼0.8 ps for the sample H-5 × 1014 cm−2. In the progress of current rise dominated by laser pump, carrier acceleration should not be affected by implantation defects because the ion concentration in this region is several orders of magnitude lower than the peak concentration and the carrier mobility is able to keep very close to that in SI GaAs. However, the defects for LT-GaAs and the sample of H-1 × 1015 cm−2 have decreased the carrier mobility by scattering to some extent that the carrier acceleration turns slow when comparing with SI-GaAs in Figure 5(a), considering the momentum relaxation time (τm) may increase to be comparable with the laser pulse width (δt) and the current surge is affected accordingly. Meanwhile, the current decay is dominated by the trapping effect in the underneath THz generation layer. This structure will form vertical confinement for the distribution of photo carriers and block the carriers in SI GaAs substrate, which makes the trapping layer return the original insulating state after the fast carrier trapping. It is noted that the carrier trapping time (ttrap) for samples of H-5 × 1014 and H-1 × 1015 cm−2 is significantly shorter than that of H-1 × 1014 cm−2, LT-GaAs, and SI-GaAs samples because the latter did not have efficient structures for vertical confinement of photo carriers. Therefore, we conclude that this confinement structure for photoconductive antennas will relieve the screen effect caused by charges accumulation in photoconductive region and reduce the saturation effect by laser excitation.
\nIn Figure 6(a), we show variation of the peak of emitted THz field amplitude with the pump laser power for all samples measured under TDS in Figure 4. The bias voltage of 140 V was used. The SI-GaAs sample without H implantation became saturated as the pump laser power exceeded 30 mW, similar to the reports in Refs. [6, 7, 8, 9, 10]. Thermal breakdown of SI-GaAs emitters easily occurred as they are saturated by the pump laser and the bias voltage. Normally, SI-GaAs emitters are recommended to operate far enough away from the saturation status. Hydrogen-implanted GaAs emitter with dose of 1 × 1014 cm−2 showed relatively linear increase of THz amplitude as the pump laser power. We are able to get the maximum THz field 3.5 times bigger than that from SI-GaAs emitter but no obvious saturation is found at the laser power of over 60 mW. The H-5 × 1014 cm−2 sample provides the best performance that almost linear dependence of THz fields emitted on the pump laser power is demonstrated, and the maximum THz field we could obtain from H-5 × 1014 cm−2 sample is five times bigger than that from SI-GaAs emitter. It should be emphasized that the H-implanted GaAs with dose of 5 × 1014 cm−2 did not show any saturation property with the pump laser approaching 100 mW in the TDS measurement range and the bias voltage increasing up to 260 V. The sample of H-1 × 1015 cm−2 showed deteriorated mobility, and THz fields are smaller than those emitted from sample 1 × 1014 cm−2. Because point defects created by H implantation at lower dose of 1 × 1014–5 × 1014 cm−2 are more uniform and fewer, carrier mobility is kept to be very close to that of SI-GaAs with the carrier momentum relaxation time (τm) as short as 10 fs also. In the optimum operation conditions (i.e., 80 mW of the laser power and 260 V of the bias voltage for 5 × 1014 cm−2 sample versus 30 mW of the laser power and 140 V of the bias voltage for SI-GaAs), THz power emitted from the H-implanted sample was ∼100 times bigger than that of traditional SI-GaAs THz emitter.
\n(a) Peak THz field amplitude from GaAs emitters as a function of pump laser power under a bias voltage of 140 V. (b) Photocurrent-voltage (
Figure 6(b) presents the photocurrent as a function of the bias voltage (
To further confirm the mobility in the THz generation layer of ion-implanted PCAs is superior to that of LT-GaAs, Figure 7 relates the THz radiation power to photocurrents for all ion-implanted PCA samples for a constant laser power in a logarithmic scale. The relationships for all samples are curve-fitted to parallel lines with a slope of 2, indicating the quadratic dependence of the radiation power on the induced photocurrents by the pump laser, and the fact that operation conditions (laser alignment, output THz coupling efficiency, antenna structure, etc.) are the same for all PCAs. The ion-implanted GaAs antennas for H-1 × 1014, H-1 × 1015, and O 1 × 1012 cm−2 generated stronger THz radiation than LT-GaAs PCAs under the excitation of constant laser power 200 mW, however the DC photocurrents are reduced by about 100 times. This enhancement for THz generation may mainly be attributed to the better quality of photoconductive GaAs with higher mobility than that of LT-GaAs since the conversion efficiency is proportional to the carrier mobility, while the carrier concentration is tightly confined by deep trapping layer at ∼2.5 μm-distance in ion-implanted PCAs.
\nThe terahertz power as a function of the photocurrent is represented for ion-implanted GaAs PCAs.
In order to further interpret the THz radiation power and the optical-to-THz conversion efficiency for GaAs PCAs, we deduced the theoretical model accordingly for photoconductive antennas.
\nAccording to the Ref. [28], transient photocurrent under fs laser excitations can be written as below Eq. (5).
\nwhere \n
Meanwhile, the transient resistance under laser excitations can be approximately formulated as Eq. (6) [15].
\nwhere \n
Therefore, using Eqs. (5) and (6), we can obtain the expression for the electric power generated between the photoconductive gap, subjected to the pump laser power \n
where \n
As seen from Eq. (8), the optical-to-THz conversion efficiency is directly proportional to the square of the bias voltage \n
According to [28] and the references wherein, the saturation behavior of THz radiation amplitude \n
where \n
Eq. (10) shows that the saturation behavior for PC antennas will easily take place when the carrier mobility of the photoconductive material is high, and \n
In summary, the GaAs PCAs’ saturation effect for the excitation of pump laser is efficiently reduced by hydrogen implantation, due to the vertical confinement of photo carriers in H-implanted emitters. THz emitter implanted by H ions of 300 keV and 5 × 1014 cm−2 has both excellent mobility and short enough carrier lifetime. Thus, the optical-to-THz conversion efficiency is improved 16 times and the electrical-to-THz conversion efficiency is 1600 times compared to conventional GaAs emitters. Electrically robust H-implanted GaAs PCA is able to operate from ∼80 to >260 V without any thermal breakdown. The emitted THz power from H-implanted GaAs antenna is more than two order of magnitude stronger than that from traditional GaAs emitter.
\nThis work was supported by the National Natural Science Foundation of China (Grant No. U1613223). The authors acknowledge Ms. Ho Lai Ching, a staff member at the Department of Electronic Engineering, the Chinese University of Hong Kong, Hong Kong, China, for her assistance in equipment maintenance.
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After introducing the link between PSE and parental competence, the role of PSE on parenting quality, its multiple influences, and transactional effects connected to contextual or cultural variables are discussed. The chapter addresses some key issues: (a) the levels of PSE measurement (i.e., domain- or task-specific approach), their interrelationship and magnitude as mutual predictors (study 1); (b) infant-caring, parent’s adjustment, and PSE development in the transition to parenthood (study 2); (c) parenting difficult children and the role of PSE as a “buffer” variable moderating the effects of negative child’s characteristics on parenting skills; and (d) PSE beliefs in family context, the relationships with other family measures (marital self-efficacy and stress), and their associations with children’s adjustments (study 3). Finally, in the study 4, PSE is presented as an outcome variable in a parent training. In all summarized studies, a special attention was devoted to father’s PSE as a specific factor affecting childrearing and parent’s well-being. As Bandura says, PSE is not a personality trait, but a learnable set of beliefs producing positive effects on parenting quality. Suggestions for family-based interventions enhancing PSE are discussed.",book:{id:"5605",slug:"parenting-empirical-advances-and-intervention-resources",title:"Parenting",fullTitle:"Parenting - Empirical Advances and Intervention Resources"},signatures:"Loredana Benedetto and Massimo Ingrassia",authors:[{id:"193200",title:"Prof.",name:"Loredana",middleName:null,surname:"Benedetto",slug:"loredana-benedetto",fullName:"Loredana Benedetto"},{id:"193901",title:"Prof.",name:"Massimo",middleName:null,surname:"Ingrassia",slug:"massimo-ingrassia",fullName:"Massimo Ingrassia"}]},{id:"53767",doi:"10.5772/66985",title:"Parenting Practices and the Development of Internalizing/ Externalizing Problems in Adolescence",slug:"parenting-practices-and-the-development-of-internalizing-externalizing-problems-in-adolescence",totalDownloads:1708,totalCrossrefCites:5,totalDimensionsCites:8,abstract:"This chapter examines the existing relationship between different types of parental practices and the development of internalizing and externalizing behavioral problems in adolescence. Parental involvement and parenting styles are defined and analyzed as possible parameters of adolescent problems, including bullying and victimization. Special emphasis is given to the distinction between behavioral and psychological parental control. Furthermore, issues such as parent‐adolescent conflict, locus of control, and parental values are discussed as correlates of these problems, since prior research has identified them as either risk or protective factors for child and adolescent social and emotional adaptation.",book:{id:"5605",slug:"parenting-empirical-advances-and-intervention-resources",title:"Parenting",fullTitle:"Parenting - Empirical Advances and Intervention Resources"},signatures:"Stelios N. Georgiou and Maria Symeou",authors:[{id:"193345",title:"Prof.",name:"Stelios",middleName:null,surname:"Georgiou",slug:"stelios-georgiou",fullName:"Stelios Georgiou"},{id:"197682",title:"Dr.",name:"Maria",middleName:null,surname:"Symeou",slug:"maria-symeou",fullName:"Maria Symeou"}]},{id:"67167",doi:"10.5772/intechopen.86517",title:"Aligning Human Resource Management with Knowledge Management for Better Organizational Performance: How Human Resource Practices Support Knowledge Management Strategies?",slug:"aligning-human-resource-management-with-knowledge-management-for-better-organizational-performance-h",totalDownloads:1961,totalCrossrefCites:6,totalDimensionsCites:7,abstract:"Contributing to the HR-approach to knowledge management (KM), this chapter aims at outlining the role of human resource management (HRM) in supporting KM through utilizing the theoretical and empirical literature. The article is divided into two sections. The first section presents various knowledge concepts, KM perspectives and KM strategies. This section ends up by linking these topics in a KM sequential model which helps us to track the philosophical underpinnings and perspectives of each KM strategy. The second section investigates various HR orientations and HR practices and situates their differing contextual characteristics under each KM strategy. It aligns various HR practices with different KM strategies; suggesting that HRM is most effective as a combination of practices that are consistent and sharpened in supporting each KM strategy, which is part of the organizational strategy. The debated practices are recruitment and selection, compensation management, training and development, performance management, retention management and career management. Each of those practices is speculated to alter based on the chosen KM strategy; presenting a framework that is useful for practitioners and academics alike. The review ends up by identifying some research gaps and opportunities to be carried out in future studies. Those research gaps, if addressed, will extend our understanding of KM and the supporting role HRM.",book:{id:"7808",slug:"current-issues-in-knowledge-management",title:"Current Issues in Knowledge Management",fullTitle:"Current Issues in Knowledge Management"},signatures:"Hadi El-Farr and Rezvan Hosseingholizadeh",authors:[{id:"293827",title:"Dr.",name:"Hadi",middleName:null,surname:"El-Farr",slug:"hadi-el-farr",fullName:"Hadi El-Farr"},{id:"293834",title:"Dr.",name:"Rezvan",middleName:null,surname:"Hosseingholizadeh",slug:"rezvan-hosseingholizadeh",fullName:"Rezvan Hosseingholizadeh"}]},{id:"59135",doi:"10.5772/intechopen.73540",title:"The Relationship between Parenting and Internalizing Problems in Childhood",slug:"the-relationship-between-parenting-and-internalizing-problems-in-childhood",totalDownloads:1478,totalCrossrefCites:2,totalDimensionsCites:5,abstract:"Several types of stress factors are likely to be implied in the development, maintenance, and transmission of internalizing symptomatology: genetic/temperamental factors, cognitive factors, family factors, and societal/cultural factors. Nonetheless, family factors—especially those related to parenting—seem to be crucial during childhood, because children are nested within their families and family factors are able to indirectly influence other factors as well. The current chapter focuses on the relationship between parental style and internalizing symptoms in childhood. In the first part of the chapter, the most important studies on the topic are reviewed in detail and differences in parenting behaviors between mothers and fathers are illustrated. A discussion on the cognitive and metacognitive factors as possible pathways of the relation between parenting and childhood symptoms is also proposed. The last part of the chapter reviews studies investigating the efficacy of parental involvement in cognitive behavior therapy for children who exhibit internalizing symptoms.",book:{id:"5605",slug:"parenting-empirical-advances-and-intervention-resources",title:"Parenting",fullTitle:"Parenting - Empirical Advances and Intervention Resources"},signatures:"Simona Scaini, Sara Palmieri and Marcella Caputi",authors:[{id:"240074",title:"Dr.",name:"Simona",middleName:null,surname:"Scaini",slug:"simona-scaini",fullName:"Simona Scaini"},{id:"240906",title:"Dr.",name:"Marcella",middleName:null,surname:"Caputi",slug:"marcella-caputi",fullName:"Marcella Caputi"}]},{id:"67575",doi:"10.5772/intechopen.86757",title:"Toward Management Based on Knowledge",slug:"toward-management-based-on-knowledge",totalDownloads:1128,totalCrossrefCites:3,totalDimensionsCites:3,abstract:"In a world overwhelmed with pervasive digital technologies, the organization is transformed and becomes a socio-technical system which is constantly renewed. Organization needs specific skills, adapted to the values and to the cultures peculiar to each location. The cooperation and the mobility become a shape of inescapable work which rests on a permanent personal and collective learning. Beyond the information handled in the digital information systems, the role of the tacit knowledge, which is in each individual’s head, cannot be ignored. A constructivist attitude replaces a determinist attitude strongly deep-rooted in our educational modes. The managers have to pass from a posture of authority and of control to a posture of incitation, of support, and of accompaniment. The notions that are introduced in this chapter result from a managerial and socio-technical vision of knowledge management. They arouse essential reflections to develop a mode of management adapted to the digital transformation of the organizations called management based on knowledge.",book:{id:"7808",slug:"current-issues-in-knowledge-management",title:"Current Issues in Knowledge Management",fullTitle:"Current Issues in Knowledge Management"},signatures:"Michel Grundstein",authors:[{id:"292425",title:"Mr.",name:"Michel",middleName:null,surname:"Grundstein",slug:"michel-grundstein",fullName:"Michel Grundstein"}]}],mostDownloadedChaptersLast30Days:[{id:"55633",title:"Parental Self-efficacy in Promoting Children Care and Parenting Quality",slug:"parental-self-efficacy-in-promoting-children-care-and-parenting-quality",totalDownloads:2099,totalCrossrefCites:9,totalDimensionsCites:13,abstract:"Parental self-efficacy (PSE) emerges as a crucial variable into exploring variability in parenting quality. After introducing the link between PSE and parental competence, the role of PSE on parenting quality, its multiple influences, and transactional effects connected to contextual or cultural variables are discussed. The chapter addresses some key issues: (a) the levels of PSE measurement (i.e., domain- or task-specific approach), their interrelationship and magnitude as mutual predictors (study 1); (b) infant-caring, parent’s adjustment, and PSE development in the transition to parenthood (study 2); (c) parenting difficult children and the role of PSE as a “buffer” variable moderating the effects of negative child’s characteristics on parenting skills; and (d) PSE beliefs in family context, the relationships with other family measures (marital self-efficacy and stress), and their associations with children’s adjustments (study 3). Finally, in the study 4, PSE is presented as an outcome variable in a parent training. In all summarized studies, a special attention was devoted to father’s PSE as a specific factor affecting childrearing and parent’s well-being. As Bandura says, PSE is not a personality trait, but a learnable set of beliefs producing positive effects on parenting quality. Suggestions for family-based interventions enhancing PSE are discussed.",book:{id:"5605",slug:"parenting-empirical-advances-and-intervention-resources",title:"Parenting",fullTitle:"Parenting - Empirical Advances and Intervention Resources"},signatures:"Loredana Benedetto and Massimo Ingrassia",authors:[{id:"193200",title:"Prof.",name:"Loredana",middleName:null,surname:"Benedetto",slug:"loredana-benedetto",fullName:"Loredana Benedetto"},{id:"193901",title:"Prof.",name:"Massimo",middleName:null,surname:"Ingrassia",slug:"massimo-ingrassia",fullName:"Massimo Ingrassia"}]},{id:"67528",title:"The Management, Sharing and Transfer of Knowledge in the Oil Districts - The Case Study of An Italian District",slug:"the-management-sharing-and-transfer-of-knowledge-in-the-oil-districts-the-case-study-of-an-italian-d",totalDownloads:1172,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"Knowledge management is one of the most innovative and effective tools available to companies to manage an economic and organizational ever-changing environment. The chapter is based on an empirical study starting from the classification of oil district and aims to understand how firms’ position affect knowledge transfer process within the district. We support the idea that knowledge transfer is deeply affected by firms’ contractual power as well as by their position within the district. The companies of the industrial districts have the advantage of exploiting and sharing knowledge with each other. The literature generally holds that knowledge transfer requires a sense of equality and fairness among the firms, to create conditions in which firms will share their own knowledge for joint competitive advantage. However, empirical evidence shows that the value chains are often characterized by hierarchical relations and asymmetry between the parties: this feature is particularly evident in the oil districts. For companies attempting to acquire new information, the typologies of their intercompany collaboration and their cultural relationships are crucial.",book:{id:"7808",slug:"current-issues-in-knowledge-management",title:"Current Issues in Knowledge Management",fullTitle:"Current Issues in Knowledge Management"},signatures:"Giovanna Testa",authors:[{id:"293404",title:"Dr.",name:"Giovanna",middleName:null,surname:"Testa",slug:"giovanna-testa",fullName:"Giovanna Testa"}]},{id:"67167",title:"Aligning Human Resource Management with Knowledge Management for Better Organizational Performance: How Human Resource Practices Support Knowledge Management Strategies?",slug:"aligning-human-resource-management-with-knowledge-management-for-better-organizational-performance-h",totalDownloads:1961,totalCrossrefCites:6,totalDimensionsCites:7,abstract:"Contributing to the HR-approach to knowledge management (KM), this chapter aims at outlining the role of human resource management (HRM) in supporting KM through utilizing the theoretical and empirical literature. The article is divided into two sections. The first section presents various knowledge concepts, KM perspectives and KM strategies. This section ends up by linking these topics in a KM sequential model which helps us to track the philosophical underpinnings and perspectives of each KM strategy. The second section investigates various HR orientations and HR practices and situates their differing contextual characteristics under each KM strategy. It aligns various HR practices with different KM strategies; suggesting that HRM is most effective as a combination of practices that are consistent and sharpened in supporting each KM strategy, which is part of the organizational strategy. The debated practices are recruitment and selection, compensation management, training and development, performance management, retention management and career management. Each of those practices is speculated to alter based on the chosen KM strategy; presenting a framework that is useful for practitioners and academics alike. The review ends up by identifying some research gaps and opportunities to be carried out in future studies. Those research gaps, if addressed, will extend our understanding of KM and the supporting role HRM.",book:{id:"7808",slug:"current-issues-in-knowledge-management",title:"Current Issues in Knowledge Management",fullTitle:"Current Issues in Knowledge Management"},signatures:"Hadi El-Farr and Rezvan Hosseingholizadeh",authors:[{id:"293827",title:"Dr.",name:"Hadi",middleName:null,surname:"El-Farr",slug:"hadi-el-farr",fullName:"Hadi El-Farr"},{id:"293834",title:"Dr.",name:"Rezvan",middleName:null,surname:"Hosseingholizadeh",slug:"rezvan-hosseingholizadeh",fullName:"Rezvan Hosseingholizadeh"}]},{id:"53767",title:"Parenting Practices and the Development of Internalizing/ Externalizing Problems in Adolescence",slug:"parenting-practices-and-the-development-of-internalizing-externalizing-problems-in-adolescence",totalDownloads:1708,totalCrossrefCites:5,totalDimensionsCites:8,abstract:"This chapter examines the existing relationship between different types of parental practices and the development of internalizing and externalizing behavioral problems in adolescence. Parental involvement and parenting styles are defined and analyzed as possible parameters of adolescent problems, including bullying and victimization. Special emphasis is given to the distinction between behavioral and psychological parental control. Furthermore, issues such as parent‐adolescent conflict, locus of control, and parental values are discussed as correlates of these problems, since prior research has identified them as either risk or protective factors for child and adolescent social and emotional adaptation.",book:{id:"5605",slug:"parenting-empirical-advances-and-intervention-resources",title:"Parenting",fullTitle:"Parenting - Empirical Advances and Intervention Resources"},signatures:"Stelios N. Georgiou and Maria Symeou",authors:[{id:"193345",title:"Prof.",name:"Stelios",middleName:null,surname:"Georgiou",slug:"stelios-georgiou",fullName:"Stelios Georgiou"},{id:"197682",title:"Dr.",name:"Maria",middleName:null,surname:"Symeou",slug:"maria-symeou",fullName:"Maria Symeou"}]},{id:"59028",title:"Parent Training Interventions for Children and Adolescents with Aggressive Behavioral Problems",slug:"parent-training-interventions-for-children-and-adolescents-with-aggressive-behavioral-problems",totalDownloads:1630,totalCrossrefCites:0,totalDimensionsCites:2,abstract:"Children who display early disruptive and aggressive behavior are also at greater risk for delinquency, mood and anxiety disorders, and substance use in the long term. As is the case for many forms of childhood psychopathology, a number of factors are associated with the emergence of aggressive and disruptive behavior, including family factors. Indeed, conduct problems during childhood are usually associated with peculiar parenting practices, such as increasingly coercive cycles of harsh parenting and noncompliance exhibited by child; insensitive and nonresponsive parenting; inconsistent, severe discipline and vague commands and directions; lack of parental warmth and involvement; and absence of parental monitoring and supervision. That is why behavioral parent trainings (BPTs) represent one of the gold standard interventions for conduct problems. The main goal of BPT is to decrease coercive interchanges and, consequently, children aggressive problems by teaching parents strategies in order to apply a more effective discipline. Therefore, the putative mechanism for change in youth behavior in BPT is change in parent behavior. Some of the most employed parent training interventions for aggressive behavior problems are presented.",book:{id:"5605",slug:"parenting-empirical-advances-and-intervention-resources",title:"Parenting",fullTitle:"Parenting - Empirical Advances and Intervention Resources"},signatures:"Pietro Muratori, Valentina Levantini, Azzurra Manfredi, Laura\nRuglioni and Furio Lambruschi",authors:[{id:"238556",title:"Dr.",name:"Pietro",middleName:null,surname:"Muratori",slug:"pietro-muratori",fullName:"Pietro Muratori"}]}],onlineFirstChaptersFilter:{topicId:"1388",limit:6,offset:0},onlineFirstChaptersCollection:[],onlineFirstChaptersTotal:0},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:0,limit:8,total:null},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:9,numberOfPublishedChapters:89,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:31,numberOfPublishedChapters:314,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:11,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:129,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:105,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:2,numberOfUpcomingTopics:1,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:14,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. The whole process of submitting an article and editing of the submitted article goes extremely smooth and fast, the number of reads and downloads of chapters is high, and the contributions are also frequently cited.",author:{id:"55578",name:"Antonio",surname:"Jurado-Navas",institutionString:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRisIQAS/Profile_Picture_1626166543950",slug:"antonio-jurado-navas",institution:{id:"720",name:"University of Malaga",country:{id:null,name:"Spain"}}}}]},series:{item:{id:"11",title:"Biochemistry",doi:"10.5772/intechopen.72877",issn:"2632-0983",scope:"Biochemistry, the study of chemical transformations occurring within living organisms, impacts all areas of life sciences, from molecular crystallography and genetics to ecology, medicine, and population biology. Biochemistry examines macromolecules - proteins, nucleic acids, carbohydrates, and lipids – and their building blocks, structures, functions, and interactions. 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. He has published more than 100 peer-reviewed research articles and graduated numerous Ph.D. and postdoctoral students.",institutionString:null,institution:{name:"New York University Langone Medical Center",institutionURL:null,country:{name:"United States of America"}}},editorTwo:null,editorThree:null},subseries:{paginationCount:4,paginationItems:[{id:"14",title:"Cell and Molecular Biology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/14.jpg",isOpenForSubmission:!0,annualVolume:11410,editor:{id:"165627",title:"Dr.",name:"Rosa María",middleName:null,surname:"Martínez-Espinosa",slug:"rosa-maria-martinez-espinosa",fullName:"Rosa María Martínez-Espinosa",profilePictureURL:"https://mts.intechopen.com/storage/users/165627/images/system/165627.jpeg",biography:"Dr. Rosa María Martínez-Espinosa has been a Spanish Full Professor since 2020 (Biochemistry and Molecular Biology) and is currently Vice-President of International Relations and Cooperation development and leader of the research group 'Applied Biochemistry” (University of Alicante, Spain). Other positions she has held at the university include Vice-Dean of Master Programs, Vice-Dean of the Degree in Biology and Vice-Dean for Mobility and Enterprise and Engagement at the Faculty of Science (University of Alicante). She received her Bachelor in Biology in 1998 (University of Alicante) and her PhD in 2003 (Biochemistry, University of Alicante). She undertook post-doctoral research at the University of East Anglia (Norwich, U.K. 2004-2005; 2007-2008).\nHer multidisciplinary research focuses on investigating archaea and their potential applications in biotechnology. She has an H-index of 21. She has authored one patent and has published more than 70 indexed papers and around 60 book chapters.\nShe has contributed to more than 150 national and international meetings during the last 15 years. Her research interests include archaea metabolism, enzymes purification and characterization, gene regulation, carotenoids and bioplastics production, antioxidant\ncompounds, waste water treatments, and brines bioremediation.\nRosa María’s other roles include editorial board member for several journals related\nto biochemistry, reviewer for more than 60 journals (biochemistry, molecular biology, biotechnology, chemistry and microbiology) and president of several organizing committees in international meetings related to the N-cycle or respiratory processes.",institutionString:null,institution:{name:"University of Alicante",institutionURL:null,country:{name:"Spain"}}},editorTwo:null,editorThree:null},{id:"15",title:"Chemical Biology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/15.jpg",isOpenForSubmission:!0,annualVolume:11411,editor:{id:"441442",title:"Dr.",name:"Şükrü",middleName:null,surname:"Beydemir",slug:"sukru-beydemir",fullName:"Şükrü Beydemir",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00003GsUoIQAV/Profile_Picture_1634557147521",biography:"Dr. Şükrü Beydemir obtained a BSc in Chemistry in 1995 from Yüzüncü Yıl University, MSc in Biochemistry in 1998, and PhD in Biochemistry in 2002 from Atatürk University, Turkey. He performed post-doctoral studies at Max-Planck Institute, Germany, and University of Florence, Italy in addition to making several scientific visits abroad. He currently works as a Full Professor of Biochemistry in the Faculty of Pharmacy, Anadolu University, Turkey. Dr. Beydemir has published over a hundred scientific papers spanning protein biochemistry, enzymology and medicinal chemistry, reviews, book chapters and presented several conferences to scientists worldwide. He has received numerous publication awards from various international scientific councils. He serves in the Editorial Board of several international journals. Dr. Beydemir is also Rector of Bilecik Şeyh Edebali University, Turkey.",institutionString:null,institution:{name:"Anadolu University",institutionURL:null,country:{name:"Turkey"}}},editorTwo:{id:"13652",title:"Prof.",name:"Deniz",middleName:null,surname:"Ekinci",slug:"deniz-ekinci",fullName:"Deniz Ekinci",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYLT1QAO/Profile_Picture_1634557223079",biography:"Dr. Deniz Ekinci obtained a BSc in Chemistry in 2004, MSc in Biochemistry in 2006, and PhD in Biochemistry in 2009 from Atatürk University, Turkey. He studied at Stetson University, USA, in 2007-2008 and at the Max Planck Institute of Molecular Cell Biology and Genetics, Germany, in 2009-2010. Dr. Ekinci currently works as a Full Professor of Biochemistry in the Faculty of Agriculture and is the Head of the Enzyme and Microbial Biotechnology Division, Ondokuz Mayıs University, Turkey. He is a member of the Turkish Biochemical Society, American Chemical Society, and German Genetics society. Dr. Ekinci published around ninety scientific papers, reviews and book chapters, and presented several conferences to scientists. He has received numerous publication awards from several scientific councils. Dr. Ekinci serves as the Editor in Chief of four international books and is involved in the Editorial Board of several international journals.",institutionString:null,institution:{name:"Ondokuz Mayıs University",institutionURL:null,country:{name:"Turkey"}}},editorThree:null},{id:"17",title:"Metabolism",coverUrl:"https://cdn.intechopen.com/series_topics/covers/17.jpg",isOpenForSubmission:!0,annualVolume:11413,editor:{id:"138626",title:"Dr.",name:"Yannis",middleName:null,surname:"Karamanos",slug:"yannis-karamanos",fullName:"Yannis Karamanos",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002g6Jv2QAE/Profile_Picture_1629356660984",biography:"Yannis Karamanos, born in Greece in 1953, completed his pre-graduate studies at the Université Pierre et Marie Curie, Paris, then his Masters and Doctoral degree at the Université de Lille (1983). He was associate professor at the University of Limoges (1987) before becoming full professor of biochemistry at the Université d’Artois (1996). He worked on the structure-function relationships of glycoconjugates and his main project was the investigations on the biological roles of the de-N-glycosylation enzymes (Endo-N-acetyl-β-D-glucosaminidase and peptide-N4-(N-acetyl-β-glucosaminyl) asparagine amidase). From 2002 he contributes to the understanding of the Blood-brain barrier functioning using proteomics approaches. He has published more than 70 papers. 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In 1985, Prof. Iadarola became Associate Professor at the Department of Biology and Biotechnologies of the University of Pavia and retired in October 2017. Since then, he has been working as an Adjunct Professor in the same Department at the University of Pavia. His research activity during the first years was primarily focused on the purification and structural characterization of enzymes from animal and plant sources. During this period, Prof. Iadarola familiarized himself with the conventional techniques used in column chromatography, spectrophotometry, manual Edman degradation, and electrophoresis). Since 1995, he has been working on: i) the determination in biological fluids (serum, urine, bronchoalveolar lavage, sputum) of proteolytic activities involved in the degradation processes of connective tissue matrix, and ii) on the identification of biological markers of lung diseases. In this context, he has developed and validated new methodologies (e.g., Capillary Electrophoresis coupled to Laser-Induced Fluorescence, CE-LIF) whose application enabled him to determine both the amounts of biochemical markers (Desmosines) in urine/serum of patients affected by Chronic Obstructive Pulmonary Disease (COPD) and the activity of proteolytic enzymes (Human Neutrophil Elastase, Cathepsin G, Pseudomonas aeruginosa elastase) in sputa of these patients. More recently, Prof. Iadarola was involved in developing techniques such as two-dimensional electrophoresis coupled to liquid chromatography/mass spectrometry (2DE-LC/MS) for the proteomic analysis of biological fluids aimed at the identification of potential biomarkers of different lung diseases. He is the author of about 150 publications (According to Scopus: H-Index: 23; Total citations: 1568- According to WOS: H-Index: 20; Total Citations: 1296) of peer-reviewed international journals. He is a Consultant Reviewer for several journals, including the Journal of Chromatography A, Journal of Chromatography B, Plos ONE, Proteomes, International Journal of Molecular Science, Biotech, Electrophoresis, and others. He is also Associate Editor of Biotech.",institutionString:null,institution:{name:"University of Pavia",institutionURL:null,country:{name:"Italy"}}},editorTwo:{id:"201414",title:"Dr.",name:"Simona",middleName:null,surname:"Viglio",slug:"simona-viglio",fullName:"Simona Viglio",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRKDHQA4/Profile_Picture_1630402531487",biography:"Simona Viglio is an Associate Professor of Biochemistry at the Department of Molecular Medicine at the University of Pavia. She has been working since 1995 on the determination of proteolytic enzymes involved in the degradation process of connective tissue matrix and on the identification of biological markers of lung diseases. She gained considerable experience in developing and validating new methodologies whose applications allowed her to determine both the amount of biomarkers (Desmosine and Isodesmosine) in the urine of patients affected by COPD, and the activity of proteolytic enzymes (HNE, Cathepsin G, Pseudomonas aeruginosa elastase) in the sputa of these patients. Simona Viglio was also involved in research dealing with the supplementation of amino acids in patients with brain injury and chronic heart failure. She is presently engaged in the development of 2-DE and LC-MS techniques for the study of proteomics in biological fluids. The aim of this research is the identification of potential biomarkers of lung diseases. 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He received his Ph.D. in Environmental Analytical Chemistry from Assiut University, Egypt, in 1989. His research interest is in analytical and environmental chemistry with special emphasis on: (1) monitoring and assessing biological trace elements and toxic metals in human blood, urine, water, crops, vegetables, and medicinal plants; (2) relationships between environmental heavy metals and human diseases; (3) uses of biological indicators for monitoring water pollution; (4) environmental chemistry of lakes, rivers, and well water; (5) water and wastewater treatment by adsorption and photocatalysis techniques; (6) soil and water pollution monitoring, control, and treatment; and (7) advanced oxidation treatment. Prof. Rashed has supervised several MSc and Ph.D. theses in the field of analytical and environmental chemistry. He served as an examiner for several Ph.D. theses in analytical chemistry in India, Kazakhstan, and Botswana. He has published about ninety scientific papers in peer-reviewed international journals and several papers in national and international conferences. He participated as an invited speaker at thirty international conferences. Prof. Rashed is the editor-in-chief and an editorial board member for several international journals in the fields of chemistry and environment. He is a member of several national and international societies. He received the Egyptian State Award for Environmental Research in 2001 and the Aswan University Merit Award for Basic Science in 2020. 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She is now a lecturer at the University of Witwatersrand, South Africa, and a principal researcher at the Health Economics and Epidemiology Research Office (HE2RO), South Africa. Dr. Moolla holds a Ph.D. in Psychology with her research being focused on mental health and resilience. In her professional work capacity, her research has further expanded into the fields of early childhood development, mental health, the HIV and TB care cascades, as well as COVID. She is also a UNESCO-trained International Bioethics Facilitator.",institutionString:"University of the Witwatersrand",institution:{name:"University of the Witwatersrand",country:{name:"South Africa"}}},{id:"342152",title:"Dr.",name:"Santo",middleName:null,surname:"Grace Umesh",slug:"santo-grace-umesh",fullName:"Santo Grace Umesh",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/342152/images/16311_n.jpg",biography:null,institutionString:null,institution:{name:"SRM Dental College",country:{name:"India"}}},{id:"333647",title:"Dr.",name:"Shreya",middleName:null,surname:"Kishore",slug:"shreya-kishore",fullName:"Shreya Kishore",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/333647/images/14701_n.jpg",biography:"Dr. Shreya Kishore completed her Bachelor in Dental Surgery in Chettinad Dental College and Research Institute, Chennai, and her Master of Dental Surgery (Orthodontics) in Saveetha Dental College, Chennai. She is also Invisalign certified. She’s working as a Senior Lecturer in the Department of Orthodontics, SRM Dental College since November 2019. She is actively involved in teaching orthodontics to the undergraduates and the postgraduates. Her clinical research topics include new orthodontic brackets, fixed appliances and TADs. She’s published 4 articles in well renowned indexed journals and has a published patency of her own. Her private practice is currently limited to orthodontics and works as a consultant in various clinics.",institutionString:null,institution:{name:"SRM Dental College",country:{name:"India"}}},{id:"323731",title:"Prof.",name:"Deepak M.",middleName:"Macchindra",surname:"Vikhe",slug:"deepak-m.-vikhe",fullName:"Deepak M. Vikhe",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/323731/images/13613_n.jpg",biography:"Dr Deepak M.Vikhe .\n\n\t\n\tDr Deepak M.Vikhe , completed his Masters & PhD in Prosthodontics from Rural Dental College, Loni securing third rank in the Pravara Institute of Medical Sciences Deemed University. He was awarded Dr.G.C.DAS Memorial Award for Research on Implants at 39th IPS conference Dubai (U A E).He has two patents under his name. He has received Dr.Saraswati medal award for best research for implant study in 2017.He has received Fully funded scholarship to Spain ,university of Santiago de Compostela. He has completed fellowship in Implantlogy from Noble Biocare. \nHe has attended various conferences and CDE programmes and has national publications to his credit. His field of interest is in Implant supported prosthesis. Presently he is working as a associate professor in the Dept of Prosthodontics, Rural Dental College, Loni and maintains a successful private practice specialising in Implantology at Rahata.\n\nEmail: drdeepak_mvikhe@yahoo.com..................",institutionString:null,institution:{name:"Pravara Institute of Medical Sciences",country:{name:"India"}}},{id:"204110",title:"Dr.",name:"Ahmed A.",middleName:null,surname:"Madfa",slug:"ahmed-a.-madfa",fullName:"Ahmed A. Madfa",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/204110/images/system/204110.jpg",biography:"Dr. Madfa is currently Associate Professor of Endodontics at Thamar University and a visiting lecturer at Sana'a University and University of Sciences and Technology. He has more than 6 years of experience in teaching. His research interests include root canal morphology, functionally graded concept, dental biomaterials, epidemiology and dental education, biomimetic restoration, finite element analysis and endodontic regeneration. Dr. Madfa has numerous international publications, full articles, two patents, a book and a book chapter. Furthermore, he won 14 international scientific awards. Furthermore, he is involved in many academic activities ranging from editorial board member, reviewer for many international journals and postgraduate students' supervisor. Besides, I deliver many courses and training workshops at various scientific events. Dr. Madfa also regularly attends international conferences and holds administrative positions (Deputy Dean of the Faculty for Students’ & Academic Affairs and Deputy Head of Research Unit).",institutionString:"Thamar University",institution:null},{id:"210472",title:"Dr.",name:"Nermin",middleName:"Mohammed Ahmed",surname:"Yussif",slug:"nermin-yussif",fullName:"Nermin Yussif",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/210472/images/system/210472.jpg",biography:"Dr. Nermin Mohammed Ahmed Yussif is working at the Faculty of dentistry, University for October university for modern sciences and arts (MSA). Her areas of expertise include: periodontology, dental laserology, oral implantology, periodontal plastic surgeries, oral mesotherapy, nutrition, dental pharmacology. She is an editor and reviewer in numerous international journals.",institutionString:"MSA University",institution:null},{id:"204606",title:"Dr.",name:"Serdar",middleName:null,surname:"Gözler",slug:"serdar-gozler",fullName:"Serdar Gözler",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/204606/images/system/204606.jpeg",biography:"Dr. Serdar Gözler has completed his undergraduate studies at the Marmara University Faculty of Dentistry in 1978, followed by an assistantship in the Prosthesis Department of Dicle University Faculty of Dentistry. Starting his PhD work on non-resilient overdentures with Assoc. Prof. Hüsnü Yavuzyılmaz, he continued his studies with Prof. Dr. Gürbüz Öztürk of Istanbul University Faculty of Dentistry Department of Prosthodontics, this time on Gnatology. He attended training programs on occlusion, neurology, neurophysiology, EMG, radiology and biostatistics. In 1982, he presented his PhD thesis \\Gerber and Lauritzen Occlusion Analysis Techniques: Diagnosis Values,\\ at Istanbul University School of Dentistry, Department of Prosthodontics. As he was also working with Prof. Senih Çalıkkocaoğlu on The Physiology of Chewing at the same time, Gözler has written a chapter in Çalıkkocaoğlu\\'s book \\Complete Prostheses\\ entitled \\The Place of Neuromuscular Mechanism in Prosthetic Dentistry.\\ The book was published five times since by the Istanbul University Publications. Having presented in various conferences about occlusion analysis until 1998, Dr. Gözler has also decided to use the T-Scan II occlusion analysis method. Having been personally trained by Dr. Robert Kerstein on this method, Dr. Gözler has been lecturing on the T-Scan Occlusion Analysis Method in conferences both in Turkey and abroad. Dr. Gözler has various articles and presentations on Digital Occlusion Analysis methods. He is now Head of the TMD Clinic at Prosthodontic Department of Faculty of Dentistry , Istanbul Aydın University , Turkey.",institutionString:"Istanbul Aydin University",institution:{name:"Istanbul Aydın University",country:{name:"Turkey"}}},{id:"240870",title:"Ph.D.",name:"Alaa Eddin Omar",middleName:null,surname:"Al Ostwani",slug:"alaa-eddin-omar-al-ostwani",fullName:"Alaa Eddin Omar Al Ostwani",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/240870/images/system/240870.jpeg",biography:"Dr. Al Ostwani Alaa Eddin Omar received his Master in dentistry from Damascus University in 2010, and his Ph.D. in Pediatric Dentistry from Damascus University in 2014. Dr. Al Ostwani is an assistant professor and faculty member at IUST University since 2014. \nDuring his academic experience, he has received several awards including the scientific research award from the Union of Arab Universities, the Syrian gold medal and the international gold medal for invention and creativity. Dr. Al Ostwani is a Member of the International Association of Dental Traumatology and the Syrian Society for Research and Preventive Dentistry since 2017. He is also a Member of the Reviewer Board of International Journal of Dental Medicine (IJDM), and the Indian Journal of Conservative and Endodontics since 2016.",institutionString:"International University for Science and Technology.",institution:{name:"Islamic University of Science and Technology",country:{name:"India"}}},{id:"42847",title:"Dr.",name:"Belma",middleName:null,surname:"Işik Aslan",slug:"belma-isik-aslan",fullName:"Belma Işik Aslan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/42847/images/system/42847.jpg",biography:"Dr. Belma IşIk Aslan was born in 1976 in Ankara-TURKEY. After graduating from TED Ankara College in 1994, she attended to Gazi University, Faculty of Dentistry in Ankara. She completed her PhD in orthodontic education at Gazi University between 1999-2005. Dr. Işık Aslan stayed at the Providence Hospital Craniofacial Institude and Reconstructive Surgery in Michigan, USA for three months as an observer. She worked as a specialist doctor at Gazi University, Dentistry Faculty, Department of Orthodontics between 2005-2014. She was appointed as associate professor in January, 2014 and as professor in 2021. Dr. Işık Aslan still works as an instructor at the same faculty. She has published a total of 35 articles, 10 book chapters, 39 conference proceedings both internationally and nationally. Also she was the academic editor of the international book 'Current Advances in Orthodontics'. She is a member of the Turkish Orthodontic Society and Turkish Cleft Lip and Palate Society. She is married and has 2 children. Her knowledge of English is at an advanced level.",institutionString:"Gazi University Dentistry Faculty Department of Orthodontics",institution:null},{id:"178412",title:"Associate Prof.",name:"Guhan",middleName:null,surname:"Dergin",slug:"guhan-dergin",fullName:"Guhan Dergin",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/178412/images/6954_n.jpg",biography:"Assoc. Prof. Dr. Gühan Dergin was born in 1973 in Izmit. He graduated from Marmara University Faculty of Dentistry in 1999. He completed his specialty of OMFS surgery in Marmara University Faculty of Dentistry and obtained his PhD degree in 2006. In 2005, he was invited as a visiting doctor in the Oral and Maxillofacial Surgery Department of the University of North Carolina, USA, where he went on a scholarship. Dr. Dergin still continues his academic career as an associate professor in Marmara University Faculty of Dentistry. He has many articles in international and national scientific journals and chapters in books.",institutionString:null,institution:{name:"Marmara University",country:{name:"Turkey"}}},{id:"178414",title:"Prof.",name:"Yusuf",middleName:null,surname:"Emes",slug:"yusuf-emes",fullName:"Yusuf Emes",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/178414/images/6953_n.jpg",biography:"Born in Istanbul in 1974, Dr. Emes graduated from Istanbul University Faculty of Dentistry in 1997 and completed his PhD degree in Istanbul University faculty of Dentistry Department of Oral and Maxillofacial Surgery in 2005. He has papers published in international and national scientific journals, including research articles on implantology, oroantral fistulas, odontogenic cysts, and temporomandibular disorders. Dr. Emes is currently working as a full-time academic staff in Istanbul University faculty of Dentistry Department of Oral and Maxillofacial Surgery.",institutionString:null,institution:{name:"Istanbul University",country:{name:"Turkey"}}},{id:"192229",title:"Ph.D.",name:"Ana Luiza",middleName:null,surname:"De Carvalho Felippini",slug:"ana-luiza-de-carvalho-felippini",fullName:"Ana Luiza De Carvalho Felippini",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/192229/images/system/192229.jpg",biography:null,institutionString:"University of São Paulo",institution:{name:"University of Sao Paulo",country:{name:"Brazil"}}},{id:"256851",title:"Prof.",name:"Ayşe",middleName:null,surname:"Gülşen",slug:"ayse-gulsen",fullName:"Ayşe Gülşen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/256851/images/9696_n.jpg",biography:"Dr. Ayşe Gülşen graduated in 1990 from Faculty of Dentistry, University of Ankara and did a postgraduate program at University of Gazi. \nShe worked as an observer and research assistant in Craniofacial Surgery Departments in New York, Providence Hospital in Michigan and Chang Gung Memorial Hospital in Taiwan. \nShe works as Craniofacial Orthodontist in Department of Aesthetic, Plastic and Reconstructive Surgery, Faculty of Medicine, University of Gazi, Ankara Turkey since 2004.",institutionString:"Univeristy of Gazi",institution:null},{id:"255366",title:"Prof.",name:"Tosun",middleName:null,surname:"Tosun",slug:"tosun-tosun",fullName:"Tosun Tosun",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/255366/images/7347_n.jpg",biography:"Graduated at the Faculty of Dentistry, University of Istanbul, Turkey in 1989;\nVisitor Assistant at the University of Padua, Italy and Branemark Osseointegration Center of Treviso, Italy between 1993-94;\nPhD thesis on oral implantology in University of Istanbul and was awarded the academic title “Dr.med.dent.”, 1997;\nHe was awarded the academic title “Doç.Dr.” (Associated Professor) in 2003;\nProficiency in Botulinum Toxin Applications, Reading-UK in 2009;\nMastership, RWTH Certificate in Laser Therapy in Dentistry, AALZ-Aachen University, Germany 2009-11;\nMaster of Science (MSc) in Laser Dentistry, University of Genoa, Italy 2013-14.\n\nDr.Tosun worked as Research Assistant in the Department of Oral Implantology, Faculty of Dentistry, University of Istanbul between 1990-2002. \nHe worked part-time as Consultant surgeon in Harvard Medical International Hospitals and John Hopkins Medicine, Istanbul between years 2007-09.\u2028He was contract Professor in the Department of Surgical and Diagnostic Sciences (DI.S.C.), Medical School, University of Genova, Italy between years 2011-16. \nSince 2015 he is visiting Professor at Medical School, University of Plovdiv, Bulgaria. \nCurrently he is Associated Prof.Dr. at the Dental School, Oral Surgery Dept., Istanbul Aydin University and since 2003 he works in his own private clinic in Istanbul, Turkey.\u2028\nDr.Tosun is reviewer in journal ‘Laser in Medical Sciences’, reviewer in journal ‘Folia Medica\\', a Fellow of the International Team for Implantology, Clinical Lecturer of DGZI German Association of Oral Implantology, Expert Lecturer of Laser&Health Academy, Country Representative of World Federation for Laser Dentistry, member of European Federation of Periodontology, member of Academy of Laser Dentistry. Dr.Tosun presents papers in international and national congresses and has scientific publications in international and national journals. He speaks english, spanish, italian and french.",institutionString:null,institution:{name:"Istanbul Aydın University",country:{name:"Turkey"}}},{id:"171887",title:"Prof.",name:"Zühre",middleName:null,surname:"Akarslan",slug:"zuhre-akarslan",fullName:"Zühre Akarslan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/171887/images/system/171887.jpg",biography:"Zühre Akarslan was born in 1977 in Cyprus. She graduated from Gazi University Faculty of Dentistry, Ankara, Turkey in 2000. \r\nLater she received her Ph.D. degree from the Oral Diagnosis and Radiology Department; which was recently renamed as Oral and Dentomaxillofacial Radiology, from the same university. \r\nShe is working as a full-time Associate Professor and is a lecturer and an academic researcher. \r\nHer expertise areas are dental caries, cancer, dental fear and anxiety, gag reflex in dentistry, oral medicine, and dentomaxillofacial radiology.",institutionString:"Gazi University",institution:{name:"Gazi University",country:{name:"Turkey"}}},{id:"256417",title:"Associate Prof.",name:"Sanaz",middleName:null,surname:"Sadry",slug:"sanaz-sadry",fullName:"Sanaz Sadry",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/256417/images/8106_n.jpg",biography:null,institutionString:null,institution:null},{id:"272237",title:"Dr.",name:"Pinar",middleName:"Kiymet",surname:"Karataban",slug:"pinar-karataban",fullName:"Pinar Karataban",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/272237/images/8911_n.png",biography:"Assist.Prof.Dr.Pınar Kıymet Karataban, DDS PhD \n\nDr.Pınar Kıymet Karataban was born in Istanbul in 1975. After her graduation from Marmara University Faculty of Dentistry in 1998 she started her PhD in Paediatric Dentistry focused on children with special needs; mainly children with Cerebral Palsy. She finished her pHD thesis entitled \\'Investigation of occlusion via cast analysis and evaluation of dental caries prevalance, periodontal status and muscle dysfunctions in children with cerebral palsy” in 2008. She got her Assist. Proffessor degree in Istanbul Aydın University Paediatric Dentistry Department in 2015-2018. ın 2019 she started her new career in Bahcesehir University, Istanbul as Head of Department of Pediatric Dentistry. In 2020 she was accepted to BAU International University, Batumi as Professor of Pediatric Dentistry. She’s a lecturer in the same university meanwhile working part-time in private practice in Ege Dental Studio (https://www.egedisklinigi.com/) a multidisciplinary dental clinic in Istanbul. Her main interests are paleodontology, ancient and contemporary dentistry, oral microbiology, cerebral palsy and special care dentistry. She has national and international publications, scientific reports and is a member of IAPO (International Association for Paleodontology), IADH (International Association of Disability and Oral Health) and EAPD (European Association of Pediatric Dentistry).",institutionString:null,institution:null},{id:"202198",title:"Dr.",name:"Buket",middleName:null,surname:"Aybar",slug:"buket-aybar",fullName:"Buket Aybar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/202198/images/6955_n.jpg",biography:"Buket Aybar, DDS, PhD, was born in 1971. She graduated from Istanbul University, Faculty of Dentistry, in 1992 and completed her PhD degree on Oral and Maxillofacial Surgery in Istanbul University in 1997.\nDr. Aybar is currently a full-time professor in Istanbul University, Faculty of Dentistry Department of Oral and Maxillofacial Surgery. She has teaching responsibilities in graduate and postgraduate programs. Her clinical practice includes mainly dentoalveolar surgery.\nHer topics of interest are biomaterials science and cell culture studies. She has many articles in international and national scientific journals and chapters in books; she also has participated in several scientific projects supported by Istanbul University Research fund.",institutionString:null,institution:null},{id:"260116",title:"Dr.",name:"Mehmet",middleName:null,surname:"Yaltirik",slug:"mehmet-yaltirik",fullName:"Mehmet Yaltirik",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/260116/images/7413_n.jpg",biography:"Birth Date 25.09.1965\r\nBirth Place Adana- Turkey\r\nSex Male\r\nMarrial Status Bachelor\r\nDriving License Acquired\r\nMother Tongue Turkish\r\n\r\nAddress:\r\nWork:University of Istanbul,Faculty of Dentistry, Department of Oral Surgery and Oral Medicine 34093 Capa,Istanbul- TURKIYE",institutionString:null,institution:null},{id:"172009",title:"Dr.",name:"Fatma Deniz",middleName:null,surname:"Uzuner",slug:"fatma-deniz-uzuner",fullName:"Fatma Deniz Uzuner",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/172009/images/7122_n.jpg",biography:"Dr. Deniz Uzuner was born in 1969 in Kocaeli-TURKEY. After graduating from TED Ankara College in 1986, she attended the Hacettepe University, Faculty of Dentistry in Ankara. \nIn 1993 she attended the Gazi University, Faculty of Dentistry, Department of Orthodontics for her PhD education. After finishing the PhD education, she worked as orthodontist in Ankara Dental Hospital under the Turkish Government, Ministry of Health and in a special Orthodontic Clinic till 2011. Between 2011 and 2016, Dr. Deniz Uzuner worked as a specialist in the Department of Orthodontics, Faculty of Dentistry, Gazi University in Ankara/Turkey. In 2016, she was appointed associate professor. Dr. Deniz Uzuner has authored 23 Journal Papers, 3 Book Chapters and has had 39 oral/poster presentations. She is a member of the Turkish Orthodontic Society. Her knowledge of English is at an advanced level.",institutionString:null,institution:null},{id:"332914",title:"Dr.",name:"Muhammad Saad",middleName:null,surname:"Shaikh",slug:"muhammad-saad-shaikh",fullName:"Muhammad Saad Shaikh",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Jinnah Sindh Medical University",country:{name:"Pakistan"}}},{id:"315775",title:"Dr.",name:"Feng",middleName:null,surname:"Luo",slug:"feng-luo",fullName:"Feng Luo",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Sichuan University",country:{name:"China"}}},{id:"423519",title:"Dr.",name:"Sizakele",middleName:null,surname:"Ngwenya",slug:"sizakele-ngwenya",fullName:"Sizakele Ngwenya",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of the Witwatersrand",country:{name:"South Africa"}}},{id:"419270",title:"Dr.",name:"Ann",middleName:null,surname:"Chianchitlert",slug:"ann-chianchitlert",fullName:"Ann Chianchitlert",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Walailak University",country:{name:"Thailand"}}},{id:"419271",title:"Dr.",name:"Diane",middleName:null,surname:"Selvido",slug:"diane-selvido",fullName:"Diane Selvido",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Walailak University",country:{name:"Thailand"}}},{id:"419272",title:"Dr.",name:"Irin",middleName:null,surname:"Sirisoontorn",slug:"irin-sirisoontorn",fullName:"Irin Sirisoontorn",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Walailak University",country:{name:"Thailand"}}},{id:"355660",title:"Dr.",name:"Anitha",middleName:null,surname:"Mani",slug:"anitha-mani",fullName:"Anitha Mani",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"SRM Dental College",country:{name:"India"}}},{id:"355612",title:"Dr.",name:"Janani",middleName:null,surname:"Karthikeyan",slug:"janani-karthikeyan",fullName:"Janani Karthikeyan",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"SRM Dental College",country:{name:"India"}}},{id:"334400",title:"Dr.",name:"Suvetha",middleName:null,surname:"Siva",slug:"suvetha-siva",fullName:"Suvetha Siva",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"SRM Dental College",country:{name:"India"}}},{id:"334239",title:"Prof.",name:"Leung",middleName:null,surname:"Wai Keung",slug:"leung-wai-keung",fullName:"Leung Wai Keung",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Hong Kong",country:{name:"China"}}}]}},subseries:{item:{id:"90",type:"subseries",title:"Human Development",keywords:"Neuroscientific research, Brain functions, Human development, UN’s human development index, Self-awareness, Self-development",scope:"