\\n\\n
These books synthesize perspectives of renowned scientists from the world’s most prestigious institutions - from Fukushima Renewable Energy Institute in Japan to Stanford University in the United States, including Columbia University (US), University of Sidney (AU), University of Miami (USA), Cardiff University (UK), and many others.
\\n\\nThis collaboration embodied the true essence of Open Access by simplifying the approach to OA publishing for Academic editors and authors who contributed their research and allowed the new research to be made available free and open to anyone anywhere in the world.
\\n\\nTo celebrate the 50 books published, we have gathered them at one location - just one click away, so that you can easily browse the subjects of your interest, download the content directly, share it or read online.
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IntechOpen and Knowledge Unlatched formed a partnership to support researchers working in engineering sciences by enabling an easier approach to publishing Open Access content. Using the Knowledge Unlatched crowdfunding model to raise the publishing costs through libraries around the world, Open Access Publishing Fee (OAPF) was not required from the authors.
\n\nInitially, the partnership supported engineering research, but it soon grew to include physical and life sciences, attracting more researchers to the advantages of Open Access publishing.
\n\n\n\nThese books synthesize perspectives of renowned scientists from the world’s most prestigious institutions - from Fukushima Renewable Energy Institute in Japan to Stanford University in the United States, including Columbia University (US), University of Sidney (AU), University of Miami (USA), Cardiff University (UK), and many others.
\n\nThis collaboration embodied the true essence of Open Access by simplifying the approach to OA publishing for Academic editors and authors who contributed their research and allowed the new research to be made available free and open to anyone anywhere in the world.
\n\nTo celebrate the 50 books published, we have gathered them at one location - just one click away, so that you can easily browse the subjects of your interest, download the content directly, share it or read online.
\n\n\n\n\n'}],latestNews:[{slug:"webinar-introduction-to-open-science-wednesday-18-may-1-pm-cest-20220518",title:"Webinar: Introduction to Open Science | Wednesday 18 May, 1 PM CEST"},{slug:"step-in-the-right-direction-intechopen-launches-a-portfolio-of-open-science-journals-20220414",title:"Step in the Right Direction: IntechOpen Launches a Portfolio of Open Science Journals"},{slug:"let-s-meet-at-london-book-fair-5-7-april-2022-olympia-london-20220321",title:"Let’s meet at London Book Fair, 5-7 April 2022, Olympia London"},{slug:"50-books-published-as-part-of-intechopen-and-knowledge-unlatched-ku-collaboration-20220316",title:"50 Books published as part of IntechOpen and Knowledge Unlatched (KU) Collaboration"},{slug:"intechopen-joins-the-united-nations-sustainable-development-goals-publishers-compact-20221702",title:"IntechOpen joins the United Nations Sustainable Development Goals Publishers Compact"},{slug:"intechopen-signs-exclusive-representation-agreement-with-lsr-libros-servicios-y-representaciones-s-a-de-c-v-20211123",title:"IntechOpen Signs Exclusive Representation Agreement with LSR Libros Servicios y Representaciones S.A. de C.V"},{slug:"intechopen-expands-partnership-with-research4life-20211110",title:"IntechOpen Expands Partnership with Research4Life"},{slug:"introducing-intechopen-book-series-a-new-publishing-format-for-oa-books-20210915",title:"Introducing IntechOpen Book Series - A New Publishing Format for OA Books"}]},book:{item:{type:"book",id:"1380",leadTitle:null,fullTitle:"Corrosion Resistance",title:"Corrosion Resistance",subtitle:null,reviewType:"peer-reviewed",abstract:"The book has covered the state-of-the-art technologies, development, and research progress of corrosion studies in a wide range of research and application fields. The authors have contributed their chapters on corrosion characterization and corrosion resistance. The applications of corrosion resistance materials will also bring great values to reader's work at different fields. \nIn addition to traditional corrosion study, the book also contains chapters dealing with energy, fuel cell, daily life materials, corrosion study in green materials, and in semiconductor industry.",isbn:null,printIsbn:"978-953-51-0467-4",pdfIsbn:"978-953-51-6188-2",doi:"10.5772/1844",price:139,priceEur:155,priceUsd:179,slug:"corrosion-resistance",numberOfPages:484,isOpenForSubmission:!1,isInWos:1,isInBkci:!1,hash:"07e772d5bde6effcc31982a3f4fc0038",bookSignature:"Hong Shih",publishedDate:"March 30th 2012",coverURL:"https://cdn.intechopen.com/books/images_new/1380.jpg",numberOfDownloads:84775,numberOfWosCitations:99,numberOfCrossrefCitations:45,numberOfCrossrefCitationsByBook:15,numberOfDimensionsCitations:122,numberOfDimensionsCitationsByBook:20,hasAltmetrics:1,numberOfTotalCitations:266,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"April 5th 2011",dateEndSecondStepPublish:"May 3rd 2011",dateEndThirdStepPublish:"September 7th 2011",dateEndFourthStepPublish:"October 7th 2011",dateEndFifthStepPublish:"February 6th 2012",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6,7",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"89658",title:"Dr",name:null,middleName:null,surname:"Shih",slug:"shih",fullName:"Shih",profilePictureURL:"https://mts.intechopen.com/storage/users/89658/images/system/89658.jpg",biography:"Dr. Hong Shih, Senior Technology Director at Lam Research Corporation, received his Ph.D. in Metallurgy from the Pennsylvania State University in 1986. 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Cyanophycin, abbreviated CGP (cyanophycin granule peptide), is next to poly-γ-glutamic acid and poly-ε-lysine, the third polyamino acid known to occur in nature [1]. It serves as a nitrogen/carbon reserve polymer in many cyanobacterial strains as well as in a few heterotrophic bacteria. CGP consists of the two amino acids, aspartate and arginine, forming a poly-l-aspartic acid backbone with arginine side chains. The arginine residues are linked to the β-carboxyl group of every aspartyl moiety via isopeptide bond [2].
\nCGP was discovered in 1887 by the botanist Antonio Borzi during microscopic studies of filamentous cyanobacteria [3]. He observed opaque and light scattering inclusions by using light microscopy and created the name
With a C/N ratio of 2:1, CGP is extremely rich in nitrogen and consequently an excellent nitrogen storage compound. During the degradation of CGP and subsequent degradation of arginine, a function as energy source was also proposed [8].
\nMost cyanobacteria, including unicellular and filamentous, as well as diazotrophic and non-diazotrophic groups are able to accumulate CGP (Figure 1).
\nLight and electron microscopic pictures of CGP accumulating cyanobacteria. In light microscopic pictures, CGP was stained using the Sakaguchi reaction [
In non-diazotrophic cyanobacteria, the amount of CGP is usually less than 1% of the cell dry mass during exponential growth. CGP accumulates conspicuously under unbalanced growth conditions including stationary phase, light stress or nutrient limitation (sulfate, phosphate or potassium starvation) that do not involve nitrogen starvation [9, 10]. Under such unbalanced conditions, the amount of CGP may increase up to 18% of the cell dry mass [10]. During the recovery from nitrogen starvation by the addition of a usable nitrogen source, CGP is transiently accumulated [11, 12].
\nIn the unicellular diazotrophic cyanobacterium
Furthermore, in heterocysts of diazotrophic cyanobacteria of the order
Akinetes are resting spore-like cells of a subgroup of heterocyst-forming cyanobacteria for surviving long periods of unfavorable conditions. During akinete development, the cells transiently accumulate storage compounds, namely glycogen, lipid droplets and CGP [19, 20] (Figure 1). CGP granules also appear during germination of dormant akinetes [21].
CGP was formally thought to be unique in cyanobacteria. In 2002, Krehenbrink et al. and Ziegler et al. discovered through evaluation of obligate heterotrophic bacteria genomes that many heterotrophic bacteria possess CGP synthetase genes [23, 24]. Genes of CGP metabolism occur in a wide range of different phylogenetic taxa and not closely related to cyanobacteria [25].
\nIn 1971, Robert Simon isolated CGP granules for the first time by using differential centrifugation. Along with this study, CGP has shown its special and unique solubility behavior [26]. CGP is insoluble at physiological ionic strength and at neutral pH, but soluble in solutions which are acidic, basic or highly ionic. In non-ionic detergents such as Triton X-100, CGP is insoluble; however, in ionic detergents like SDS, it is soluble [6]. Present-day CGP extraction methods are based on its solubility at low pH and insolubility at neutral pH [27].
\nThe chemical structure of CGP was proposed in 1976 by Simon and Weathers [2]. According to this model, CGP has a polymer backbone consisting of α-linked aspartic acid residues. The α-amino group of arginine is linked via isopeptide bonds to the β-carboxylic group of every aspartyl moiety. Because every aspartate residue is linked to an arginine residue, CGP contains equimolar amounts of aspartate and arginine [2]. This structure has been confirmed via enzymatic degradation studies. CGP-degrading enzymes (see below) release β-Asp-Arg dipeptides [28]. CD spectroscopy data suggest that the acid-soluble and neutral insoluble forms of CGP have similar conformations. Both forms contain substantial fractions of β-pleated sheet structure [29].
\nCyanobacterial CGP has a molecular weight and polydispersity ranging from 25 to 100 kDa [26]. In contrast, the native CGP producer
Native CGP is exclusively composed of aspartate and arginine. By contrast, in CGP isolated from recombinant
CGP is non-ribosomally synthesized from aspartate and arginine by cyanophycin synthetase (CphA1) (Figure 2). In 1976, CphA1 was enriched and characterized for the first time by Simion [35]. The enzyme incorporates aspartate and arginine in an elongation reaction, which requires ATP, KCl, MgCl2 and a sulfhydryl reagent (β-mercaptoethanol or DTT). For its activity, CphA1 needs a so far unknown CGP primer, as a starting point of the elongation reaction [35]. By using synthetically primers, Berg et al. could show that a single building block of CGP (β-Asp-Arg) does not serve as an efficient primer for CphA1 elongation reaction in vitro. The primers need to consist of at least three Asp-Arg building blocks (β-Asp-Arg)3 to detect CphA1 activity [36]. Other peptides, like cell wall or other cellular components, have been suggested to serve as an alternative priming substance for the CphA1 reaction [37]. This could be an explanation for the functionality of CGP synthesis in recombinant bacteria, without the ability to produce native CGP primers [38]. Interestingly, the CphA1 of
Schematic illustration of CGP metabolism in cyanobacteria. CGP is synthesized from aspartate and arginine by CGP synthetase (CphA1) in an ATP-depending elongation reaction using CGP primers, containing of at least three Asp-Arg building blocks. Intracellular CGP degradation is catalyzed by the CGPase (CphB). The β-Asp-Arg dipeptides resulting from cleavage of CGP are further hydrolyzed by isoaspartyl dipeptidase, releasing aspartate and arginine. In many nitrogen-fixing cyanobacteria, an additional CGP synthetase is present, termed CphA2. CphA2 can use β-aspartyl-arginine dipeptides to resynthesize CGP.
Today, CphA1 enzymes from several bacteria, including cyanobacteria and heterotrophic bacteria, have been purified and characterized [33, 39, 40, 41, 42]. The molecular mass of the characterized CphA1 enzymes ranges from 90 to 130 kDa. The active form of CphA1s from
The mechanism of CGP synthesis by CphA1 has been suggested by Berg et al. in 2000, by measuring the step-wise incorporation of amino acids to the C-terminus of the CGP primer. The putative CGP elongation cycle starts at the C-terminal end of the poly-aspartate backbone. First, the carboxylic acid group of the poly-aspartate backbone is activated by transfer of the γ-phosphoryl group of ATP. In the second step, one aspartate is bound at the C-terminus of the growing polymer by its amino group, forming a peptide bound. Subsequently, the intermediate (β-Asp-Arg)n-Asp is transferred to the second active site of CphA1 and phosphorylated at the β-carboxyl group of the aspartate. Finally, the α-group of arginine is linked to the β-carboxyl group of aspartate, forming an isopeptide bound [36].
\nVarious CphA1 enzymes have been characterized with respect to their substrate affinity and specificity. For CphA1 of
CphA homologs are widely distributed in eubacteria. In silico analysis proposes 10 different groups of cyanophycin synthetases [25]. In cyanobacteria, cyanophycin synthetases of group I–III (CphA, CphA2 and CphA2’) can be found.
\nRecently, the function of a cyanophycin synthetase of group II (CphA2) has been characterized. Most non-diazotrophic cyanobacteria use a single type of cyanophycin synthetase (CphA1). However, in many nitrogen-fixing cyanobacteria, an additional version of CphA is present, termed CphA2. In 2016, Klemke et al. resolved the function of CphA2 [44]. Compared to CphA1, CphA2 has a reduced size and just one ATP-binding site. CphA2 uses the product of CGP hydrolysis, β-aspartyl-arginine dipeptide as substrate to resynthesize cyanophycin, consuming one molecule of ATP per elongation. A mutant lacking CphA2 shows only a minor decrease in the overall CGP content. However, a CphA2-deficient mutant displays similar defects under diazotrophic and high light conditions than a CphA1 mutant [15, 44]. This observation suggests that the apparent “futile cycle” of CGP hydrolysis and immediate repolymerization is probably of physiological significance in the context of nitrogen fixation [17].
\nSince 1976, it is known that CGP is resistant against hydrolytic cleavage by several proteases or arginase [2, 45]. This resistance is probably due to the branched structure of CGP [38]. Therefore, the presence of a highly specified peptidase for CGP hydrolysis was suggested.
\nIn 1999, Richter et al. reported a CGP hydrolyzing enzyme from the unicellular cyanobacterium
In addition to CphB, which catalyzes the intracellular cleavage of CGP, other versions of cyanophycinase exist, catalyzing the extracellular hydrolysis of CGP. In 2002, Obst et al. isolated several Gram-negative bacteria from different habitats, which were able to utilize CGP as a source of carbon and energy [47, 48]. One isolate was affiliated as
In 2007, in silico analysis showed that CphB homologs are widely distributed in eubacteria, proposing eight different groups including intracellular and extracellular CGPases. CGPases from cyanobacteria belong to group I, II and partially group III (CphB1–3). Groups IV–VIII, including CphE, are present in a large variety of non-photosynthetic bacteria [25].
\nThe last step in catabolism of CGP is the cleavage of β-Asp-Arg dipeptides to monomeric amino acids, arginine and aspartate (Figure 2). In 1999, Richter et al. found β-Asp-Arg dipeptides hydrolyzing activity in extracts of
The mature isoaspartyl dipeptidases of
In
Usually, genes involved in CGP metabolism are clustered. The organization of these clusters can be different, depending on the respective organism [25]. In
In
In cluster
In addition to these two gene clusters, a third set of ORFs containing putative
Generally, CGP accumulation is triggered by cell growth arresting stress conditions, such as entry into stationary phase, light or temperature stress, limitation of macronutrients (with the exception of nitrogen starvation) or inhibition of translation by adding antibiotics like chloramphenicol [9, 10, 61]. All of these CGP triggering conditions result in a reduced or arrested growth. In exponential growth phase the amino acids arginine and aspartate are mostly used for protein biosynthesis with the consequence of a low intracellular level of free amino acids. Under growth-limiting conditions, protein biosynthesis is slowed down, which yields an excess of monomeric amino acids in the cytoplasm, triggering the CGP biosynthesis [10].
\nCGP accumulation also requires an excess of nitrogen. For the filamentous cyanobacterium
A potential link between regulation of arginine biosynthesis and GCP metabolism was suggested in many previous studies. In a transposon mutagenesis study in the filamentous cyanobacterium
In metabolic engineering studies of the CGP production strain
Bacteria produce arginine from glutamate in eight steps. The first five steps involving N-acetylated intermediates lead to ornithine. The conversion of ornithine to arginine requires three additional steps [66]. The second enzyme of ornithine biosynthesis is the N-acetylglutamate kinase (NAGK), which catalyzes the phosphorylation of N-acetyl glutamate to N-acetylglutamyl-phosphate. NAGK catalyzes the controlling step in arginine biosynthesis [67]. NAGK activity is subjected to allosteric feedback inhibition by arginine and is, moreover, positively controlled by the PII signal transduction protein (see below) [67, 68]. Maheswaran et al. showed that arginine production and the following CGP accumulation depend on the catalytic activation of NAGK by the signal transduction protein PII [69]. In a PII-deficient mutant of
The nitrogen-regulated response regulator NrrA also has influence on arginine and CGP biosynthesis. An NrrA-deficient mutant in
All these results and observations point towards arginine as main bottleneck of CGP biosynthesis, while aspartate plays a minor role. CGP accumulation occurs as a result of arginine enrichment in the cytoplasm. Reasons for increased arginine content in the cell are lowered protein biosynthesis as a result of various growth limiting conditions. Furthermore, an excess of nitrogen and energy sensed by PII leads to NAGK activation and thereby increased arginine biosynthesis.
\nThe PII signal transduction proteins are widely distributed in prokaryotes and chloroplasts, where they play a coordinating role in the regulation of nitrogen assimilatory processes [71, 72, 73]. For this purpose, PII senses the energy status of the cell by binding ATP or ADP in a competitive way [74]. Binding of ATP and synergistic binding of 2-oxoglutarate (2-OG) allows PII to sense the current carbon/nitrogen status of the cell [75]. 2-OG is the carbon skeleton for the GS/GOGAT reactions and thereby links the carbon and nitrogen metabolism in all domains of life [76, 77]. The pool size of 2-OG reacts quickly to changes in nitrogen availability, wherefore 2-OG is an indicator of the carbon/nitrogen balance [78, 79]. Depending on the nitrogen supply, PII may be phosphorylated at the apex of the T-loop at position Ser49 [80, 81]. Binding of the effector molecules ATP, ADP and 2-OG as well as phosphorylation leads to conformational rearrangements of the large surface-exposed T-loop, PII’s major protein-interaction structure [82]. These conformational states direct the interaction of PII with its various interaction partners and thereby regulate the cellular C/N balance [83].
\nIn cyanobacteria, PII regulates the global nitrogen control transcriptional factor NtcA, through binding to the NtcA co-activator PipX [84]. In common with other bacteria, cyanobacterial PII proteins can interact with the biotin carboxyl carrier protein (BCCP) of acetyl-CoA carboxylase (ACC) and thereby control the acetyl-CoA levels [85]. Furthermore, PII controls arginine biosynthesis via regulation of NAGK [68, 69, 86].
\nPII proteins form a cylindrical-shaped homotrimer with 12–13 kDa per subunits. The T-loop, a large and surface-exposed loop, protrudes from each subunit. The effector binding sites are positioned in the three inter-subunit clefts [87, 88]. If sufficient energy and nitrogen are available, indicated by a high ATP and low 2-OG level, non-phosphorylated PII forms an activating complex with NAGK.
\nThe crystal structure of the PII-NAGK complex from
During PII mutagenesis, a PII variant was identified that binds constitutively NAGK in vitro. This PII variant exhibits a single amino acid replacement, Ile86 to Asn86, hereafter referred as PII(I86N) [89]. The crystal structure of PII(I86N) has been solved, showing an almost identical backbone than wild-type PII. However, the T-loop adopts a compact conformation, which is a structural mimic of PII in the NAGK complex [89, 90]. Addition of 2-OG in the presence of ATP normally leads to a dissociation of the PII-NAGK complex, however PII(I86N) no longer responds to 2-OG [90].
\nThe PII(I86N) variant enables a novel approach of metabolic pathway engineering by using custom-tailored PII signaling proteins. By replacing the wild-type PII with a PII carrying the mutation for I86N in
Industrial applications for CGP have previously mainly focused on chemical derivatives. CGP can be converted via hydrolytic β-cleavage to poly(α-l-aspartic acid) (PAA) and free arginine. PAA is biodegradable and has a high number of negatively charged carboxylic groups, making PAA to a possible substituent for polyacrylates [48, 50, 91]. PAA can be employed as antiscalant or dispersing ingredient in many fields of applications, including washing detergents or suntan lotions. Furthermore, PAA has potential application areas as an additive in paper, paint, building or oil industry [48, 50].
\nCGP can also serve as a source for dipeptides and amino acids in food, feed and pharmaceutical industry. The amino acids arginine (semi-essential), aspartate (non-essential) and lysine (essential) derived from CGP have a broad spectrum of nutritional or therapeutic applications. Large-scale production of these amino acids, as mixtures or dipeptides, is established in industry, with various commercial products already available on the market (reviewed by Sallam and Steinbuchel [92]).
\nPotential applications of non-modified CGP have been discussed but remain so far largely unexplored. This can partially be explained by the lack of research being conducted on the material properties of CGP. Recently in 2017, the first study regarding CGP material properties has been published. In this study, Khlystov et al. focused on the structural, thermal, mechanical and solution properties of CGP produced by recombinant
Previous ventures to produce CGP in high amounts were mainly focused on heterotrophic bacteria, yeasts and plants as production host. These recombinant production hosts heterologously express CGP synthetase genes, mostly from cyanobacteria. In this way, heterotrophic bacteria, which are established in biotechnological industry including
Strain
The industrially established host
CGP and CGP derivates are important sources for β-dipeptides for several applications. A large-scale method was developed to convert CGP into its constituting β-dipeptides by using CphE from
Production of CGP has also been attempted in several transgenic plants. Here, ectopic expression of the primer-independent CphA from
Compared to bacteria that are used so far in biotechnological industry, cyanobacteria are unique as they use sunlight and CO2 as energy and carbon source. Cyanobacteria have been identified as rich source of various biologically active compounds, biofertilizers, bioplastics, energy, food and feed [104]. Obviously, the importance of environmentally friendly production processes increases more and more. Hence, Cyanobacteria are expected to play a major role in future industry.
The main bottleneck of CGP production in Cyanobacteria is the relatively slow growth rate, which is much lower than in biotechnologically established bacteria. Conventional cultivation methods of cyanobacteria reach a biomass of roughly 1 g dry mass per liter [107]. To overcome this limitation, a new cultivation method was developed, using a two-tier vessel with membrane-mediated CO2 supply. By using this cultivation setup, it was possible to enable rapid growth of
In comparison, the recombinant
CGP is well researched and its occurrence in cyanobacteria is known for more than 100 years. However, many questions are still open. Most obviously, the cell biology of the CGP granules remains largely unknown. In the last decades, research on CGP mainly focused on biotechnological purposes, like strain or process optimization. Most work has been carried out with short-chain CGP from recombinant producer strains; however the biophysical properties of the long-chain native CGP remain largely unexplored. So far, heterotrophic bacteria were mainly used to produce industrial biocompounds including CGP. In this chapter, we discussed the possibility of a cyanobacterial CGP production strain. The main disadvantages of cyanobacteria, their slower growth and the low abundance of product can be compensated using genetic engineering together with appropriate production processes. Future industry has to cope with the manifold challenges to counteract environmental pollution and climate change. The use of cyanobacteria in CGP production and, more generally, in biotechnological applications for bioproduct synthesis provides an environmentally friendly alternative to conventional biotechnological approaches.
\nThis work was supported by grants from the DFG (Fo195/9), the research training group GRK 1708 and the Baden-Württemberg foundation grant 7533-10-5-92B. We thank Iris Maldener for provision of the electron micrographs of
The authors declare that they have no competing interests.
Among the Schwann cells (SCs), non-myelinating Schwann cells (NMSCs) represent an important category that was not extensively studied, although the gathered data demonstrate they are essential for axon maintenance and neuronal survival in the peripheral nervous system (PNS). Extending the knowledge on NMSCs biology could open new perspectives on the normal functioning of PNS as well as for better understanding the mechanisms underlying various pathological conditions and further on for developing new therapeutic approaches in peripheral nerve diseases.
The NMSCs encompass two major cell types, according to their distribution: Schwann cells of Remak fibers and the specialized perisynaptic/terminal Schwann cells at neuromuscular junctions (NMJ). In addition in this category are also included the glial cells found in some sensory transducers, such as the Pacinian and Meissner’s corpuscles, as well as in the sensory and autonomic ganglia, where they are called satellite cells [1]. In pathological circumstances like axonal loss or demyelination, the former myelinating Schwann cells also become a class of NMSCs. Conversely, all NMSCs retain the potential to myelinate [2], if they receive the appropriate cues, most of which derive from the associated axons, along with some fate-controlling genes that act cell-autonomously within SCs [3, 4].
All Schwann cells derive from multipotent progenitor cells of the neural crest (Figure 2). The fate decision mechanism of SCs to become myelinating cells or to form RSCs is not fully understood, although the plasticity of SCs in various studies is recognized. Thus, some studies proved that if myelinated nerve segments are grafted, on a nerve that contains especially unmyelinated fibers, transplanted SCs do not myelinate, and equally, RSCs can produce a myelin sheath when they are grafted onto a myelinated nerve [2, 5].
After contacting nascent nerves during embryogenesis, neural crest cells give rise to SC precursors (SCP), which further differentiate into immature Schwann cells (iSC), in late embryonic and perinatal nerves (Figure 1). After birth, iSC will further differentiate either toward myelinating cells or non-myelinating cells according to axon-derived signals. The myelinating SCs form the myelin sheath of large axons (Figure 2A). The non-myelinating cells ensheath small axons forming unmyelinated fibers, called Remak bundles (Figure 2B), or they migrate toward the neuromuscular junctions, covering the axon terminals, where they become terminal/perisynaptic/teloglia SCs (Figure 2C and D).
Schwann cell lineage. SCs derive from the neural crest cells, after contacting nascent nerves during embryogenesis. Neural crest cells give rise to SC precursors, in early embryonic nerves which further differentiate into immature Schwann cells, in late embryonic and perinatal nerves. Postnatally, iSch will further differentiate either toward myelinating cells or non-myelinating cells according to axon-derived signals. The myelinating cells form the myelin sheath of large axons. The non-myelinating cells ensheath small axons forming unmyelinated fibers, called Remak bundles, or they migrate toward the neuromuscular junctions, covering the axon terminals, where they become terminal/perisynaptic/teloglia Schwann cells.
Transmission electron microscopy of myelinated (mn, in A) and nonmyelinated (nn, in B) axons of peripheral nerves embedded in the cytoplasm of Schwann cell (Sch). C and D show the Schwann cells and nerve terminals (nt) in neuromuscular junction. (C) The motor end plate formed by folded sarcolemma (junctional folds, arrows) accommodates knob-like terminal buttons of the motor nerve (nt). (D) The myelin sheath (m) covering the axon ends (nt) in the vicinity of neuromuscular junction and Schwann cell extends into the synaptic cleft (arrowheads).
This chapter addresses the main types of NMSCs, in terms of biological aspects and their role, aiming to highlight their importance for a better understanding of pathological mechanisms underlying various peripheral nervous system diseases.
Robert Remak first described the unmyelinated nerve fibers using the nerve fiber teasing technique in 1838 [6], so, in his honor, they were named “Remak fibers.”
In the PNS most nerve fibers are unmyelinated [1], formed by RSCs accommodating a variable number of small-caliber axons (less than 1 μm diameter) (Figure 2B).
RSCs do not produce myelin, but they are essential for normal PNS development and functioning.
During PNS formation, pockets with multiple axons within a single mesaxon can be encountered. This aspect occurs only occasionally in normal adult Remak fibers where the small diameter axons of C nerve fibers (sensory/afferent), postganglionic sympathetic fibers, and some preganglionic sympathetic or parasympathetic fibers are accommodated in separate grooves of longitudinally interconnected RSCs forming the Remak bundles. Each RSC surrounds many axons, during radial sorting, forming a mesaxon for each axon. It is uncommon for an axon to be in direct contact with the basement membrane of the Schwann cell [4].
The number of axons surrounded by a RSC varies depending on the type of nerve fibers or a particular region along them. Thus, there is a higher number of axons exiting the dorsal root ganglion than in the distal segments of the peripheral nerve. In the cutaneous nerves, the number of axons per RSC decreases as they approach the skin [7], suggesting the existence of specific mechanisms regulating RSC-axons association as they approach their target. Moreover, the distribution of the axons within the Remak bundles varies along the peripheral nerve, with multiple axons within one pocket of the RSC toward the dorsal root and completely isolated axons in the distal segments [8].
There are studies reporting the presence of few short, myelinated internodes along a unmyelinated fiber especially in older animals [9].
Thus, it appears that the “ensheathment fate” of axons to either become myelinated or unmyelinated fibers relies on local/environmental cues. One of the most extensively studied is the neuregulin 1 type III signaling through ErbB receptors, an axolemmal myelin-inducing factor [3] that promotes the formation of a mesaxon for each unmyelinated axon as well as SC differentiation into myelinating cells, depending on the expression level [10].
Another feature of unmyelinated nerve fibers is that axons may switch between neighboring Remak bundles along the nerve.
Moreover, a RSC can surround axons with different functions, for example, both sensitive and sympathetic axons, both axons expressing TrkA (tropomyosin receptor kinase A) receptors with a high affinity for nerve growth factor (NGF) and axons expressing RET (rearranged during transfection) receptors that respond to glial cell line-derived neurotrophic factor (GDNF) and artemin or axons derived from different dorsal ganglia [1].
The RSCs differentiation is governed, at least in part, by neuronal cues, especially by the signaling pathway neuregulin 1 type III (Nrg1-III)/ErbB2/ErbB3 receptor cascades. However, a number of cell-autonomous genes also contribute to SCs differentiation toward RSCs, one of which is gamma-aminobutyric acid type B1 receptor (GABBR1) [4].
SCs derive from the neural crest cells, after contacting nascent nerves during embryogenesis. Neural crest cells give rise to SCP, in early embryonic nerves, which further differentiate into iSCs, in late embryonic and perinatal nerves. Postnatally, iSCs will further differentiate either toward myelinating cells or non-myelinating cells according to axon-derived signals. The myelinating cells form the myelin sheath of large axons (larger than 1 μm diameter). The non-myelinating cells ensheath small axons forming unmyelinated fibers, called Remak bundles, or they migrate toward the neuromuscular junctions, where they become terminal/perisynaptic/teloglia Schwann cells (Figure 3).
Schwann cell development and maturation: their role in the evolution of myelinated and unmyelinated peripheral nerve fibers. Schwann cell precursors differentiate into immature Schwann cells which start the process of “radial sorting”. A pro-myelinating Schwann cell envelops a large axon and becomes a myelinating Schwann cell. An immature Schwann cell which ensheaths many small axons becomes mature non-myelinating Schwann cell, forming a Remak bundle.
There are four distinct genes for neuregulins, but neuregulin 1 NRG1 is the best studied. NRG1, also known as glial growth factor (GGF), is a growth factor with EGF domain homology known to induce growth, differentiation, and migration of Schwann cells throughout development [10, 11]. NRG1 has three isoforms out of which type III is considered to be the most important signaling molecule for SC-axon interactions. NRG1 type III is produced by neurons and is released from axons by proteases, such as BACE1, or may remain anchored to the axonal membrane. NR1-III interacts with high-affinity tyrosine kinase receptors ErbB2/ErbB3 heterodimers, triggering the activation of downstream pathways, such as Ras/MAPK and PI3K/Akt SCs. Stimulation of mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) cascade was proven to lead to the suppression of myelinating state [12] through ErbB2 and ErbB3 receptors that are expressed in Schwann cells [13]. The NRG1-ErbB signaling pathway seems to play a crucial role in the SCs lineage for both myelinating and non-myelinating SCs and promotes SCP precursor survival after birth as well as during in vitro culturing [10, 14].
However, recent studies showed that in transgenic animal models where NRG1 is conditionally ablated during postnatal life, there is no reduction in the number of sensory axons but larger, unordered Remak bundles with polyaxonal pockets, where axons are not separated by SC processes, are formed, and some large-diameter axons lose the myelin sheath. Only the sensory function was affected, without changing the survival and axonal maintenance of the neurons [15]. However, after nerve injury, RSCs re-establish normal Remak bundles, suggesting that during adulthood, after the basal lamina was established, axonal sorting is no more required [16].
Another experimental in vivo study on mouse sciatic nerve showed that NRG1 type III Erb2/Erb3 signaling regulates the morphological changes of the SCs. The study used a NRG1 type III knockout mouse model (+/−) with a low expression of NRG1 type III, which produced Remak bundles with a higher number of axons and smaller spaces between axons [17].
A number of studies have shown that there are certain genes that control SCs fate [4, 12, 18, 19] and that they act cell-autonomously in SCs. There are genes that can trigger upregulation of NRG1 during differentiation after injury, thus stimulating remyelination and redifferentiation of SCs [20].
An important genetically determining factor during SCs development is the gene for gamma-aminobutyric acid type B1 receptor (GABBR1), which is active mainly in RSCs as compared to myelinating SCs [21]. An in vivo experimental research showed that the absence of
During maturation, RSCs extend cell processes that individually encircle each axon with the plasmatic membrane and cytoplasm, separating it from surrounding axons. Naked axons, which were not completely surrounded by RSC cytoplasm and which come into direct contact with other axons, demonstrate failed RSC maturation after nerve injury [22]. Recent studies have shown that the expression level of a protein that is highly expressed in non-myelinating SCs, neuropathy target esterase (Nte), is correlated with SC developmental maturation and remyelination after neuronal injury. However, this protein is not involved in myelination [23].
Other proteins, such as mTOR [24, 25, 26], or G-G protein-coupled receptor Gpr126/Adgrg6, through laminin-211 and collagen type IV interactions, are required for both myelinating and non-myelinating SCs growth and function, during developmental stages as well as after nerve injury. Gpr126 controls radial sorting, myelination, SC-axon interactions, as well as Remak bundle formation [27, 28, 29, 30].
In SCs, both deletion and overexpression of mTOR complex I adapter (Raptor) disrupts Remak bundle formation by increasing the number of axons in Remak bundles, with many naked axons [26], or decreasing the number of axons in Remak bundles and aberrant wrapping of multiple membrane-layered axons by RSCs, respectively [24, 31].
The absence of myelin gives Remak fibers a certain plasticity, sprouting, and growth abilities that exceed that of myelinated fibers. That is why they are found especially in PNS, where the risk of physical injuries is much higher than in the CNS.
Although Remak fibers are found mainly in the PNS, they are also found in the CNS, associated with unmyelinated fibers in the parallel fiber system of the cerebellum and nigrostriatal pathway [1, 32].
NMSCs, like other SCs, can also function as immunocompetent cells playing an essential contribution in mounting and modulating of immune response in certain conditions, by antigen presentation and cytokine secretion, as well as by their direct interaction with immune cells. Moreover, NMSCs express specific pattern recognition receptors (PRR) for the detection of pathogens, such as Toll-like receptors (TLRs) and the nucleotide-binding and oligomerization domain (NOD)-like receptor (NLR) family [33, 34, 35].
The crosstalk between immune- and peripheral nerve SCs through a large array of molecules either expressed or recognized by SCs build up the base for nervous-immune system interactions. The subject was extensively reviewed by Tzekova et al. [34]. Moreover, Hu et al. showed that NMSCs located in the thymus develop correlations with thymocytes, lymphocytes, and dendritic cells under normal and pathological conditions. They concluded that NMSCs are highly suitable for studying the local interactions of the PNS and primary lymphoid tissues or organs [36]. The same observations were made by Ma et al. studying the mouse spleen and the interactions between NMSCs and leukocytes [37].
Another role for NMSCs was concluded by the study of Yamazaki et al. which showed that NMSCs maintain hematopoietic stem cell hibernation in the bone marrow niche. They demonstrated that NMSCs proved responsible for activation of TGF-beta latent form. These glial cells, ensheathing autonomic nerves, get in contact with hematopoietic stem cells and maintain them in hibernation by regulating activation of latent TGF-beta [38].
Transection of a nerve fiber initiates Wallerian degeneration of the distal stump. As opposed to oligodendrocytes, SCs maintain the ability to dedifferentiate to an immature phenotype in response to nerve injury or disease, and they can actively promote the repair and functional recovery. The repair SCs express inflammatory mediators, such as interleukins and TNFα, as well as anti-inflammatory cytokines (IL-10, Epo, or TGFβ) and growth factors shown to promote Wallerian degeneration, macrophage attraction, and axonal regeneration upon nerve injury [34].
A number of molecules have been shown to play important roles in modulating SC behavior after nerve injury.
LDL receptor-related protein 1 (LRP1) is a significant factor involved in the development and maintenance of Schwann Cells, both myelinating and NMSCs [39]. LRP1 is one of the molecules upregulated after various types of peripheral nerve injury.
The study of Campana et al. proved that LPR1 upregulation was directly correlated with local production of TNFα and TNFα/LPR1 signaling is one of the survival mechanisms for SC migration and survival observed in in vitro studies [40].
Another signaling receptor that plays an important role in regulation of Schwann cell-axon interactions is fibroblast growth factor receptor (FGFR). Fibroblast growth factor 2 (FGF2) is one of the essential regulators of peripheral nerve regeneration after injury [41]. Three of its receptors, expressed by Schwann cells and dorsal root ganglia neurons, are FGFR1, FGFR2, and FGFR3 which are all upregulated after nerve injury [42].
One day after nerve transection, all SCs start to proliferate within the basal lamina. One week post-injury, RSCs double in length, and after 4 weeks they are three-fold longer and were called repair-supportive Schwann cells. About 50% of repair cells derive from RSCs. The loss of axonal contact determines cells to branch. They form branches lying parallel to the main cell axis, building cellular columns and Bungner bands distal to injury site and offering the support of regenerating sprouts. They will further differentiate to myelinating cells after regeneration [43].
Most unmyelinated C-fibers ensheathed by Remak cells are nociceptors [39]. They transmit pain information to the brain. Thus, the dysfunction of RSC induces an altered transmission of the nociceptive stimuli, which leads to severe neuropathic pain.
The specific loss of GABBR1 in SCs results in an increased number of C-unmyelinated fibers, leading to a hypersensitivity to thermal and mechanical stimuli. There is also an alteration of the locomotor coordination, without any injury. It is not known whether these consequences are caused only by the modification of the unmyelinated axon number [19].
Other in vivo studies showed that after injury, in LRP1 knockout animals, the resulting hypomyelination and impaired RSCs ensheathment lead to motor dysfunction and mechanical allodynia [39] without any traumatic injury. These pathological changes can cause notable painful symptoms such as mechanical allodynia [39]. In a model with partial nerve injury, the LRP-negative mice have a higher degree of RSC apoptosis, an accelerated degeneration, and further more severe pain in the LRP than the nonmutant mice [39]. These findings suggest the involvement of RSC in the pathophysiology of neuropathic pain and the importance of LRP1 in the physiology of RSC and open the possibility of using RSC as a new therapeutic target in the treatment of neuropathic pain.
In an experimental study in vivo on FGFR1 and FGFR2 single and FGFR1/FGFR2 double conditional knockout mice, Furusho et al. showed that lack of FGFR1 and FGFR2 signaling in NMSCs resulted in sensory axonal neuropathy in unmyelinated C-fibers and the impairment of thermal pain sensitivity [42]. Another study by Chen et al. performed on transgenic mice that postnatally express a dominant-negative ErbB receptor in NMSCs but not in the myelinating ones led to a progressive peripheral neuropathy with loss of unmyelinated axons and heat/cold pain [44]. Altogether, such data suggest the important role of RSCs in in the modulation of pain sensitivity in peripheral sensory neuropathies.
Charcot-Marie-Tooth type 1A (CMTA1A) is a genetic disease of the peripheral nervous system in which demyelination and further aberrant remyelination occur in a repeated cycle, with an “onion bulb” appearance in microscopy. From the clinical point of view, CMT1A is characterized by weakness and muscle atrophy in the lower limbs and later on by sensory loss. Myelinating Schwann cells are classically known to be impaired in CMT1A, but it seems that there is also an impairment of the RSC [45]. A proliferation of RSC takes place as a response to the degeneration of the myelinated axons that appear to secrete mitogenic factors [45]. Unexpectedly, no degeneration occurs in the unmyelinated fibers [45]. These findings reveal that RSC are altered in CMT1A, but without any impact on the unmyelinated fibers, in comparison to the relation between myelinating SCs alteration and degenerated myelinated axons. Further studies need to elucidate the contribution of RSC to the pathogenesis of CMT1A.
PSC, also known as teloglia or terminal Schwann cell, is a type of non-myelinating Schwann cell which is found above the presynaptic nerve terminal at the level of the NMJ. Louis-Antoine Ranvier described in 1878 the presence of a type of cell in the NMJ distinct from the axon terminal or the muscle fiber. He named this cells “arborization nuclei” because of their widespread projections along the NMJs. Later on, with improved histology techniques and in the era of electron microscopy, several studies identified the presence of this specific type of cell in the NMJ (Figure 2C).
PSCs express several markers that are used to highlight them in situ. The most common approach used is anti-S100b immunolabeling [46]. S100b is a nonspecific marker for all types of SCs, either myelinating or non-myelinating ones. In amphibians only, to distinguish PSCs from myelinating SCs, two specific antibodies are used, peanut agglutinin (PNA) [47] and 2A12 monoclonal antibody [48], which mark the extracellular matrix and the cells’ surface, respectively. Interestingly, PSCs express several myelin proteins such as myelin-associated glycoprotein (MAG), galactocerebroside, protein zero (P0), and 2′,3′-cyclic nucleotide 3′-phosphodiesterase [49]. The cells are not involved in the process of myelination, though the presence of these proteins proves the common origin of the two types of Scs. Additionally, PSCs express on their surface several receptors such as acetylcholine receptors, ATP, purinergic receptors, and L-type voltage-dependent calcium channels that usually take part in the synaptic transmission [50, 51, 52, 53] supporting the hypothesis that PSCs play an active role in the NMJ rather than having only a structural role.
Several studies determined that the number of PSCs gradually increase after birth [54]. Adult NMJ may contain one up to five PSCs [55, 56, 57], and their number is modulated by PSC-muscle cross talk through neurotrophins [58].
PSCs tend to be positioned at the presynaptic side, on top of the motor axon terminal, without the intervention of a basal lamina [55, 56]. Recently a new population of fibroblast-like cells named kranocytes—NMJ-capping cells—was detected on the other side, above the basal lamina of the PSC, covering all other cells of the NMJ. They are thought to have important roles in the NMJ repair after nerve injury [59, 60]. Kranocytes appear to communicate with PSCs via neuregulin signaling pathway to act synergistically after nerve damage [59].
Most studies about PSCs were performed either on amphibian (frog) or rodent (mouse) samples [53]. A peculiarity of the frog’s NMJ, where the unmyelinated nerve terminal is completely surrounded by PSCs and does not form dilated terminal buttons and the synaptic contact is formed all along, is that PSCs send finger-like projections into the synaptic cleft, on the presynaptic side, which separate, at a regular distance, active areas where the neurotransmitters are released from covered areas [52, 61]. These active areas correspond on the opposite side to the folds of the sarcolemma, the postsynaptic element of the NMJ, which are rich in nicotinic acetylcholine receptors [52, 61]. In mammals, PSC projections do not reach the synaptic cleft (Figure 2D).
PSCs are involved in the growth and maintenance of the NMJ during development.
Although these cells do not take part in the initial formation of the axon-muscle junction, PSCs have key contributions in the next stages of NMJ development. In animal models lacking SCs, the axon reaches the muscle in the initial step of the NMJ formation, but only for a brief time [62, 63]. In the absence of SCs, the NMJ gets disrupted, suggesting the vital role of PSCs in the NMJ maintenance during development [64]. Soon after the contact between the axon and the muscle, PSCs intensively divide, sprout, and are primarily involved in the growth of the synapse [64].
PSCs are also involved in the physiological processes of polyneuronal innervation and synapse elimination. PSCs are involved in the multiple innervation process of the muscles and suffer a regression in parallel with the axonal withdrawal [1, 65, 66]. After the process of axonal withdrawal, PSCs are engaged in the removal of nerve debris, through phagocytosis [67].
The signaling pathway which facilitates the survival and growth of PSCs and the tight communication between PSCs and motor axons is the neuregulin1-ErbB pathway [1].
PSCs have important roles in the maintenance of the NMJ during the adult life as the structural support. Ablation in PSCs on the adult NMJ does not impede the immediate structure and function of the synapse, but after a period of time, the motor axon terminals retract, and the NMJ collapses [64, 68]. Thus PSCs have a significant contribution to the structural maintenance of the synapse under the action of physical factors such as the intense tractions between the nerve and the muscle [53].
These cells dynamically participate in the process of synaptic transmission of information between the motor axons and the muscles, having an important role in the modulation of NMJ activity [53, 57, 69]. Not only PSCs can alter the synaptic transmission, but PSC activity can also be modified by synaptic transmission. Or, as some authors like to say, PSCs can both “talk” and “listen” in the synapse [53, 69].
When the nerve terminal increases its firing rate and a large amount of neurotransmitter is released in the synaptic cleft, a simultaneous increase of intracellular calcium occurs in PSCs [70, 71]. A similar effect is obtained by applying exogenous acetylcholine and ATP, molecules normally released by the synaptic vesicles, to PSCs [51]. Moreover, the levels of intracellular calcium vary depending on the type of the nerve firing rate, either burst or continuous [72]. These events do not occur in the myelinating SCs and emphasize the detection of synaptic activity by PSCs and the modification of their cellular behavior secondary to the synaptic transmission [69]. This is similar to a decoding process of the synaptic activity. Thereby, the events correspond to the “listening” ability of PSCs in the synapse.
The increase of the PSC intracellular calcium levels does not play only a “decoder” role. This transient raising modulates the synapse by intensifying the neuromuscular transmission. PSCs are expressed on the surface of several G protein-coupled receptors with contributions in the modulation of the synapse activity [73]. Evidences suggest that different ligands of these G protein-coupled receptors determine different changes in the neuromuscular transmission, as follows: a GTP analogue decreased the neurotransmitter release, while a GDP analogue reduced the synaptic depression [73]. These events correspond to the “talking” ability of PSCs in the synapse.
Therefore, PSCs are not only a structural, passive component of the NMJ, but an active one. These evidences confirm that the NMJ is a tripartite synapse.
PSCs induce and guide the growth of nerve sprouts to re-establish the NMJ after nerve injury.
All the actions that PSCs perform in an attempt to regain the activity of the NMJ appear to be mediated by neuregulin1-ErbB signaling pathway [74].
First of all, after nerve degeneration, PSCs develop phagocytic traits for the clearance of the debris from the nerve terminals [75].
Second of all, PSCs are involved in the guiding of reinnervation. A few days after the nerve injury, PSCs from the altered NMJ begin to abundantly sprout, and these new processes reach adjacent undamaged synapses [76]. In this manner, “bridges” are established between the innervated and the dennervated NMJs. The role of the newly formed bridges is to facilitate the nerve pathway to find the altered NMJ and to regenerate the synapse more rapidly [69, 76]. However, satellite NMSCs seem to play a role in nerve regeneration after insult as well and might be involved in pathogenic pathways of neuropathic pain [77].
Miller Fisher syndrome is a Guillain-Barré syndrome variant with antibodies against GQ1b ganglioside that is clinically characterized by ataxia, ophthalmoplegia, and areflexia. Studies on mouse models revealed that PSCs represent an important target of the autoimmune process, the cellular destruction is complement dependent, and this pathogenic mechanism might be relevant for the human disease [68, 78].
Amyotrophic lateral sclerosis (ALS) is a challenge for both the clinician and the researcher due to the obscure pathological mechanisms that are still not completely understood. The role of glial cells in the pathophysiology of the disease is not clear yet. Most probably the SC modifications are a consequence of the neurodegeneration process. However in human patients with ALS, PSCs have abnormal features with cellular processes that extend into the synaptic cleft [79]. Additionally, in ALS mouse models, PSCs have abnormal intracellular levels of calcium, causing a flaw in the synaptic “decoding” function [80].
Another neuromuscular disease in which PSCs appear to be involved is spinal muscular atrophy (SMA). In an ultrastructural study on SMA mouse models, PSCs in the diaphragmatic muscle show changes in their morphology such as vacuole-like translucent profiles and an electron-dense cytoplasm [81]. Another study on SMA mouse models revealed that in the evolution of the disease, there is a progressive loss of PSCs, leading to an improperly remodeling and regeneration of the NMJ [82].
Although little is known on the NMSC, they are very important players for normal PNS function. Recent studies showed that RSCs play a very important role in the development of peripheral nerves and regeneration after injury. RSCs are also involved in the modulation of pain sensitivity in peripheral sensory neuropathies. Even in the absence of injury, disturbance in axonal-RSC interaction is followed by neuropathic pain.
Additionally, PSCs are mandatorily involved not only in synaptogenesis but also in the growth and maintenance of the normal synapse as well as after denervation. Morphological changes of PSCs were detected in various pathological conditions suggesting their potential involvement in the pathogenic mechanism of such diseases.
A better understanding of the molecular mechanisms that govern the development and functioning of NMSCs could broaden the perspective on the pathogenesis and potential therapeutic targets for neuropathy and peripheral nerve injuries.
This work was funded by Ministry of Education and Research in Romania under grants no. 7PFE/16.10.2018 and PN 1N/2019_19.29.01.02.
The authors declare no conflict of interest.
Schwann cells Remak Schwann cells nonmyelinated Schwann cells nerve growth factor glial growth factor extracellular signal-regulated kinase neuropathy target esterase fibroblast growth factor receptor neuregulin 1 neuregulin 1 type III glial cell line-derived neurotrophic factor gamma-aminobutyric acid type B1 receptor SC precursors immature Schwann cells perisynaptic Schwann cells neuromuscular junction peanut agglutinin amyotrophic lateral sclerosis Charcot-Marie-Tooth type 1A
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He is also active in popular science writing data science stories for reputed blogs (KDNuggets, TowardsDataScience, Naukas). Besides, he has recently embarked on mentoring programmes as mentor, and has also worked as data science trainer.",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"103779",title:"Prof.",name:"Yalcin",middleName:null,surname:"Isler",slug:"yalcin-isler",fullName:"Yalcin Isler",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRyQ8QAK/Profile_Picture_1628834958734",biography:"Yalcin Isler (1971 - Burdur / Turkey) received the B.Sc. degree in the Department of Electrical and Electronics Engineering from Anadolu University, Eskisehir, Turkey, in 1993, the M.Sc. degree from the Department of Electronics and Communication Engineering, Suleyman Demirel University, Isparta, Turkey, in 1996, the Ph.D. degree from the Department of Electrical and Electronics Engineering, Dokuz Eylul University, Izmir, Turkey, in 2009, and the Competence of Associate Professorship from the Turkish Interuniversity Council in 2019.\n\nHe was Lecturer at Burdur Vocational School in Suleyman Demirel University (1993-2000, Burdur / Turkey), Software Engineer (2000-2002, Izmir / Turkey), Research Assistant in Bulent Ecevit University (2002-2003, Zonguldak / Turkey), Research Assistant in Dokuz Eylul University (2003-2010, Izmir / Turkey), Assistant Professor at the Department of Electrical and Electronics Engineering in Bulent Ecevit University (2010-2012, Zonguldak / Turkey), Assistant Professor at the Department of Biomedical Engineering in Izmir Katip Celebi University (2012-2019, Izmir / Turkey). He is an Associate Professor at the Department of Biomedical Engineering at Izmir Katip Celebi University, Izmir / Turkey, since 2019. In addition to academics, he has also founded Islerya Medical and Information Technologies Company, Izmir / Turkey, since 2017.\n\nHis main research interests cover biomedical signal processing, pattern recognition, medical device design, programming, and embedded systems. He has many scientific papers and participated in several projects in these study fields. He was an IEEE Student Member (2009-2011) and IEEE Member (2011-2014) and has been IEEE Senior Member since 2014.",institutionString:null,institution:{name:"Izmir Kâtip Çelebi University",country:{name:"Turkey"}}},{id:"339677",title:"Dr.",name:"Mrinmoy",middleName:null,surname:"Roy",slug:"mrinmoy-roy",fullName:"Mrinmoy Roy",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/339677/images/16768_n.jpg",biography:"An accomplished Sales & Marketing professional with 12 years of cross-functional experience in well-known organisations such as CIPLA, LUPIN, GLENMARK, ASTRAZENECA across different segment of Sales & Marketing, International Business, Institutional Business, Product Management, Strategic Marketing of HIV, Oncology, Derma, Respiratory, Anti-Diabetic, Nutraceutical & Stomatological Product Portfolio and Generic as well as Chronic Critical Care Portfolio. A First Class MBA in International Business & Strategic Marketing, B.Pharm, D.Pharm, Google Certified Digital Marketing Professional. Qualified PhD Candidate in Operations and Management with special focus on Artificial Intelligence and Machine Learning adoption, analysis and use in Healthcare, Hospital & Pharma Domain. Seasoned with diverse therapy area of Pharmaceutical Sales & Marketing ranging from generating revenue through generating prescriptions, launching new products, and making them big brands with continuous strategy execution at the Physician and Patients level. Moved from Sales to Marketing and Business Development for 3.5 years in South East Asian Market operating from Manila, Philippines. Came back to India and handled and developed Brands such as Gluconorm, Lupisulin, Supracal, Absolut Woman, Hemozink, Fabiflu (For COVID 19), and many more. In my previous assignment I used to develop and execute strategies on Sales & Marketing, Commercialization & Business Development for Institution and Corporate Hospital Business portfolio of Oncology Therapy Area for AstraZeneca Pharma India Ltd. Being a Research Scholar and Student of ‘Operations Research & Management: Artificial Intelligence’ I published several pioneer research papers and book chapters on the same in Internationally reputed journals and Books indexed in Scopus, Springer and Ei Compendex, Google Scholar etc. Currently, I am launching PGDM Pharmaceutical Management Program in IIHMR Bangalore and spearheading the course curriculum and structure of the same. I am interested in Collaboration for Healthcare Innovation, Pharma AI Innovation, Future trend in Marketing and Management with incubation on Healthcare, Healthcare IT startups, AI-ML Modelling and Healthcare Algorithm based training module development. I am also an affiliated member of the Institute of Management Consultant of India, looking forward to Healthcare, Healthcare IT and Innovation, Pharma and Hospital Management Consulting works.",institutionString:null,institution:{name:"Lovely Professional University",country:{name:"India"}}},{id:"1063",title:"Prof.",name:"Constantin",middleName:null,surname:"Volosencu",slug:"constantin-volosencu",fullName:"Constantin Volosencu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/1063/images/system/1063.png",biography:"Prof. Dr. Constantin Voloşencu graduated as an engineer from\nPolitehnica University of Timișoara, Romania, where he also\nobtained a doctorate degree. He is currently a full professor in\nthe Department of Automation and Applied Informatics at the\nsame university. Dr. Voloşencu is the author of ten books, seven\nbook chapters, and more than 160 papers published in journals\nand conference proceedings. He has also edited twelve books and\nhas twenty-seven patents to his name. He is a manager of research grants, editor in\nchief and member of international journal editorial boards, a former plenary speaker, a member of scientific committees, and chair at international conferences. His\nresearch is in the fields of control systems, control of electric drives, fuzzy control\nsystems, neural network applications, fault detection and diagnosis, sensor network\napplications, monitoring of distributed parameter systems, and power ultrasound\napplications. He has developed automation equipment for machine tools, spooling\nmachines, high-power ultrasound processes, and more.",institutionString:"Polytechnic University of Timişoara",institution:{name:"Polytechnic University of Timişoara",country:{name:"Romania"}}},{id:"221364",title:"Dr.",name:"Eneko",middleName:null,surname:"Osaba",slug:"eneko-osaba",fullName:"Eneko Osaba",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/221364/images/system/221364.jpg",biography:"Dr. Eneko Osaba works at TECNALIA as a senior researcher. He obtained his Ph.D. in Artificial Intelligence in 2015. He has participated in more than twenty-five local and European research projects, and in the publication of more than 130 papers. He has performed several stays at universities in the United Kingdom, Italy, and Malta. Dr. Osaba has served as a program committee member in more than forty international conferences and participated in organizing activities in more than ten international conferences. He is a member of the editorial board of the International Journal of Artificial Intelligence, Data in Brief, and Journal of Advanced Transportation. He is also a guest editor for the Journal of Computational Science, Neurocomputing, Swarm, and Evolutionary Computation and IEEE ITS Magazine.",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"275829",title:"Dr.",name:"Esther",middleName:null,surname:"Villar-Rodriguez",slug:"esther-villar-rodriguez",fullName:"Esther Villar-Rodriguez",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/275829/images/system/275829.jpg",biography:"Dr. Esther Villar obtained a Ph.D. in Information and Communication Technologies from the University of Alcalá, Spain, in 2015. She obtained a degree in Computer Science from the University of Deusto, Spain, in 2010, and an MSc in Computer Languages and Systems from the National University of Distance Education, Spain, in 2012. Her areas of interest and knowledge include natural language processing (NLP), detection of impersonation in social networks, semantic web, and machine learning. Dr. Esther Villar made several contributions at conferences and publishing in various journals in those fields. Currently, she is working within the OPTIMA (Optimization Modeling & Analytics) business of TECNALIA’s ICT Division as a data scientist in projects related to the prediction and optimization of management and industrial processes (resource planning, energy efficiency, etc).",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"49813",title:"Dr.",name:"Javier",middleName:null,surname:"Del Ser",slug:"javier-del-ser",fullName:"Javier Del Ser",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/49813/images/system/49813.png",biography:"Prof. Dr. Javier Del Ser received his first PhD in Telecommunication Engineering (Cum Laude) from the University of Navarra, Spain, in 2006, and a second PhD in Computational Intelligence (Summa Cum Laude) from the University of Alcala, Spain, in 2013. He is currently a principal researcher in data analytics and optimisation at TECNALIA (Spain), a visiting fellow at the Basque Center for Applied Mathematics (BCAM) and a part-time lecturer at the University of the Basque Country (UPV/EHU). His research interests gravitate on the use of descriptive, prescriptive and predictive algorithms for data mining and optimization in a diverse range of application fields such as Energy, Transport, Telecommunications, Health and Industry, among others. In these fields he has published more than 240 articles, co-supervised 8 Ph.D. theses, edited 6 books, coauthored 7 patents and participated/led more than 40 research projects. He is a Senior Member of the IEEE, and a recipient of the Biscay Talent prize for his academic career.",institutionString:"Tecnalia Research & Innovation",institution:null},{id:"278948",title:"Dr.",name:"Carlos Pedro",middleName:null,surname:"Gonçalves",slug:"carlos-pedro-goncalves",fullName:"Carlos Pedro Gonçalves",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRcmyQAC/Profile_Picture_1564224512145",biography:'Carlos Pedro Gonçalves (PhD) is an Associate Professor at Lusophone University of Humanities and Technologies and a researcher on Complexity Sciences, Quantum Technologies, Artificial Intelligence, Strategic Studies, Studies in Intelligence and Security, FinTech and Financial Risk Modeling. He is also a progammer with programming experience in:\n\nA) Quantum Computing using Qiskit Python module and IBM Quantum Experience Platform, with software developed on the simulation of Quantum Artificial Neural Networks and Quantum Cybersecurity;\n\nB) Artificial Intelligence and Machine learning programming in Python;\n\nC) Artificial Intelligence, Multiagent Systems Modeling and System Dynamics Modeling in Netlogo, with models developed in the areas of Chaos Theory, Econophysics, Artificial Intelligence, Classical and Quantum Complex Systems Science, with the Econophysics models having been cited worldwide and incorporated in PhD programs by different Universities.\n\nReceived an Arctic Code Vault Contributor status by GitHub, due to having developed open source software preserved in the \\"Arctic Code Vault\\" for future generations (https://archiveprogram.github.com/arctic-vault/), with the Strategy Analyzer A.I. module for decision making support (based on his PhD thesis, used in his Classes on Decision Making and in Strategic Intelligence Consulting Activities) and QNeural Python Quantum Neural Network simulator also preserved in the \\"Arctic Code Vault\\", for access to these software modules see: https://github.com/cpgoncalves. He is also a peer reviewer with outsanding review status from Elsevier journals, including Physica A, Neurocomputing and Engineering Applications of Artificial Intelligence. Science CV available at: https://www.cienciavitae.pt//pt/8E1C-A8B3-78C5 and ORCID: https://orcid.org/0000-0002-0298-3974',institutionString:"University of Lisbon",institution:{name:"Universidade Lusófona",country:{name:"Portugal"}}},{id:"241400",title:"Prof.",name:"Mohammed",middleName:null,surname:"Bsiss",slug:"mohammed-bsiss",fullName:"Mohammed Bsiss",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/241400/images/8062_n.jpg",biography:null,institutionString:null,institution:null},{id:"276128",title:"Dr.",name:"Hira",middleName:null,surname:"Fatima",slug:"hira-fatima",fullName:"Hira Fatima",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/276128/images/14420_n.jpg",biography:"Dr. Hira Fatima\nAssistant Professor\nDepartment of Mathematics\nInstitute of Applied Science\nMangalayatan University, Aligarh\nMobile: no : 8532041179\nhirafatima2014@gmal.com\n\nDr. Hira Fatima has received his Ph.D. degree in pure Mathematics from Aligarh Muslim University, Aligarh India. Currently working as an Assistant Professor in the Department of Mathematics, Institute of Applied Science, Mangalayatan University, Aligarh. She taught so many courses of Mathematics of UG and PG level. Her research Area of Expertise is Functional Analysis & Sequence Spaces. She has been working on Ideal Convergence of double sequence. She has published 17 research papers in National and International Journals including Cogent Mathematics, Filomat, Journal of Intelligent and Fuzzy Systems, Advances in Difference Equations, Journal of Mathematical Analysis, Journal of Mathematical & Computer Science etc. She has also reviewed few research papers for the and international journals. She is a member of Indian Mathematical Society.",institutionString:null,institution:null},{id:"414880",title:"Dr.",name:"Maryam",middleName:null,surname:"Vatankhah",slug:"maryam-vatankhah",fullName:"Maryam Vatankhah",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Borough of Manhattan Community College",country:{name:"United States of America"}}},{id:"414879",title:"Prof.",name:"Mohammad-Reza",middleName:null,surname:"Akbarzadeh-Totonchi",slug:"mohammad-reza-akbarzadeh-totonchi",fullName:"Mohammad-Reza Akbarzadeh-Totonchi",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Ferdowsi University of Mashhad",country:{name:"Iran"}}},{id:"414878",title:"Prof.",name:"Reza",middleName:null,surname:"Fazel-Rezai",slug:"reza-fazel-rezai",fullName:"Reza Fazel-Rezai",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"American Public University System",country:{name:"United States of America"}}},{id:"302698",title:"Dr.",name:"Yao",middleName:null,surname:"Shan",slug:"yao-shan",fullName:"Yao Shan",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Dalian University of Technology",country:{name:"China"}}},{id:"125911",title:"Prof.",name:"Jia-Ching",middleName:null,surname:"Wang",slug:"jia-ching-wang",fullName:"Jia-Ching Wang",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"National Central University",country:{name:"Taiwan"}}},{id:"357085",title:"Mr.",name:"P. Mohan",middleName:null,surname:"Anand",slug:"p.-mohan-anand",fullName:"P. Mohan Anand",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Indian Institute of Technology Kanpur",country:{name:"India"}}},{id:"356696",title:"Ph.D. Student",name:"P.V.",middleName:null,surname:"Sai Charan",slug:"p.v.-sai-charan",fullName:"P.V. Sai Charan",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Indian Institute of Technology Kanpur",country:{name:"India"}}},{id:"357086",title:"Prof.",name:"Sandeep K.",middleName:null,surname:"Shukla",slug:"sandeep-k.-shukla",fullName:"Sandeep K. Shukla",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Indian Institute of Technology Kanpur",country:{name:"India"}}},{id:"356823",title:"MSc.",name:"Seonghee",middleName:null,surname:"Min",slug:"seonghee-min",fullName:"Seonghee Min",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Daegu University",country:{name:"Korea, South"}}},{id:"353307",title:"Prof.",name:"Yoosoo",middleName:null,surname:"Oh",slug:"yoosoo-oh",fullName:"Yoosoo Oh",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:"Yoosoo Oh received his Bachelor's degree in the Department of Electronics and Engineering from Kyungpook National University in 2002. He obtained his Master’s degree in the Department of Information and Communications from Gwangju Institute of Science and Technology (GIST) in 2003. In 2010, he received his Ph.D. degree in the School of Information and Mechatronics from GIST. In the meantime, he was an executed team leader at Culture Technology Institute, GIST, 2010-2012. In 2011, he worked at Lancaster University, the UK as a visiting scholar. In September 2012, he joined Daegu University, where he is currently an associate professor in the School of ICT Conver, Daegu University. Also, he served as the Board of Directors of KSIIS since 2019, and HCI Korea since 2016. From 2017~2019, he worked as a center director of the Mixed Reality Convergence Research Center at Daegu University. From 2015-2017, He worked as a director in the Enterprise Supporting Office of LINC Project Group, Daegu University. His research interests include Activity Fusion & Reasoning, Machine Learning, Context-aware Middleware, Human-Computer Interaction, etc.",institutionString:null,institution:{name:"Daegu Gyeongbuk Institute of Science and Technology",country:{name:"Korea, South"}}},{id:"262719",title:"Dr.",name:"Esma",middleName:null,surname:"Ergüner Özkoç",slug:"esma-erguner-ozkoc",fullName:"Esma Ergüner Özkoç",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Başkent University",country:{name:"Turkey"}}},{id:"346530",title:"Dr.",name:"Ibrahim",middleName:null,surname:"Kaya",slug:"ibrahim-kaya",fullName:"Ibrahim Kaya",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Izmir Kâtip Çelebi University",country:{name:"Turkey"}}},{id:"419199",title:"Dr.",name:"Qun",middleName:null,surname:"Yang",slug:"qun-yang",fullName:"Qun Yang",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Auckland",country:{name:"New Zealand"}}},{id:"351158",title:"Prof.",name:"David W.",middleName:null,surname:"Anderson",slug:"david-w.-anderson",fullName:"David W. Anderson",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Calgary",country:{name:"Canada"}}}]}},subseries:{item:{id:"41",type:"subseries",title:"Water Science",keywords:"Water, Water resources, Freshwater, Hydrological processes, Utilization, Protection",scope:"