\r\n\tThe hope is that this book will include three main topics: threshold-based segmentation, clustering-based segmentation, and artificial neural networks based segmentation. But it is not limited to these topics in any specific way. This is a purely organizational division, seeking to present papers that describe the segmentation process through traditional, intermediate, and advanced approaches.
",isbn:"978-1-83881-906-4",printIsbn:"978-1-83881-113-6",pdfIsbn:"978-1-83881-907-1",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,isSalesforceBook:!1,isNomenclature:!1,hash:"687a58dfbb2e544237cda3807153ff2c",bookSignature:"Dr. Paulo Eduardo Ambrosio",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11923.jpg",keywords:"Thresholding, Binarization, Threshold Determination, Thresholding Methods and Techniques, Clustering, Similarity, Segmentation by Regions, Clustering Methods and Techniques, Artificial Neural Networks, Deep Learning, Artificial Intelligence, AI Methods and Techniques",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"April 13th 2022",dateEndSecondStepPublish:"June 21st 2022",dateEndThirdStepPublish:"August 20th 2022",dateEndFourthStepPublish:"November 8th 2022",dateEndFifthStepPublish:"January 7th 2023",dateConfirmationOfParticipation:null,remainingDaysToSecondStep:"24 days",secondStepPassed:!1,areRegistrationsClosed:!1,currentStepOfPublishingProcess:2,editedByType:null,kuFlag:!1,biosketch:"Dr. Paulo E. Ambrósio is vice-director of the Center for Radiation Sciences and Technology (CPqCTR/UESC) and coordinates a Special Committee on Computing Applied to Health, Brazilian Computer Society. His research interests include applied computing, with an emphasis on health and biology, working mainly with pattern recognition, medical imaging, and computational modeling.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"256064",title:"Dr.",name:"Paulo",middleName:"Eduardo",surname:"Ambrosio",slug:"paulo-ambrosio",fullName:"Paulo Ambrosio",profilePictureURL:"https://mts.intechopen.com/storage/users/256064/images/system/256064.png",biography:"Paulo E. Ambrósio has a Ph.D. in Medical Sciences from the Medical School of Ribeirão Preto, University of São Paulo (FMRP/USP), Brazil. He is currently an associate professor in the Department of Exact and Technological Sciences, State University of Santa Cruz (UESC); vice-director of the Center for Radiation Sciences and Technology (CPqCTR/UESC); and coordinator of the Special Committee on Computing Applied to Health, Brazilian Computer Society. His research interests include applied computing, with emphasis on health and biology, working mainly with pattern recognition, medical imaging, and computational modeling.",institutionString:"Universidade Estadual de Santa Cruz",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"1",institution:{name:"Universidade Estadual de Santa Cruz",institutionURL:null,country:{name:"Brazil"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"9",title:"Computer and Information Science",slug:"computer-and-information-science"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"347259",firstName:"Karmen",lastName:"Daleta",middleName:null,title:"Ms.",imageUrl:"//cdnintech.com/web/frontend/www/assets/author.svg",email:"karmen@intechopen.com",biography:null}},relatedBooks:[{type:"book",id:"1591",title:"Infrared Spectroscopy",subtitle:"Materials Science, Engineering and Technology",isOpenForSubmission:!1,hash:"99b4b7b71a8caeb693ed762b40b017f4",slug:"infrared-spectroscopy-materials-science-engineering-and-technology",bookSignature:"Theophile Theophanides",coverURL:"https://cdn.intechopen.com/books/images_new/1591.jpg",editedByType:"Edited by",editors:[{id:"37194",title:"Dr.",name:"Theophile",surname:"Theophanides",slug:"theophile-theophanides",fullName:"Theophile Theophanides"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3161",title:"Frontiers in Guided Wave Optics and Optoelectronics",subtitle:null,isOpenForSubmission:!1,hash:"deb44e9c99f82bbce1083abea743146c",slug:"frontiers-in-guided-wave-optics-and-optoelectronics",bookSignature:"Bishnu Pal",coverURL:"https://cdn.intechopen.com/books/images_new/3161.jpg",editedByType:"Edited by",editors:[{id:"4782",title:"Prof.",name:"Bishnu",surname:"Pal",slug:"bishnu-pal",fullName:"Bishnu Pal"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"371",title:"Abiotic Stress in Plants",subtitle:"Mechanisms and Adaptations",isOpenForSubmission:!1,hash:"588466f487e307619849d72389178a74",slug:"abiotic-stress-in-plants-mechanisms-and-adaptations",bookSignature:"Arun Shanker and B. 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"}},{type:"book",id:"72",title:"Ionic Liquids",subtitle:"Theory, Properties, New Approaches",isOpenForSubmission:!1,hash:"d94ffa3cfa10505e3b1d676d46fcd3f5",slug:"ionic-liquids-theory-properties-new-approaches",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/72.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"2270",title:"Fourier Transform",subtitle:"Materials Analysis",isOpenForSubmission:!1,hash:"5e094b066da527193e878e160b4772af",slug:"fourier-transform-materials-analysis",bookSignature:"Salih Mohammed Salih",coverURL:"https://cdn.intechopen.com/books/images_new/2270.jpg",editedByType:"Edited by",editors:[{id:"111691",title:"Dr.Ing.",name:"Salih",surname:"Salih",slug:"salih-salih",fullName:"Salih Salih"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"117",title:"Artificial Neural Networks",subtitle:"Methodological Advances and Biomedical Applications",isOpenForSubmission:!1,hash:null,slug:"artificial-neural-networks-methodological-advances-and-biomedical-applications",bookSignature:"Kenji Suzuki",coverURL:"https://cdn.intechopen.com/books/images_new/117.jpg",editedByType:"Edited by",editors:[{id:"3095",title:"Prof.",name:"Kenji",surname:"Suzuki",slug:"kenji-suzuki",fullName:"Kenji Suzuki"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3828",title:"Application of Nanotechnology in Drug Delivery",subtitle:null,isOpenForSubmission:!1,hash:"51a27e7adbfafcfedb6e9683f209cba4",slug:"application-of-nanotechnology-in-drug-delivery",bookSignature:"Ali Demir Sezer",coverURL:"https://cdn.intechopen.com/books/images_new/3828.jpg",editedByType:"Edited by",editors:[{id:"62389",title:"PhD.",name:"Ali Demir",surname:"Sezer",slug:"ali-demir-sezer",fullName:"Ali Demir Sezer"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"872",title:"Organic Pollutants Ten Years After the Stockholm Convention",subtitle:"Environmental and Analytical Update",isOpenForSubmission:!1,hash:"f01dc7077e1d23f3d8f5454985cafa0a",slug:"organic-pollutants-ten-years-after-the-stockholm-convention-environmental-and-analytical-update",bookSignature:"Tomasz Puzyn and Aleksandra Mostrag-Szlichtyng",coverURL:"https://cdn.intechopen.com/books/images_new/872.jpg",editedByType:"Edited by",editors:[{id:"84887",title:"Dr.",name:"Tomasz",surname:"Puzyn",slug:"tomasz-puzyn",fullName:"Tomasz Puzyn"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3569",title:"Biodegradation",subtitle:"Life of Science",isOpenForSubmission:!1,hash:"bb737eb528a53e5106c7e218d5f12ec6",slug:"biodegradation-life-of-science",bookSignature:"Rolando Chamy and Francisca Rosenkranz",coverURL:"https://cdn.intechopen.com/books/images_new/3569.jpg",editedByType:"Edited by",editors:[{id:"165784",title:"Dr.",name:"Rolando",surname:"Chamy",slug:"rolando-chamy",fullName:"Rolando Chamy"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"42581",title:"Effect of Abiotic Stress on Photosystem I-Related Gene Transcription in Photosynthetic Organisms",doi:"10.5772/55350",slug:"effect-of-abiotic-stress-on-photosystem-i-related-gene-transcription-in-photosynthetic-organisms",body:'Photosystem I (PSI) from cyanobacteria and chloroplasts is a multisubunit membrane-protein complex that catalyses electron transfer from reduced plastocyanin in the thylakoid lumen to oxidized ferredoxin in the chloroplast stroma or cyanobacterial cytoplasm [1-4]. PSI is responsible for NADP+ reduction and cyclic photophosphorylation and consists of at least 8 polypeptides. Its major components are the P700 chlorophyll a A1 and A2 apoproteins whose molecular weights vary between 60 and 70 kd, depending on the species [5]. In this chapter, we discuss recent progress on several topics related to the functions of the PSI complex, like the protein composition of the complex in the plant and algae, the structure and organization of the PSI subunits and the regulation of photosystem I-related gene under abiotic stress conditions. Furthermore, PSI seems to be well protected from photoinhibition in vivo in many plant and algae species and many environmental conditions. The physiology and molecular mechanism during short term adaptation to changes under oxidative stress is discussed in functional and structural terms. Finally, such characteristics of PSI photoinhibition with special emphasis on the relationship between two photosystems as well as the protective mechanism of PSI in vivo is reviewed with respect to function of the thylakoid membrane.
PSI catalyzes the light-driven electron transfer from the soluble electron carrier plastocyanin on the luminal side of thylakoid membrane, to ferredoxin on the stromal side of thylakoid membrane. In plants, the PSI complex consists of at least 19 protein subunits, approximately 175 chlorophyll molecules, 2 phylloquinones and 3 Fe4S4 clusters [6]. The crystal structure of PSI from
The PSI complex of most plants and algae consists of 13 subunits: at least five chloroplast-encoded subunits (PsaA, PsaB, PsaC, PsaI and PsaJ) and eight nucleusencoded subunits (PsaD, PsaE, PsaF, PsaG, PsaH, PsaK, PsaL, PsaN) and numerous redox cofactors and antenna chlorophylls [8]. An additional subunit, PsaM, has only been found in cyanobacteria and in the chloroplast genomes of some lower plants and algae. The PSI subunits PsaG, PsaH and PsaN are only found in eukaryotic photosynthetic organisms and are missing in cyanobacteria[8,9,10].
The major subunits of photosystem I,
Previous studies showed that mutants deficient in PsaB are unable to synthesize both PsaB and PsaA whereas mutants affected primarily in PsaA synthesis are still able to produce PsaB [2,3,11]. Based on these results it was proposed that PsaB is an anchor protein during PSI assembly, which needs to be synthesized and integrated into the thylakoid membrane before the other PSI subunits are synthesized [12]. In its absence these polypeptides are no longer synthesized and/or are rapidly degraded. Elucidating how PsaB is translated and inserted into the thylakoid membrane is thus important for understanding the initial steps of PSI assembly.
The subunits PsaC, PsaD and PsaE do not contain transmembrane α-helices [3,2,14]. They are located on the stromal side of the complex, forming the stromal hump. They are in close contact to the stromal loop regions of PsaA and PsaB. Subunit PsaC carries the two terminal FeS clusters FA and FB, and is located in the central part of the stromal hump. PsaD forms the part of this hump, which is closest to the trimeric axis [15,2,3]. The C-terminal part of PsaD forms a `clamp\' surrounding PsaC. PsaE is located on the side of the hump, which is distal from the trimer axis[16,17].
The clusters of PsaC are characterised by their distinct electron paramagnetic resonance (EPR) spectra [18,19]. PsaC is likely to posses a pseudo-C2 symmetry axis that is oriented perpendicular to distance vector connecting the two iron-sulfur clusters, FA and FB. The role of subunit PsaC in coordination of the two terminal FeS clusters was suggested from the conserved sequence motif CXXCXXCXXXCP which is found twice in the gene of PsaC [3,20]. A homology of subunit PsaC to bacterial ferredoxins, also containing two [4Fe-4S] clusters, was proposed from sequence similarity [21]. The structures of PsaC and these ferredoxins, such as that from
PsaD is a peripheral subunit of photosystem I (PSI1), an integral protein complex in the thylakoid membrane of oxygenic photosynthetic organisms. Biochemical experiments [20, 21] and analyses of the primary structure of PsaD suggest that it does not posses a transmembranal segment and that it faces the stromal side of the thylakoid membrane. The PsaD is a polypeptide of 139-144 amino acids in cyanobacteria, but has an N-terminal extension of several residues in higher plants, yielding a total length of 158-162 residues [20]. Topological studies [3, 2, 19, 22, 23] and data from an X-ray structure of PSI at 4 Å [24, 25]show that PsaD probably contains an R-helix and is in contact principally with PsaC and PsaE, and also with PsaH and PsaL [25, 26, 27]. The three-dimensional structure of the higher-plant PSI as determined by electron crystallography has been recently reported [27], confirming that the stromal ridge of higher-plant PSI can also be interpreted as being due to the PsaC, -D, and -E subunits. The N-terminal part of the PsaD subunit can be accessed by the proteases, and its C-terminal region is exposed to solvent [23, 14]. Comparison of the amino acid sequences of PsaD from several species shows that the C-terminal part is highly conserved, especially in a region containing many basic residues[23].
In spinach, PsaD is synthesized in the cytoplasm as a precursor of 23.2 kDa [2,23, 21] that is processed to produce the mature 17.9-kDa PasD. In vitro assembly assays indicated that both forms of the protein, pre-PsaD and PsaD, can assemble into the thylakoid membranes, specifically into the PSI complex [2, 14, 22, 24, 25, 26]
PsaD is known to interact strongly with ferredoxin. Chemical cross-linking of PSI and ferredoxin consistently yield a product consisting of PSI-D and ferredoxin [14, 23, 25], and recently the interaction has been shown even with isolated PSI-D and ferredoxin [47]. These observations clearly point to an important function of PSI-D in docking of ferredoxin in both eukaryotes and cyanobacteria. The position of ferredoxin in these crosslinked complexes was also identified by electron microscopy [28]. The same docking site was also found for flavodoxin [29] and is in agreement with a docking site proposed from the structural model of PS I at 6 Å resolution. Subunit PsaD is essential for electron transfer to ferredoxin [28].
PsaE is like PsaD a hydrophilic subunit exposed to the stroma. PsaE is encoded in the nucleus and the mature protein is about 11 kDa. Just like PsaD, the mature PsaE in plants has an extended N-terminal region. The extension is variable from 30-40 amino acid residues. As was the case for PsaD, there is no extension in the chloroplast encoded PsaE in
The structure of subunit PsaE (8 kDa) in solution was determined by 1H and 15N-NMR [32, 33]. The loop connecting L-strands 3 and 4 was found to be flexible in the NMR structure[33]. The structure of PsaE in the PSI complex is very similar to the solution structure, with some remarkable deviations in the loop region E-L3L4, which corresponds to the CD loop in the NMR structure. The twist of this loop reported at 4 Å [34] is fully confirmed in the structural model at 2.5 Å resolution. This loop is involved in interactions with PsaA, PsaB and PsaC, suggesting a change of the loop conformation during assembly of the photosystem I complex.
Different functions have been reported for PsaE. PsaE in barley has also been found to be associated with ferredoxin NADP oxidoreductase (FNR) [35]. In cyanobacteria, FNR has a domain linking it to the phycobilisomes [36]. However, recent observations have shown that in spite of this domain, FNR does appear to interact with PsaE [37].
Six small intrinsic membrane protein components of photosystem I have been identified from the gene sequence in
The small subunits can also be divided into two groups according to their location in the complex: PsaL, PsaI and PsaM are located in the region where the adjacent monomers face each other in the trimeric PS I complex, whereas PsaF, PsaJ, PsaK and PsaX are located at the detergent exposed surface of photosystem[40].
PsaF binds the luminal electron donor, plastocyanin [41, 42, 43, 44], and It is essential for providing excitation energy transfer from LHCI to the core complex. Early work showed that PsaF (then called subunit III) was required for electron transfer from Pc to P700 [45, 46]. Subsequently, it was demonstrated that Pc cross-linked to PSI is capable of fast electron transfer to P700 and the cross-linking partner was identified as PsaF.
PsaG and PsaK are two small membrane intrinsic proteins of approximately 10-11 kDa each with two transmembrane α-helices connected by a stromal-exposed loop [47, 48] and they show a 30 % sequence homology in
PsaH is a 10 kDa protein with one predicted transmembrane helix [54]. The subunit can be chemically cross-linked to PsaD, PsaI and PsaL [50, 54, 55, 56]. Thus, PsaH must be located near the region that constitutes the domain of interaction between monomers in
PsaN is a small extrinsic subunit of about 10 kDa [54]. PsaN is synthesized with a presequence directing it to the lumen and is the only subunit located exclusively on the lumenal side of PSI [59]. The Psa-G, -H, and -N fulfill functions in PSI that are unique to eukaryotic PSI. PsaH has been shown to be involved in state 1–state 2 transitions probably in the interaction with LHCII [54], PsaN is involved in interaction with plastocyanin [41], and PsaG is involved in the stabilization of LHCI and regulation of PSI activity [53]. It is therefore likely that PsaO plays a role in the interaction between the PSI core and other complexes in the thylakoid membrane such as LHCI or LHCII [50, 60]. Alternatively PsaO is involved in the regulation or fine tuning of PSI activity. Together with PsaO, the subunits Psa-G, -H, and -N are unique to higher plants and algae. Structure of plant PSI at 4.4 Å, the structure and position of the Psa-G and -H subunits within the PSI complex are revealed [49]. However, Psa-N and -O are either not resolved at the current resolution or are lost from the complex during preparation and their structure and exact position in the PSI complex are therefore not known.
PsaJ is a hydrophobic subunit of 4-5 kDa. The protein is chloroplast encoded as is the case also for PsaI, which has a similar size and hydrophobicity [54]. PsaJ is located near PsaF as evidenced by cross-linking [56]. The protein has been thought to be membrane spanning, however, the structural model of cyanobacterial PSI suggest that PsaJ may form an unusual bend helix in the plane of the membrane [60]. In the unicellular green alga
Psa-K from spinach may be tightly associated with the PSIA/B heterodimer [61, 62]. However, PsaK from spinach, pea, and barley was depleted from the PSI core by methods used for separation of LHCI from PSI [65, 64]. Treatment of thylakoids with proteases resulted in degradation of PsaK, indicating that part of the PSI-K polypeptide is exposed on the stromal side of the thylakoid membrane. It has therefore been proposed that the membrane-spanning PsaK subunit is located near the rim of the PSI complex between the PSI and LHCI and is thus easily lost upon detergent treatment [51].
There is significant sequence similarity between PsaG and PsaK from eukaryotes [64]. A computer comparison of PsaG and PsaK from
X-ray crystallography of the PSI core from cyanobacteria [22, 25, 50, 55] as well as modeling studies indicates strong interpigment interactions and unique protein environment as a source for the low energy shifts in absorption of PSI. Biochemical and spectroscopic studies of Light Harvesting Complex I (LHCI) suggest that in the PSI-LHCI super complexes the peripheral antenna and the PSI core antenna have structurally and spectrally distinct pools of red pigments [22]. As in the PSI core antenna, excitonically coupled dimers or trimers of Chl
The antenna of PSI consists of two structurally and functionally parts; the core antenna and preripheral antenna.
The core antenna of PSI contains in total appromeximately 100 chla and 15 β-carotene of which the majority is bound to the PsaA/PsaB dimmer [49]. The chlorophylls have their Q4 absorption maxima around 680 nm. A comparison of absorbtion spectra of PSI, LHCI complexes from wild type A, thaliana and from a mutant lacking the PsaL and PsaH subunits revealed that the about five chlorophylls that are bound to these subunits absorb preferentially at 638 and 667 nm [73].
The prepheral antenna of PSI consists of nuclear encoded chlorophyll binding proteins (Lhca) which are transported into the chloroplast and form a light-harvesting complex (LHCI) which increases the light-harvesting capacity of PSI [74].
The protein contacts between the core complex and LHCI appear to be relatively weak, which explains the biochemical sensitivity of the PSI-LHCI supercomplex to detergent attack. It is clear, however, that each of the four light-harvesting proteins fits its specific binding site, because the interface of the core complex formed by subunits PsaG, PsaB, PsaF, PsaJ, PsaA, and PsaK is asymmetric [4, 49]. Lhca1 antenna protein is bound to the core through PsaB and PsaG. Previous studies showed that plants in which
The extrinsic protein, PsaD, has two reported functions in the PS I complex of cyanobacteria, algae and higher plants. The first function, deduced from
While the function of the ten PSI subunits common to plants, algae and cyanobacteria has been studied extensively, the role of the three eukaryotic-specific subunits PsaH, PsaG and PsaN is less well understood. One reason is that these subunits are nucleus-encoded and thus less amenable to genetic manipulation [2, 53]. However it has recently been possible to generate transgenic
The analysis of the PsaF-deficient strain and its suppressor reveals that in the presence of a functional antenna, an intact donor side of PSI is required for protection of
The function of the PsaF protein (15 kDa) at the lumenal side has been subject to discussion. In intact cells of the green alga Chlamydomonas reinhardtii, PsaF is implicated in the electron transfer from plastocyanin to oxidized P700 by providing a docking site for the electron donor: psaFÿ mutants of this organism had a dramatically reduced electron transfer rate [15, 45, 76]. In contrast, a psaFÿ mutant of the cyanobacterium Synechocystis PCC 6803 exhibited normal electron transfer to P700., implying that PsaF is not essential for the docking of either cytochrome c6 or plastocyanin to PSI [15, 76, 82]. While PSI is extracted as a mixture of trimers and monomers from thylakoid membranes of wild-type cyanobacteria, PSI from mutants that lack the PsaL protein (16 kDa) exists exclusively as a monomer after membrane solubilization [73]. In addition, proteolysis studies have shown PsaL to be located about the 3-fold axis of the trimer, thus holding it together [5, 15]. Little is known about the function of the four other membrane intrinsic subunits (PsaI, -J, -K and -M) that have molecular masses ranging from 3 to 8 kDa [63].
Comparison of deduced primary sequences indicates that the PsaL subunits contain a greater diversity than seen in other subunits [15, 54]. Function of PsaL in the formation of PS I trimers was revealed by the inactivation of the psaL gene in
Photosystem I (PSI) is a multiprotein complex in the thylakoid membrane of chloroplasts, providing an interesting system for studying the nucleo-choloroplast relationship in plants.. The core subunits of the PSI reaction centre are still encoded by the chloroplast genome, whereas the genes for the peripheral subunits are located in the nucleus in green algae and land plants. In this study, we dissected the promoter architecture of a nuclear-encoded PSI gene in tobacco, and investigated whether the characteristics found in this promoter are shared by those of the other photosynthesis nuclear genes.
Sequencing of these proteins and/or their corresponding genes have registered two genes,
The genes for the two subunits, psaA and psaB, are located adjacent to each other in the large single-copy region of circular plastid genome in higher plants [89]. Gene psaB is followed by rps14 encoding the chloroplast ribosomal protein CS14 [90]. The psaA-psaB-rps14 gene cluster was found to co-transcribe into a 5- to 6-kb polycistronic mRNA in spinach [91], tobacco [90], and rice [89]. Cheng et. al. [90] have performed a detailed transcriptional analysis of the promoter of rice psaA-psaB-rps14 operon with deleted mutants in vitro. They showed that two functional promoters denoted as “-175” and “-129” were revealed.
Some of the known signals which are targeted to these genes are light, plastid signal(s) and hormones. Nuclear encoded genes of PSI are effectively activated by white and red light, while blue light is less effective. Essential promoter units which are responsive to light were identified by deletions and mutational analyses. Another set of signals is produced by the plastids reporting the state of the plastids to the nucleus. When plastids were bleached by the addition of norflurazon, transcription of nuclear PSI genes was decreased [92]. The nature of these plastid-derived signals has still to be elucidated, however it appears that the communication between the two organelles is mediated by more than one signal [93, 94]. The responsive units within the promoter appear to be the same as the light-responsive elements [93]. The third group of signals acting on genes for thylakoid proteins is plant hormones. Kusnetsov et al. [95] suggested that it could be shown that cytokinin stimulated the transcription of
In the spinach
In higher plants, the function of the nuclear-encoded subunits has been elucidated in recent years using RNAi (RNA interference), antisense techniques and insertional mutagenesis in
Plant chloroplasts include two large pigment-protein complexes, such as photosystem I and photosystem II that are located within thylakoid membranes. The reaction centres of PSI and PSII are formed by chlorophyll a-binding heterodimers, PsaA/PsaB and PsbA/PsbD proteins, respectively. PSI and PSII are both organized into supercomplexes with variable amounts of nuclear-encoded chlorophyll a/b-binding proteins forming light-harvesting antenna complexes around PSI (LHCI) and PSII (LHCII) (Figure 1).
Environmental factors such as temperature, UV-light, irradiance, drought and salinity are known to affect photosynthesis in both cyanobacteria and plants (Figure 1). In cyanobacteria, several studies have been reported on photosynthetic electron transport activities both under salt and high light stress conditions in whole cells as well as thylakoid membranes[102,103].
Schematic figure of oxidative stress effects on PSII and PSI
Photoinhibition of Photosystem I (PSI) was first reported by Jones and Kok [104], is the one who originally called them ‘photoinhibition’ [105]. The subsequent studies revealed that the activity of PSI could be photoinhibited in thylakoid membranes [106, 107] as well as in isolated PSI complexes [108, 109]. However, PSI-specific photoinhibition was never observed in intact leaves until 1994 [110]. The selective photoinhibition of PSI was first observed in cucumber leaves treated at chilling temperatures [111]. In contrast PSI is generally believed to be less sensitive to light stress and its photoprotection mechanisms were less investigated. Nevertheless, several recent evidences showed that PSI can also be targeted by photoinhibition, especially under chilling conditions and when the linear electron transport chain is unbalanced [111, 112]. PSI photoprotection has been suggested to be mainly mediated by oxygen scavenging enzymes (e.g., superoxide dismutase and ascorbate peroxidase) which efficiently detoxify reactive species produced at the reducing side of Photosystem I [113]. A decreased ability of these enzymes to scavenge ROS at low temperatures was proposed to be the reason of the major PSI photo-sensitivity in chilling conditions [111, 112, 114]. As a summary, processes during of PSI photoinhibition as follow;
Decreased rate of reducing power utilization by Calvin cycle enzymes (Rubisco) at low temperature;
Photoinduced electron transfer from PS2 and reduction of PS1 electron acceptors (FeS centres, Fd, NADP);
Cold-induced diminish of oxidative defense system (tAPX, sAPX etc.) capacity;
Recombination of separated charges in PS1 reaction centres between P700+ and A0 – or A1– and Chl triplet formation;
Energy migration from TChl to O2 and production of singlet oxygen 1O2;
Superoxide anion radical and H2O2 production in Mehler reaction;
Fenton reaction (OH• formation as result of interaction of H2O2 with reduced FeS-clusters);
Destruction of FeS-clusters by OH\n\t\t\t\t\t\t;
Inactive FeS-clusters induce the conformational changes of PS1 core complex proteins facilitating its access for proteases;
Degradation of PsaB and PsaA gene products and release of 45 kDa and 51kDa proteins;
Processes (8) and (10) result PS1 photoinhibition
The eventual effect of the abiotic stress on plant growth and crop productivity is a result not only of the extent of the damage but also on the capacity for recovery after the damage has taken place. Although the recovery and repair of PSII after photoinhibition have been a subject of many studies [115, 116, 117], there is very little known about the recovery and repair of PSI. Teicher et. al. [118] showed that PSI recovery is a very slow process, which may take several days even under optimal conditions in field-grown barley. A more recent study showed that PSI damage in cucumber is not even completely reversible [119]
The few previous studies have not shown whether PSI repair is similar to PSII repair where one particular subunit, D1, is specifically remade whereas the rest of the complex is reused [120]. Clearly, the PSI repair process must involve some protein turnover but it is not known whether the breakdown that is observed during photodamage is caused directly by the damage or is part of the recovery process.
Light are highly unpredictable resource for plants and the changes in growth irradiance induce several changes in biochemical and molecular composition of the plant cell. Murchie et al. [121] showed that there are 99-light responsive genes which were down regulated and 130 were up-regulated in rice during light treatment. Majority of these genes showed reduced levels of expression in response to high light, whereas stress related genes showed increased level of expression. In order to avoid over-excitation of chlorophyll protein complexes and photooxidation, a regulated degradation of LHC was observed in rice leaves along with a decline in CP-24, PSI genes and a 10 kD PSII gene was also noticed under high light [121].
PS I has long been reported to be less affected than PSII by high light [105]. PSI in isolated thylakoid membranes was inactivated by high light [122]. Since PSI is the terminal electron carrier in the chloroplast, it was identified as a major site producing ROS and shown to be closely associated with ROS-scavenging systems in the chloroplast [123]. The role of ROS inactivating PSI reaction center and degradation of psaA and psaB under high light conditions has been studied [124]. Very recently, Jiao et al [125] demonstrated that high light stress readily photoinhibited PSI, following the loss of psaC as well as degradation of PSI reaction center proteins (psaA and psaB). The findings suggest that PSI photoinhibition can be a limiting factor in crop productivity under high light.
Several studies demonstrated that thylakoid memebrane proteins were affected by salt stress. In
A few reports have shown the effects of metals on the activity of photosystem I (PSI) and some of them was controversial. Neelam and Rai [133] reported that cadmium treatment inhibits PSI activity in
Schizophrenia is a chronic, debilitating disorder that affects approximately 1% of the world’s population [1]. The disorder is a significant socioeconomic burden because of the early onset of the disease, the low remission rates, and their debilitating consequences: as the disease’s progression leads to the inability, for a significant share of schizophrenic patients, to fulfill their professional, social and household roles [2]. Phenomenologically schizophrenia is considered to be a heterogeneous syndrome including several dimensions: positive, disorganization, cognitive, affective, and negative dimension. These are the most commonly reported by factor analytic studies dimensions of schizophrenia [3, 4, 5].
Negative symptoms have long been recognized as a core feature of schizophrenia, and the current studies report that their severity has a more significant impact on real-world functioning and quality of life than other categories of symptoms [6, 7, 8, 9, 10]. Negative symptoms, by their definition, interfere with the patient’s ability to maintain social activities or personal relationships, to work or study, and even to live independently and are minimally influenced by antipsychotic medication [11, 12, 13]. Even though the attention has shifted from the positive to the negative symptoms in the last decades, the latter still represent an unmet therapeutical target, and very few pharmaceutical agents are labeling indications for negative symptoms [14, 15, 16, 17].
Negative symptoms have been commonly described as first symptoms of schizophrenia, and very frequently, they appear during the prodromal phase of the disorder [18, 19]. The prevalence of negative symptoms is hard to establish, with reports from literature ranging between 40% and 90%, these differences result from the heterogeneity of the used definitions, constitutive factors, and assessment methods [20]. The European First Episode Schizophrenia Trial reported that at least one negative symptom was noted in up to 54.2% of the patients at baseline [21]. The Clinical Antipsychotic Trials of Interventions Effectiveness, which is one of the most extensive controlled studies for schizophrenia, reported negative symptoms in 40% of the patients [22], and the CLAMORS study reported one or more negative symptoms were present in 57.6% of patients [23]. What is known is that they can occur at any point during the illness, but the long-term course is less clear. Some studies report stability of negative domain [24], while others describe an unstable course [25]. Many factors could be accountable for this difference, but it is widely accepted that improvement in negative symptoms is more common during the first years of the disorder, and an exacerbation is frequently seen in chronic patients [26].
Across studies, it is generally evidenced that negative symptoms are frequently reported in any disease phase. They are associated with poor functional outcomes, which is why it is imperative to assess and address these symptoms to improve the quality of life for patients with schizophrenia.
The classification of the symptoms of schizophrenia as being positive or negative regards the fact that positive symptoms are a surplus to normal experiences, for example, hallucinations or delusions, whereas the negative symptoms are represented by diminished experiences or expression [27]. The term of negative symptoms was borrowed from neurology, and it was coined by John Reynolds in 1858 and was introduced in psychiatry by the French psychiatrists Gaetan Gatian de Clerambault and Henry Ey [28].
The negative symptoms were considered a fundamental feature of the disease since its first descriptions by Emil Kraepelin and Eugen Bleuler [27]. Emil Kraepelin, influenced by the work of Alois Alzheimer, was the one who named the disease dementia praecox. He considered that the process underpinning the manifestation of the disease was an affective degeneration. In his treatise “Dementia praecox and paraphrenia”, he described the flat affect and the motivational deficits, which are now called negative symptoms, and he proposed the theory that the affective deficit represents the basis for the psychopathological process [27, 28, 29, 30].
Eugen Bleuler renamed the disease schizophrenia and emphasized that there is a group of disorders under this name. At a descriptive level, he introduces a dichotomy between the symptoms of schizophrenia, and he labels the fundamental and accessory symptoms. The fundamental symptoms are described as the essence of the illness necessary to diagnose loose associations, ambivalence, affective flattening, and avolition. The accessory symptoms are hallucinations and delusions that were not necessary to diagnose schizophrenia but were highly visible and often the reason for clinical presentation. Unlike his predecessor, he considers that the affect as a process is intact in schizophrenia and that the fundamental psychopathological process is the splitting between affect and cognition, from which the symptoms of the disease arise [27, 28, 30].
The interest for negative symptoms decreased and shifted towards the positive symptoms once Chlorpromazine was developed and introduced in psychiatric wards in 1952. The awareness regarding the importance of these symptoms reemerged in the last decades because of their negative influence on the patients’ real-life function [10, 11, 31].
The interest for the negative symptoms is constantly growing, although it has been about 40 years since Nancy Andreasen and co-workers (1982) resumed this research area and highlighted the importance of this category of symptoms. Andreasen defined twenty negative symptoms, which were grouped into five factors: flat affect, alogia, avolition/apathy, anhedonia/social withdrawal, and attention deficit. She proposed that negative and positive symptoms are part of a continuum representing the extreme and opposite poles of this continuum. Patients presenting mixed symptoms, positive and negative symptoms, were considered intermediate patients [28, 32].
Later, Timothy Crow [33] postulated the hypothesis of two types of disease, schizophrenia type I and type II. Type I is characterized by positive symptoms (hallucinations, delusions), showing a good response to neuroleptic medication, without intellectual deficit, and with an increase in D2 receptors. Type II is characterized by negative symptoms (alogia, affective flattening, decreased interest, and pleasure), an inadequate response to neuroleptic medication, intellectual deficits, and changes in the temporal lobes’ neural structures. According to this author, type I could develop negative symptoms and progress to type II, but type II could not transform into type I, even though positive symptoms could appear [33].
In 1988 William Carpenter and collaborators brought to attention a new perspective on the concept of negative symptoms and made an essential distinction between idiopathic, primary negative symptoms and secondary negative symptoms. Secondary negative symptoms occur as side effects of neuroleptic medication (extrapyramidal symptoms, sedation) or secondary to depression, social deprivation or substimulation or secondary to positive symptoms (active social withdrawal secondary to paranoid ideation, or diminished expression, which could be a coping strategy for patients in an acute psychotic episode who are unable to process tumultuous hallucinations). At a phenomenological level, primary and secondary negative are very similar and yet very hard to distinguish. The diagnosis of primary negative symptoms, according to Carpenter, should be only a diagnosis of exclusion. The importance of distinguishing these categories of symptoms is that secondary negative symptoms may be responsive to specific treatments [34].
As a result of this classification, deficit schizophrenia was introduced to define patients with primary and persistent negative symptoms. The dichotomy, deficit/non-deficit schizophrenia, is based exclusively on the presence or absence of primary and stable negative symptoms [34]. The diagnostic criteria for deficit schizophrenia are presented in Table 1. Several subsequent studies have compared patients with deficit schizophrenia versus non-deficit schizophrenia and found overwhelming evidence that the two types are different in that concerns risk factors, premorbid functioning, disease evolution, neurobiological basis, and response to treatment. The clinical picture of deficit schizophrenia shows more significant social withdrawal, anergia, more severe cognitive impairments, poorer premorbid adjustment than non-deficit schizophrenia, and often summer birth instead of non-deficit schizophrenia, which predominates winter birth [37, 38, 39, 40, 41]. Although the two diagnostic categories have been validated in several studies, the evolution over time of negative symptoms does not always allow a clear distinction between primary and secondary symptoms, making the diagnosis very difficult. Moreover, first psychotic episode patients represent another diagnostical challenge [42, 43, 44].
a. The presence of at least two of the following six negative symptoms:
|
b. The presence of symptoms described in point (a) for at least 12 months including periods of clinical stability; |
c. The symptoms described at point (a) are primary symptoms, not secondary to other factors such as anxiety, medication side effects, psychotic symptoms, intellectual disability or depression; |
d. The patient meets the DSM criteria (3rd edition, or later editions) for schizophrenia. |
A different approach, which tried to reduce the heterogeneity of negative symptoms, was proposed by the National Institute for Mental Health (USA) in The Consensus Statement on Negative Symptoms (2006), which defined the constitutive factors of the negative domain: flat affect, alogia, social withdrawal, avolition, and anhedonia, essentially the same areas that have been defined by Nancy Andreasen (1982) except for the attention deficit. A short definition of each symptom, according to this consensus, is presented in Table 2 [45].
Flat affect | A decrease in the expression of emotions and emotional reactivity to events, observed spontaneously during speech or after targeted questions (facial expression, intonation, and gestures) |
Alogia | Quantitative reduction of speech and spontaneity (the amount of information spontaneously developed by the patient in addition to the necessary answers to the questions). |
Social withdrawal | Interactions and initiatives to have social contacts are diminished due to decreased motivation and decreased desire to form or maintain relationships with other people. |
Anhedonia | Diminished experience of pleasure for a variety of activities or events, over time of the activities or events (consumer anhedonia) or for subsequent activities and events (anticipatory anhedonia) |
Avolition | Reducing the initiative and persistence of goal-oriented activities due to diminished motivation |
Definition of negative symptoms of schizophrenia [45].
As a result of the same consensus, the National Institute for mental Health defined the concept of persistent negative symptoms, which is more applicable in the clinical setting than the concept of deficit schizophrenia because of its more permissive criteria. The criteria for the persistent negative symptoms imply only a period of six months, with at least moderate intensity negative symptoms and low levels of positive, depressive, and extrapyramidal symptoms. Secondary negative symptoms can be included in this category if they are not responsive to a specific treatment [45].
In the attempt to describe the nature, the etiology, and find operational criteria for research in the field, other specific terms were defined: predominant, prominent, enduring/non-enduring negative symptoms. Unfortunately, there is no consensus regarding the exact definition of any of these terms as they were only used for research purposes [9].
Up to the present point, negative symptoms are considered to represent a heterogeneous domain of psychopathology. Recent factor analytic studies have provided evidence that the domain of negative symptoms can be grouped into two factors: avolition/apathy and diminished expression. The apathy/avolition subdomain includes avolition, social withdrawal, and anhedonia, and the diminished expression includes affective flattening and alogia [46, 47, 48]. This factorial structure has been confirmed by several studies using different scales for the evaluation of negative symptoms: Scale for the Assessment of Negative Symptoms (SANS), Positive and Negative Syndrome Scale (PANSS), Negative Symptoms Assessment Scale (NSA-16) and more recently developed scales Clinical Assessment Interview for Negative Symptoms (CAINS) and Brief Negative Symptom Scale (BNSS), which were specially developed to evaluate this factorial structure [49, 50]. Several studies have compared the importance of these domains regarding clinical features, disease progression, and impact on functioning. The domain of diminished expression (DE) turned out to be more persistent over time, have a higher prevalence in the early stages of the disease, and be associated with a longer duration of the prodromal phase of the disease than the apathy/avolition (AA) [51, 52, 53]. The AA domain is associated with poorer functioning, with a longer duration of untreated psychosis and non-adherence to treatment. These associations were not reported for the DE domain [47, 52, 54]. Research up to this point provided evidence that the AA and DE domains represent different clinical aspects of schizophrenia. Moreover, if these areas have different etiologies and should be approached differently from a therapeutic point of view are elements in an ongoing investigation, neuroimaging studies currently support this hypothesis [8, 55].
To date, no consensus has been reached on how to approach negative symptoms: categorical versus dimensional. Numerous studies demonstrated the validity of deficit schizophrenia construct or the subtype characterized by primary and persistent negative symptoms [51, 52, 54]. However, the dimensional approach is supported by several studies that have shown the presence of negative symptoms in other disorders than schizophrenia, such as schizoaffective disorder, depression, Parkinson’s disease, Huntington’s disease, Alzheimer’s disease, temporal lobe epilepsy, and even in the general population [8, 55, 56].
The heterogeneity in etiology and clinical manifestation of the negative symptoms in schizophrenia led to the exploration of several structural abnormalities, pathways, and mechanisms which may underlie this complex of symptoms. The attempt to reduce these symptoms’ heterogeneity leads to concepts of deficit and non-deficit schizophrenia and diminished expression and avolition/apathy domains. Different hypotheses have been constructed for these models’ pathophysiological mechanisms, but unfortunately without fully satisfying results [8, 9, 55, 56].
After deficit schizophrenia was described, several studies brought out data supporting the hypothesis that deficit schizophrenia differs from non-deficit schizophrenia in terms of risk factors, premorbid functioning, the evolution of the disease, neurobiological basis, and response to treatment [37, 38, 39, 40, 41]. Epidemiological studies support a prevalence of deficit schizophrenia: 15% of patients with a first episode of the disease, 25–30% in clinical trials, and 14–17% in population studies [37, 57, 58]. Structural and functional brain imaging studies have highlighted several differences between patients with deficit and non-deficit schizophrenia. Abnormalities and asymmetries in the temporal lobe level, cerebrospinal fluid accumulations in the left temporal lobe, volume reduction of the right temporal lobe have been reported in patients with deficit schizophrenia compared with patients with non-deficit schizophrenia and healthy subjects. Both groups of patients had a reduced volume of the dorsolateral prefrontal cortex and temporal lobes than healthy subjects [59, 60]. Several studies have reported white matter abnormalities, especially in the frontoparietal and frontotemporal circuits in patients with deficit schizophrenia. These patients present discontinuities in the inferior longitudinal fasciculus, arcuate fasciculus, and uncinate fasciculus, and it has been suggested that there may be a connection between these structural changes and the social and emotional dysfunctions characteristic for deficit schizophrenia [59, 60]. Functional imaging investigations report a decrease in glucose metabolism and a decrease in the frontal and parietal lobes’ blood flow in cases of deficit schizophrenia versus non-deficit schizophrenia or healthy volunteers [61, 62]. Studies that used functional MRI to assess the response to the reward reported a reduction of dorsal caudate nucleus activity in patients with deficit schizophrenia [63, 64].
Regarding the treatment of deficit schizophrenia, respectively of primary negative symptoms, the efficacy of several antipsychotics was evaluated: clozapine, olanzapine, zotepine, and amisulpride. These therapeutic options are superior to placebo therapy and first-generation antipsychotics, but not other classes of atypical antipsychotics, data suggesting that they would be effective for secondary negative symptoms [65, 66, 67, 68]. Recent studies have evaluated the efficacy of add-on therapies with agents that stimulate NMDA receptors: glycine, D-serine, and D-cycloserine, but no significant improvement in symptoms was reported on the primary negative ones [15, 40, 69, 70].
Persistent negative symptoms are a looser category than deficit schizophrenia as potential causes of secondary negative symptoms are not completely ruled out, but it is assumed that the secondary negative symptoms’ clinical expression is mild [45]. Also, this category includes all negative symptoms, primary or secondary, that do not respond to commonly used treatments, which are apparent during periods of clinical stability of the disease and interfere with the patient’s functionality [45]. There is great variability in the prevalence of persistent negative symptoms due to different definitions used for this category. Prevalence of persistent negative symptoms are higher than deficit schizophrenia and were estimated between 35% and 60% [21, 71, 72, 73].
Structural and functional imaging studies have reported volume reduction of the gray matter in the temporal lobes, cortical atrophy of the right superior temporal gyrus, right parahippocampal gyrus, and left orbitofrontal gyrus, and that structural abnormality of the white matter in the frontal lobes could be associated with persistent negative symptoms [74, 75, 76, 77].
Dopaminergic antagonism is the only common mechanism of drugs used to treat psychosis. However, subcortical dopamine excess is accompanied by a prefrontal dopaminergic function, which encompasses a reduced D1 receptor activation in the prefrontal cortex, dopamine hypoactivity in the caudate nucleus, and modifications in D3 receptor activity. These alterations appear to contribute to the pathogenesis of negative symptoms. Cariprazine is an atypical antipsychotic that is a partial agonist of dopamine receptors D3 and D2, with high selectivity for D3 receptors, which have been shown to be effective for predominant negative symptoms [78, 79]. Another compound, MIN-101, that has no affinity for dopaminergic receptors and acts on sigma-2 and serotonergic receptors 5-HT2A effectively reduces persistent negative symptoms [80].
Factor analysis studies have suggested that negative symptoms include two domains: apathy/avolition and diminished expression, which led to building separate hypotheses for these domains [45, 47, 52]. In current conceptualizations, the avolition/apathy domain is defined as deficits in different motivation areas. Two possible mechanisms and circuits are considered to be involved: the reward circuit and the salience circuit [81]. Functional MRI studies tried to elucidate the substrate of the motivational deficit using tasks involving reward anticipation, and it was found that there is an association between the activation of the ventral striatum and the apathy/avolition domain. This relationship has not been confirmed for the diminished expression domain. Only a limited number of studies have investigated the correlations between neural structures and the apathy/avolition domain, and the following results were reported: a low volume of the frontal lobes, thinning of the anterior cingulate cortex and orbitofrontal cortex, and structural abnormalities of connectivity between the medial orbitofrontal cortex and the anterior rostral cingulate cortex [55, 82, 83, 84, 85].
Cognitive-behavioral therapy was the first form of alternative therapy targeting poor motivation, anhedonia, and irrational cognitions. It promotes the patient’s involvement in defining goals and aims and targets, improving functionality and recovery of the patients. A positive effect of cognitive-behavioral therapy on negative symptoms in combination with antipsychotic medication has been proved, and the beneficial effects persist even after stopping therapy. Functional changes, highlighted by functional brain imaging studies, at striatal levels underlie this type of therapy’s effectiveness [86, 87].
Some studies suggest that dopaminergic agonists: methylphenidate, amphetamine, lisdexamfetamine, modafinil, selegiline are involved in relieving negative symptoms without worsening the positive symptoms. The exact mechanisms by which this class acts are not completely elucidated. Increasing dopamine and noradrenaline at the frontocortical level or the dopamine action at the striatal limbic level are possible mechanisms involved in the assumed action of dopaminergic agonists on a motivational deficit [17, 55, 88].
The inflammatory hypothesis of schizophrenia suggests that alterations in the prenatal immune system are involved in the disease’s etiology. Anti-inflammatory agents studied so far are pregnenolone, acetylsalicylic acid, cyclooxygenase-2, minocycline, N-acetylcysteine, and omega-3 fatty acids. To date, clinical trials have seemed promising, but these studies need to be replicated on a larger scale [89, 90, 91, 92].
High frequency transcranial magnetic stimulation (≤10 Hz) intensifies metabolism and excitability in the prefrontal cortex. It has been proved to be effective in treating negative symptoms when applied in the early stages of schizophrenia. The mechanisms of action of this method involve modulation of NDMA receptors and striatal dopamine release. This technique has not been proven effective for alogia, but only for the other negative symptoms [93, 94].
Transcranial direct current stimulation has been mainly studied for positive symptoms, auditory hallucinations, but an improvement of negative symptoms as a subsidiary result, especially motivational deficits, has been reported. The modulation of cortical–subcortical networks can explain the benefits for negative symptoms [95, 96].
The diminished expression domain’s pathophysiological mechanisms have received less attention than those involved in the apathy/avolition domain. It has been hypothesized that this domain is correlated with neurocognitive deficits and social cognition deficits [97]. In treatment naïve patients, there is an association between expressive deficits and neurological soft signs, which suggests the existence of diffuse neurodevelopmental abnormalities. Functional neuroimaging studies that investigated impaired emotional processing have shown a hypoactivity of different neural networks: the prefrontal, ventrolateral cortex, the amygdala, cingulate cortex, and the cuneus [98, 99, 100]. Activation of the anterior rostral cingulate cortex was negatively correlated with the diminished expression domain in the tasks which involve an interaction between reward and cognition [101].
Cognitive training, which aims to improve neurocognitive skills and social cognition, has been shown to restore the disrupted neural networks in the prefrontal cortex and anterior rostral cingulate cortex [102].
Social skills training for emotion perception, recognition, and expression, aims to educate patients about the necessity of social skills, verbal and nonverbal communication improvement, and it has been shown that it facilitates the release of oxytocin [103]. Considering the hypothesis that the strengthening social cognition could have beneficial effects on the diminished expression, the administration of intranasal oxytocin was studied, given its action on serotonin and dopamine in the nucleus accumbens and amygdala. Oxytocin is effective in emotion recognition and the theory of mind as add-on therapy and being used in the long term [104].
The progress in the genetics of schizophrenia in the last years has been noticeable. Heritability represents a statistical estimate to quantitate the relative genetic contribution to a trait relative to its environmental contributors. Heritability is the amount or proportion of phenotypic variance of the disease of interest in the population that is inherited through genetic factors. The heritability of schizophrenia has been established at 81% [105], making the genetic factor the most significant for the disease.
According to evidence from previous family and association studies, it has been suggested that genetic factors are involved in the development of schizophrenia and also in its clinical presentation. Studies that investigated genes potentially involved in negative symptoms pathogenesis highlighted that classifying patients with schizophrenia into specific subtypes based on predominant symptoms is useful for selecting the specific treatment. The findings, and references for these studies are summarized on Table 3.
Author | Year | Findings | Journal |
---|---|---|---|
Fanous et al. | 2005 | Variation in DTNBP1 may predispose subjects to a form of schizophrenia with high levels of negative symptoms. | American Journal of Psychiatry [106] |
DeRosse et al. | 2006 | Significant association between the CTCTAC haplotype and lifetime severity of negative symptoms in patients with schizophrenia. | American Journal of Psychiatry [107] |
Pelayo-Terán et al. | 2008 | Patients with a Val158 homozygote genotype had a higher severity of negative symptoms at the onset of the schizophrenia | American Journal of Medical Genetics [108] |
Wessman et al. | 2009 | DTNBP1 gene is associated with a schizophrenia phenotype characterized by prominent negative symptoms | Biological Psychiatry [109] |
Bertolino et al. | 2009 | Negative symptoms were weakly associated with promoter rs1236428 | Brain [110] |
Petrovsky et al. | 2010 | Association of prepulse inhibition deficits and polymorphisms in the a3 subunits of the CHRNA gene cluster. CHRNA3 polymorphisms were also associated with negative symptoms | Neuropsychopharmacology [111] |
Xu et al. | 2013 | Common genetic variations (ST3GAL1, RNF144, CTNNA3 and ZNF385D) are associated with negative symptoms of schizophrenia using meta-analysis. | PloS one [112] |
Mezquida et al. | 2016 | BDNF Val66Met polymorphism is associated with negative symptoms severity | European Psychiatry [113] |
Edwards et al. | 2016 | NKAIN2 was significantly associated with negative symptoms | Schizophrenia bulletin [114] |
Gao et al. | 2018 | Abnormal peripheral gene expression DNA methylation of MMP9 possible biomarker for negative symptom | Frontiers in Genetics [115] |
Schneider et al. | 2019 | Negative symptoms are core manifestations of psychosis in individuals with 22q11DS that strongly impact global functioning. | Schizophrenia Research [116] |
Genes potentially involved in negative symptoms’ pathogenesis.
Abbreviations: DTNBP1 (dystrobrevin binding protein 1), CHRNA3 (nicotinic acetylcholine receptor), BDNF (brain-derived neurotrophic factor), MMP9 (Matrix metalloproteinase-9), NKAIN2 (Sodium/Potassium Transporting ATPase Interacting 2), 22q11DS (22q11 deletion syndrome).
Genetics is rapidly growing, with technological discoveries making it increasingly possible to identify common and rare variants on genomic DNA. Much new and confirmatory work remains to be performed to elucidate the role of specific genetic variants in negative symptoms development and the distinct ways the genes and environment interact to result in schizophrenia susceptibility.
Conceptual work has highlighted that negative symptoms can be defined as primary or secondary, persistent, or transient, and they encompass two distinct domains: avolition/apathy and diminished expression. Deficit schizophrenia is defined as primary enduring negative symptoms, but more operative for research and clinical setting is the concept of persistent negative symptoms. Considering the heterogeneity of negative symptoms has brought some progress in research on their genetic and neurobiological basis and treatment approaches. Unfortunately, their underlying pathophysiology is still unknown, and the treatment remains a critical unmet need.
Several hypotheses have been proposed for the pathophysiology of schizophrenia, from which the dopaminergic hypothesis remains the leading one. The dopaminergic hypofunction of the frontal lobe and the mesolimbic structures seems to be underlying the negative symptoms. Despite the advances in the field, many clinical trials still consider the negative symptoms as a monolithic construct which might be the reason for the unsatisfactory results.
Further research directions should concentrate on the two distinct negative symptoms dimensions apathy/avolition and diminished expression, and even further on each symptom and its pathophysiology. Another interesting approach is the transdiagnostic one, which could be helpful in the attempt to disentangle the mechanisms underlying this category of symptoms by using information gathered from depression or Parkinson’s disease.
The authors declare no conflict of interest.
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The focus has passed from the administrative management tasks to becoming a strategic partner of the overall organization strategy, largely with the strong support of information technologies’ evolution in this field of knowledge area. The extended use of information systems has a deep effect in the way HRM is managed nowadays. It boosted a major transformation of human resources (HR) processes and practices within organizations, namely on how they collect, store, use, and share information. Several HRM processes have become more efficient and the impact of this service level improvement allowed a greater involvement of HR in the business strategy. This new role in business strategy adds significant changes to HR function and to its professionals. Along this chapter, we discuss the effects of information systems in HRM, considering the existing literature on the topic, and describe the benefits and possible limitations of using them. We also provide an overview of some applications of technology in functional areas of HRM, within organizations.",book:{id:"6259",slug:"management-of-information-systems",title:"Management of Information Systems",fullTitle:"Management of Information Systems"},signatures:"Marlene Sofia Alves e Silva and Carlos Guilherme da Silva Lima",authors:[{id:"211475",title:"M.D.",name:"Marlene",middleName:"Sofia",surname:"Silva",slug:"marlene-silva",fullName:"Marlene Silva"},{id:"211476",title:"Dr.",name:"Carlos",middleName:null,surname:"Lima",slug:"carlos-lima",fullName:"Carlos Lima"}]},{id:"62394",title:"Management Functions of Information System Components as an Integration Model",slug:"management-functions-of-information-system-components-as-an-integration-model",totalDownloads:1482,totalCrossrefCites:3,totalDimensionsCites:3,abstract:"Management functions develop first, as systematic steps to carry out management activities, while information components system follow later as part of management elements, where both must be integrated in order to make its practical implementation more clear. Management Functions and Information System Components as an integration model are (1) to explain Management Functions, Information System Components, Goals and Benefit related to Information System and (2) to explain integration process of Management Functions with Information System Component to get goals and benefits as an integrated model. Research method using expert method has done an integration of management function, which includes the cycle of P, O, A, C, E and I, to run management process, must be step by step, and as a cycle. Information components include S, H, F, B, and T and must have minimum requirement. Management of Information System needs goals and benefits that can be calculated clearly and specifically. To get goals and benefits in excellence performance are needed the integrated process to coordinate management functions and information system components, as an Integrated Model with an example in applications of software in Nosocomial Infection Control for Hospital, as the figure below.",book:{id:"6259",slug:"management-of-information-systems",title:"Management of Information Systems",fullTitle:"Management of Information Systems"},signatures:"Boy Subirosa Sabarguna",authors:[{id:"200387",title:"Ph.D.",name:"Boy Subirosa",middleName:null,surname:"Sabarguna",slug:"boy-subirosa-sabarguna",fullName:"Boy Subirosa Sabarguna"}]},{id:"57870",title:"Information and Information Technologies in Conflict Management",slug:"information-and-information-technologies-in-conflict-management",totalDownloads:1214,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"This paper analyzes information and modern information technologies as applied in different organizational environment and considers the content and peculiarities of conflict management process based on implementation of communicative scenarios. Currently, the need for escalated organizational transformations has become imminent, taking into account the intensifying development of the differentiated information society, which requires properly interactive and transparent policy-making. Correct understanding of information and effective implementation of information technologies is a rational attempt to harmonize the modern organizational environment reducing the level of conflict and improving efficiency indexes.",book:{id:"6259",slug:"management-of-information-systems",title:"Management of Information Systems",fullTitle:"Management of Information Systems"},signatures:"Andrei Aleinikov, Daria Maltseva, Alexander Kurochkin and Tatiana\nKoulakova",authors:[{id:"212005",title:"Dr.",name:"Andrey",middleName:null,surname:"Aleynikov",slug:"andrey-aleynikov",fullName:"Andrey Aleynikov"},{id:"219746",title:"Dr.",name:"Tatiana",middleName:null,surname:"Koulakova",slug:"tatiana-koulakova",fullName:"Tatiana Koulakova"},{id:"219747",title:"Dr.",name:"Daria",middleName:null,surname:"Maltseva",slug:"daria-maltseva",fullName:"Daria Maltseva"},{id:"219748",title:"Dr.",name:"Alexander",middleName:null,surname:"Kurochkin",slug:"alexander-kurochkin",fullName:"Alexander Kurochkin"}]},{id:"59493",title:"Some Methods for Evaluating Performance of Management Information System",slug:"some-methods-for-evaluating-performance-of-management-information-system",totalDownloads:1289,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"Recently, several kinds of information systems are developed for purposes and needs of business and play an important role in business organizations and management operations. Management information system, or MIS for short, is a kind of information system. It is a key factor to facilitate and attain efficient decision-making in an organization. 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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. 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In recent years, the application of chemistry to biological molecules has gained significant interest in medicinal and pharmacological studies. This topic will be devoted to understanding the interplay between biomolecules and chemical compounds, their structure and function, and their potential applications in related fields. Being a part of the biochemistry discipline, the ideas and concepts that have emerged from Chemical Biology have affected other related areas. 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Thus proteomics, an area of research that detects all protein forms expressed in an organism, including splice isoforms and post-translational modifications, is more suitable than genomics for a comprehensive understanding of the biochemical processes that govern life. The most common proteomics applications are currently in the clinical field for the identification, in a variety of biological matrices, of biomarkers for diagnosis and therapeutic intervention of disorders. From the comparison of proteomic profiles of control and disease or different physiological states, which may emerge, changes in protein expression can provide new insights into the roles played by some proteins in human pathologies. Understanding how proteins function and interact with each other is another goal of proteomics that makes this approach even more intriguing. Specialized technology and expertise are required to assess the proteome of any biological sample. Currently, proteomics relies mainly on mass spectrometry (MS) combined with electrophoretic (1 or 2-DE-MS) and/or chromatographic techniques (LC-MS/MS). MS is an excellent tool that has gained popularity in proteomics because of its ability to gather a complex body of information such as cataloging protein expression, identifying protein modification sites, and defining protein interactions. 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