Proposed classification of para aortic node assessment (Pomel et al. [7]).
\r\n\t
",isbn:"978-1-80356-477-7",printIsbn:"978-1-80356-476-0",pdfIsbn:"978-1-80356-478-4",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,isSalesforceBook:!1,isNomenclature:!1,hash:"b306ce94998737c764d08736e76d60e1",bookSignature:"Dr. Alyssa A Brewer and Dr. Brian Barton",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11636.jpg",keywords:"Mammalian, Primate, Human, Genetics and Epigenetics, Individual Variability, Adaptation, Cortical Reorganization, Cortical Recovery, Visual Field Map, Sensorimotor Maps, Bottom-Up Sensory Processing, Top-Down Visual Attention",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"March 3rd 2022",dateEndSecondStepPublish:"May 4th 2022",dateEndThirdStepPublish:"July 3rd 2022",dateEndFourthStepPublish:"September 21st 2022",dateEndFifthStepPublish:"November 20th 2022",dateConfirmationOfParticipation:null,remainingDaysToSecondStep:"2 months",secondStepPassed:!0,areRegistrationsClosed:!1,currentStepOfPublishingProcess:4,editedByType:null,kuFlag:!1,biosketch:"Dr. Brewer is a Stanford-trained physician-scientist, tenured Associate Professor at UC Irvine, and Director of the mind space Lab, who uses cutting-edge computational neuroimaging to study the organization and plasticity of the human sensory cortex.",coeditorOneBiosketch:"Dr. Barton is a UCI-trained cognitive scientist who has pioneered the study of auditory field maps in the human cortex and currently focuses his research on computational neuroimaging measurements of audiovisual cortical processing and organization.",coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"115304",title:"Dr.",name:"Alyssa",middleName:"A",surname:"Brewer",slug:"alyssa-brewer",fullName:"Alyssa Brewer",profilePictureURL:"https://mts.intechopen.com/storage/users/115304/images/system/115304.jpg",biography:"Dr. Alyssa A. Brewer completed her undergraduate degrees at Stanford University, with a B.S. with Honors in Biological Sciences and an A.B. in Comparative Literature with interdisciplinary Honors in Humanities. She continued on at Stanford in a dual-degree graduate program, graduating with an M.D. and a Ph.D. in Neuroscience in 2007. Her work in graduate school with Brian Wandell, Ph.D., focused on computational neuroimaging measurements of visual cortex organization and plasticity in humans and macaque. She now is an Associate Professor in the Departments of Cognitive Sciences and Language Science, by courtesy, at the University of California, Irvine. Dr. Brewer’s research focuses on visual, auditory, and multi-sensory neuroscience, using behavioral, genetic, and high-resolution neuroimaging techniques to investigate questions ranging from the fundamental organization of human visual and auditory cortex to plasticity in visual, auditory, and sensorimotor regions.",institutionString:"University of California, Irvine",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"6",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"University of California, Irvine",institutionURL:null,country:{name:"United States of America"}}}],coeditorOne:{id:"149246",title:"Dr.",name:"Brian",middleName:null,surname:"Barton",slug:"brian-barton",fullName:"Brian Barton",profilePictureURL:"https://mts.intechopen.com/storage/users/149246/images/system/149246.jpeg",biography:"Dr. Brian Barton received his B.S. in Psychology at the University of Oregon, where he studied visual attention and working memory with Edward Awh, Ph.D., and Edward Vogel, Ph.D. Dr. Barton then earned his Ph.D. in Psychology with a Concentration in Cognitive Neuroscience in 2013 at the University of California, Irvine (UCI), where he expanded his research into functional MRI measurements of visual cortex organization and plasticity with Alyssa A. Brewer, M.D., Ph.D. He continued on at UCI as a post-doctoral scholar for three years with Drs. Brewer, Greg Hickok, Ph.D., and Kourosh Saberi, Ph.D., applying his vision work to measurements of the organization of human auditory cortex. Dr. Barton’s current research focuses on the organization, function, and plasticity of sensory field maps in human visual and auditory cortex.",institutionString:"University of California, Irvine",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"5",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"University of California, Irvine",institutionURL:null,country:{name:"United States of America"}}},coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"18",title:"Neuroscience",slug:"life-sciences-neuroscience"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"444316",firstName:"Blanka",lastName:"Gugic",middleName:null,title:"Mrs.",imageUrl:"https://mts.intechopen.com/storage/users/444316/images/20016_n.jpg",email:"blanka@intechopen.com",biography:"As an Author Service Manager, my responsibilities include monitoring and facilitating all publishing activities for authors and editors. 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It is therefore important to understand that approximately 70% of the women will also have lymphatic spread. Even in disease, apparently confined to one or both ovaries, there is evidence of nodal metastatic spread in up to 24% of women [2].
\nAn understanding of the lymphatic drainage of the ovary and fallopian tube is important in the management of women with ovarian cancer. There are three main lymphatic pathways. The principal pathway is along the ovarian vessels through the infundibulopelvic ligament to the para aortic and para caval nodes surrounding the aorta and inferior vena cava (IVC). The second pathway occurs through the broad ligaments into the pelvic nodal region. Of note, spread to contralateral pelvic nodes in women with a unilateral cancer is reported in up to 30% of women [3]. Therefore, a bilateral pelvic node dissection (PND) is recommended even with unilateral apparent stage 1 tumours.
\nA third lesser route is through the uterine round ligament to the inguinal nodes. In addition, women with disease involving the rectum or sigmoid colon may have tumour spread to the mesocolic lymph nodes within the sigmoid mesentery.
\nOver the last decade, the understanding of the pathogenesis of epithelial ovarian cancer has changed. The most common histopathological subtype, high-grade serous cancer (approximately 70–80% of cases) appears to arise in the distal fallopian tube [4]. Most of these women present with disease spread to the transperitoneal surfaces and to the lymph system. The majority of this chapter will be concerned with the role of lymphadenectomy in this group of women.
\nLess common types of ovarian cancer include endometrioid, clear cell, low grade serous and mucinous tumours. These appear to have separate aetiologies with a different risk of lymphatic spread. The risk of nodal metastases appears to be lower in endometrioid and mucinous cancers. For example, a meta-analysis of 278 women with apparent early mucinous cancer of the ovary who underwent a full pelvic and para aortic nodal dissection reported an incidence of involved nodes of only 1.2% [5]. Most authors no longer recommend a lymphadenectomy in early mucinous cancers.
\nA definition of a pelvic node dissection (PND) is widely accepted in the gynaecological oncology literature [6]. PND includes bilateral removal of nodal tissue from the distal one-half of each common iliac artery, the anterior and medial aspect of the external iliac artery and vein to the level of the deep circumflex artery, and obturator fat pad anterior to the obturator nerve. The medial aspect of the dissection is the hypogastric artery. Enlarged nodes below the obturator nerve should also be removed. The obturator nerve should be identified and guarded prior to any sharp dissection. The nodes should be swept away from the nerve with careful attention paid to the area below the nerve to avoid damage to the numerous vessels present in this area. The ideal scenario is to remove the node in a single nodal unit to reduce the risk of nodal fracture leading to possible tumour dissemination and port site metastases. A PND may be performed either as an open procedure or as part of a laparoscopic procedure. Laparoscopic surgery lends itself to PND due to the increased magnification and illumination of the surgical field and dissected nodes can be removed through an 11/12 mm suprapubic port or removed via the vagina if a hysterectomy is performed.
\nPara aortic assessment/dissection has in contrast to pelvic nodes not been well quantified. Pomel et al. [7] have published a proposed classification of para aortic node assessment which ranges from radiological assessment and palpation to a full systematic dissection of all nodal tissue including the dorsal surfaces of the vessel (Table 1).
\nType | \n\n |
---|---|
A1 | \nComplete (includes infrarenal and suprarenal up to coeliac trunk to midpoint of common iliac vessels) | \n
A2 | \nInfrarenal (as above, but does not include suprarenal dissection) | \n
A3 | \nInfra inferior mesenteric artery (IMA) (as above but does not include dissection above IMA) | \n
B1 | \nExtensive (incudes para aortic areas, but does not allow full visualisation of structures—adventicia of vessels. Renal vessels, anterior common vertebral ligament, psoas muscle and sacrum | \n
B2 | \nMinimal (includes limited para aortic areas, and does not allow visualisation of structures above) | \n
C1 | \nPalpation (direct) following full exposure of PA area | \n
C2 | \nPalpation (indirect), transperitoneal without any exposure | \n
C3 | \nRadiological assessment by PET/CT or MRI | \n
Proposed classification of para aortic node assessment (Pomel et al. [7]).
Open para aortic dissection (type A1 to B1) requires a generous midline abdominal incision to the xiphisternum and a self-retaining retractor to allow access to the great vessels. The right side of the colon and small bowel are mobilised by incising the peritoneum at the level of the right common iliac artery extending medially and caudally to the fourth part of the duodenum and then incising the peritoneum along the right paracolic gutter to the hepatic flexure. This allows the surgeon to perform called ‘Kocher manoeuvre’ mobilising the bowel off both the right renal fascia and ureter and to be retracted out of the abdomen. Following this, the surgeon should identify the left ureter lying medially underneath the inferior mesenteric vein. The node dissection should not start until all the important anatomical structures have been identified including the inferior mesenteric artery (IMA).
\nLaparoscopic PA node dissection is well described in the literature and can be performed either via the conventional transperitoneal route or via an extra peritoneal route. Both routes require a high degree of laparoscopic training and is considered unlikely to replicate a systematic node dissection (Pommel type A) but rather an extensive node sampling (Pommel type B1–2).
\nA number of women will undergo surgery for an apparently benign ovarian cyst. Postoperatively, those women with confirmed malignancy can be offered staging including lymphadenectomy. Approximately, 30% of women with ovarian cancers apparently confined to the ovaries will be upstaged following further surgery including a pelvic/para aortic node dissection/sampling (Pommel type B1) with a gynaecological oncologist [8].
\nIt is important to understand that lymph node status is not the only factor that determines the need for adjuvant chemotherapy. Many centres offer chemotherapy to women with stage Ic or above cancers, high-grade lesions and all clear cell cancers of the ovary [9].
\nHowever, node status is important for a number of reasons: it may influence whether or not chemotherapy is given, the number of cycles or types of chemotherapy and it may result in complete cytoreduction of the cancer. Node status also partially determines the true FIGO stage and prognosis.
\nThe ACTION trial was a randomised controlled trial (RCT) of 448 women with stage IA, IB grades 2–3, all IC, IIA and all clear cell cancer stage I–IIA and compared the administration of adjuvant chemotherapy with a control arm. The main finding showed overall survival was significantly better with the administration of chemotherapy. A subset analysis revealed that stage I patients with complete surgical staging did not benefit from chemotherapy contrast to patients that underwent incomplete staging [10]. Long-term follow-up of this study has confirmed these results [11]. It has been surmised that patients that have not being staged harbour more advanced disease, and therefore have a poorer prognosis and chemotherapy does not compensate for incomplete staging.
\nIn older women with complex masses or those felt to have a high risk of cancer, an intraoperative frozen section histopathological analysis may be performed. A study from the Gateshead Gynaecological Oncology Centre reported a with a sensitivity of 92%, specificity of 88%, positive predictive value of 82% and negative predictive value of 95% for frozen section analysis [12]. This is equally important in determining which women should not be exposed to unnecessary surgery such as a para aortic node dissection.
\nLaparoscopic staging is possible, though requires a high degree of specialist training. Several centres have reported on full laparoscopic staging and have found it feasible [13, 14]. Chi et al. performed a case control study comparing staging via laparoscopy or laparotomy in 80 women [13]. They found no difference in specimen sizes and lymph nodal counts. The laparoscopic group had levels of reduced blood loss and a reduced hospital stay. A laparoscopic nodal dissection/sampling should include both the pelvic and para aortic basins to the level of the renal vessels. A case series by Nezhat et al. [15] concluded that laparoscopic staging when performed by a gynaecological oncologist did not compromise survival.
\nRobotically assisted laparoscopic surgery is an evolution of minimal access surgery rather than a revolution. Perceived benefits include three-dimensional vision, control of the laparoscope by the operating surgeon, more precise instrument movement and a shortened learning curve. Perhaps, the biggest advantage is the use of instruments that fully articulate at the end in the manner of a human wrist allowing fine delicate movements. This is particularly important in the obese patient, where the increased thickness of the anterior abdominal wall produces an increased torque effect leading to decrease manoeuvrability of standard laparoscopic instruments. Robotic platforms have been used in staging apparent ovarian cancer and appear comparable to laparoscopic surgery [16, 17, 18, 19].
\nMaggioni et al. [20] reported a randomised controlled trial of 268 women with apparent stage 1 or 2 ovarian epithelial cancer. The women were randomised to either a random sampling of pelvic and PA nodal basin or systematic dissection (pommel type A) of the same areas. Positive nodes were found in 9% of the control group and in 22% of the SLD group. No significant difference was recorded in 5 years year overall survival (84.2 vs. 81.3%) or progression free survival (PFS) (78.3 vs. 71.3). The SLD group had a significantly longer operating time, blood loss and blood transfusion.
\nIn view of the results of this study, SLD should not be offered over more limited dissection/sampling (pommel B) in women with apparent early ovarian cancer.
\nThe goal of surgery in advanced ovarian cancer is to remove all visible disease including a removal of all enlarged lymph nodes. This requires intraoperative assessment of the bilateral pelvic nodes and the para aortic region (pommel type C1–B1).
\nGiven that the nodal basin is considered by some to be relatively chemotherapy insensitive, this to the question whether removal of all involved microscopically and macroscopically involved nodes has a therapeutic benefit.
\nPanici et al. [21] reported a randomised controlled trial of 268 women with apparent stage IIIB, IIIC/IV cancer. The women were randomised to either resection bulky of pelvic and PA nodes or systematic dissection of the same areas. Positive nodes were found in 42% of the control group and in 42% of the SLD group. No significant difference was recorded in 5 years year overall survival (47 vs. 48.4%). A significant 7-month extension in progression free survival (PFS) was demonstrated (29.4 vs. 22.4 months). The SLD group had a significantly longer operating time, blood loss and blood transfusion. Subsequently, the authors have suggested that the study may be underpowered to detect an overall survival difference.
\nWorking in close proximity to the large blood vessels poses a risk of major haemorrhage. Reducing this risk involves an appropriate surgical incision with a good operative exposure involving dissection/identification of anatomical structures. This allows easier identification of vascular anomalies and reduces the risk of collateral damage to structures such as the kidney and ureter. Initial management includes pressure to the area and appropriate communication with the rest of the team including the anaesthetist. Small vascular injuries may be oversewn using a vascular needle and small monofilament suture, ideally avoiding constricting the vessel’s diameter. Larger defects require the vascular clamp and the expertise of a vascular surgeon.
\nThe incidence of lymphocyst after the para aortic/pelvic dissection maybe as high as 43% [22]. The vast majority of these will resolve spontaneously and do not require any intervention. Occasionally, a larger lymphocyst may require aspiration typically by interventional radiological drainage. Occasionally, chylous ascites develop in association with an aortic node dissection especially at the level of the renal vessels. This illustrates the importance clipping large lymphatic channels especially in this region. Management of how chylous ascites includes the low-fat diet, the administration of somatosatin and occasionally total parenteral nutrition.
\nOther complications associated with lymph node dissection include postoperative ileus, damage to the duodenum, damage to relevant nerves and long-term lymphoedema.
\nSerous tubal intraepithelial carcinoma (STIC) is now considered the precursor lesion for high-grade serous cancer [4]. STIC may be an incidental finding in women undergoing a salpingectomy for benign reasons and the incidence is expected to rise in women undergoing risk reducing surgery for ovarian/tubal cancer. The management of women with STIC as an incidental finding it is unclear. It is apparent, the percentage of these women will have disseminated spread of high-grade serious cancer. Based on small series, authors have suggested comprehensive surgical staging including lymphadenectomy [23, 24]. This is relatively a new condition with larger case series publication expected over the next few years.
\nFollowing the Panici study reporting a significant difference in PFS, the role of a full systematic node dissection is the subject of two randomised controlled trials, the Lymphadenectomy in Ovarian Neoplasia (LION) and CURACO trials [21].
\nThe Lymphadenectomy in Ovarian Neoplasia (LION) study is an AGO randomised controlled trial including women with FIGO stage IIB–IV ovarian epithelial cancer and complete macroscopic resection of all disease. Around 640 women were randomised to either a full systematic lymph node (SLN) or no lymph node dissection and the study results are due in late 2017. The primary end point is overall survival (OS) and secondary endpoints include progression free survival (PFS) and quality of life (QOL).
\nThe French CURACO trial is a randomised controlled trial including women with stage III–IV epithelial ovarian cancer with complete macroscopic resection. The women are being randomised to SLN versus no node dissection. The primary end point is progression free survival.
\nSpread to the lymphatic system is common in epithelial ovarian cancer is common and is an early event. Para aortic and bilateral pelvic node dissection sampling (Pommel type B1) should be included in surgical staging to determine chemotherapy use and to improve prognosis in ovarian cancer apparently confined to the ovary based on the results of the ACTION trial.
\nIn women with advanced ovarian, the retroperitoneal lymph nodes should be assessed and bulky lymph nodes removed in an attempt to achieve complete cytoreduction. Systematic lymph node (SLN) of the para aortic nodes should not be routinely performed pending the results of the LION and CURACO studies.
\nLead (Pb) is a ubiquitous and persistent neurotoxicant that continues to threaten human health in a global perspective [1]. Although lead has been removed from paints and gasoline, it remains a serious concern as it can still be found in a variety of daily products, including toys, batteries, food, and water [2]. Although Pb poisoning is a preventable disease, thousands of new cases in the United States were reported each year, and about 500,000 children under 5 years old have blood lead levels (BLLs) greater than a threshold level of 5 g/dl, according to Centers for Disease Control and Prevention (CDC) reports [3, 4, 5, 6, 7]. Elevated BLLs have become the first noninfection condition to be notifiable at the national level [7]. Lead can cause a series of adverse human consequences at a very low level exposure [8]. Therefore, CDC continually decreased the safe threshold of BLLs, and the current “safe” levels of exposure to lead are 5 mg/dl for children, but still there have been studies to identify cognitive impairments below that dosage, implying that “no level of lead exposure is safe” [6, 9].
Lead pervades many organs and systems in the human body, but the prime target of lead toxicity is CNS, both in adults and in children [10], resulting in the so-called “neurotoxicity.” The developing brain is particularly susceptible to lead neurotoxicity, as demonstrated by several epidemiological and experimental studies [2, 3]. Due to the fact that lead can freely cross blood brain barrier, lead neurotoxicity can also be manifested in adults, with a larger exposure dosage. Particularly, it should be noteworthy that early life exposure to lead can produce persistent alterations in the brain structure of adults, causing lasting impairment of brain function and behavior [3, 11]. Adverse neurotoxic effects caused by lead include intellectual and behavioral deficits in children; deficits in fine motor function and coordination; and deficits in lower performance on intelligence tests [10]. Higher level of lead can cause a wide spectrum of neurological disorders, such as convulsions and coma, including multiple instances of neurodegenerative disorders, such as AD and Parkinson’s disease [12, 13, 14, 15]. Thus, there is a critical need to understand the mechanisms of lead neurotoxicity.
Among the cellular and molecular mechanisms suggested to underlie lead neurotoxicity, amounting evidence underscored roles of epigenetic molecules. This fast-moving filed of epigenetics has opened a novel avenue of research for understanding how environmentally toxic signals like lead exposure could be readily sensed by organisms and then relayed to reprogram the expression of key functional genes, consequently giving rise to neurotoxic manifestations [3, 16, 17, 18, 19]. This chapter is aimed to discuss the advances of epigenetic alterations in response to lead-induced neural deficits, focusing on the concrete epigenetic species and their responsive details. We will also present a synoptic view of epigenetic implications in etiology of AD caused by long-term lead exposure and bring out the possible future perspectives of the related research topics.
Since lead was found to mediate severe neurological impairment toward both children and adults, myriad studies were appreciated to decipher the cellular and molecular alterations underlying this neurotoxic incident. Several routes of action have been most commonly proposed, such as oxidative stress, disruption of blood brain barrier, decreased cellular energy metabolism, deregulation of calcium signaling, and abnormal neural transmission [3, 20]. In terms of relevance to neuronal development and synaptic transmission, postsynaptic mechanisms represented by N-methyl-D-aspartate receptor (NMDAR), presynaptic mechanisms, and brain-derived neurotrophic factor (BDNF) signaling were shown to be involved in lead neurotoxicity [8, 21].
NMDR plays an essential role in hippocampus-mediated learning and memory, and its dysfunction is associated with spatial learning abnormalities, as well as dendritic atrophies [22]. Lead regularly disrupted NMDAR function by acting as a potent antagonist. Apart from it, lead exposure also disrupts normal NMDAR ontogeny, such as reducing NR2A content, altering expression of NR1 splice variants [23, 24].
Chronic lead exposure also results in impaired neurotransmission. A previous finding showed that chronic lead exposure reduced Ca2+-dependent glutamate and γ-aminobutyric acid (GABA) release in the rat hippocampus [25, 26]. And in cultured hippocampal neurons, lead exposure was found to impair excitatory postsynaptic currents (EPSCs) and inhibitory postsynaptic currents (IPSCs) [27]. Our lab recently published a finding that chronic lead exposure can inhibit the release of neurotransmitters by interfering with its vesicle pool recycling, and the main protein impacted is synapsin 1, which expression and phosphorylation was prone to lead invasion [28].
An emerging theme involved in lead neurotoxicity is the disruption of brain-derived neurotrophic factor (BDNF) expression. BDNF is a trans-synaptic signaling molecule that is released from both dendrites and axons [29]. In response to lead exposure, BDNF levels in cell cultures were downregulated, and the exogenous addition of BDNF can rescue the deleterious effect of Pb [30]. As a regulator of Ca2+ signaling and homeostasis, BDNF perturbation in turn led to the disrupted Ca2+-dependent pathways, which compromise severe neural representations caused by lead exposure [31]. As an alternative consequence, lead impaired the hippocampal dendritic spines, reduced their density, and changed their morphology [32].
These neuronal and molecular processes might reflect variable aspects of lead-induced neurotoxicity. Compared to it, roles of global regulators, such as the emerging epigenetic regulators, are not sufficiently understood. However, given the conformity with outstanding characteristics of lead neurotoxicity, like “early exposure, persisted effect,” epigenetics was long hypothesized to be implicated in the etiology of lead-induced psychological disorders [3]. This was supported by further identification of lead exposure as a risk factor of Alzheimer’s disease and schizophrenia. Our next section will focus on epigenetic determinants involved in lead-led neurological damages and diseases [33, 34].
Epigenetics is defined as the heritable changes in gene expression that are not related to alterations in the genetic code [3]. Epigenetic regulation is found to modify the conformational state of chromatin and the accessibility of specific gene promoters to the transcriptional machinery [14]. There are three main epigenetic mechanisms broadly studied: DNA methylation, posttranslational modifications of histones, and noncoding RNA (ncRNA) [35, 36, 37]. The basic modes of action of three epigenetic forms were shown in Figure 1. DNA methylation is the most-studied epigenetic mechanism, which involves primarily cytosine methylation of Cytosine Guanine dinucleotides (CpG) via DNA methyltransferases (DNMTs). CpG methylation is often linked with transcriptional inhibition as it interferes with the normal binding and activity of transcription binding proteins [38]. The exception to this is CpG islands, which are CpG-rich sequences that are densely populated with unmethylated CpGs [2]. CpG islands offer the possibility of being differentially regulated by the environmental signals, which are a prime site to study the influence of lead on epigenetic determinants of ensuing neurotoxic phenotypes [39].
Types of epigenetic modifications. (A) CpG methylation; (B) histone modifications represented by acetylation and methylation; (C) biogenesis and inhibitory action of microRNA (miRNA).
Gene expression is also regulated by histone modifications [36]. Histones are alkaline proteins that wrapped around DNA in nucleosomes and moderated gene transcription by modulating chromatin compaction and accessibility [40]. The terminal tails of histone can undergo covalent posttranslational modifications (PTMs), which in turn alter their interaction with DNA. Diverse modification forms were discovered and studied, as well as their influence on transcription of objective genes, including acetylation, phosphorylation, methylation, and ubiquitination [2]. The complex forms of histone modifications could coexist in regulating a common gene or genome, establishing an intricate and complex regulatory network called “histone code” [41, 42]. The proposal of this definition opens an avenue to show the potential accuracy and delicacy of gene expression regulation, via the action of histone modifications, which are operated by corresponding enzymes, such as histone acetyltransferases, histone deacetylases, histone methylases, and histone demethylases. Among them, histone deacetylases have been widely studied and identified as key molecular targets for pharmaceutical interventions [43, 44].
Another layer of epigenetic regulation involves noncoding RNAs (ncRNAs), defined as functional RNA molecules that are not translated into proteins [3]. The category of ncRNA with relevance with epigenetic regulation is composed of microRNA (miRNA), lncRNA, piRNA, and snoRNA, which regulate gene expression at both transcriptional and posttranscriptional levels [37]. miRNA received the most attention among them, and details of miRNA types involved in various epigenetic regulation and neuronal processes were studied comprehensively. For instance, a recent publication revealed that a series of miRNAs can respond to and mediate spinal muscular atrophy pathogenesis [45]; miR-137 participated in the modulation of neuronal maturation by targeting an ubiquitin ligase mind bomb-1 [46].
The different forms of epigenetic regulation are often functionally interlaced, showing an interactive relationship. DNA methylation was commonly accompanied by a specific form of histone methylation, establishing a so-called “hand-in-hand” assembly [47]. Histone deacetylase can be recruited by DNA methylation or its functional partner, and these molecules can cooperate with each other to determine (most commonly inhibit) the expressional status of the objective gene [48]. DNA methylations and histone modifications are both involved in establishing patterns of gene expression, and they may play distinct roles in inducing persistent or intermittent gene expression changes [14].
Epigenetic mechanisms are implicated in neuronal development, maintenance of cell identity, and aging process [49, 50]. Meanwhile, epigenetic perturbations that lead to chromatin remodeling are in association with a number of neuropsychiatric and neurodegenerative disorders [14, 51], and they are particularly relevant in response to environmental toxicant exposure early in life [38]. The impact of epigenetic determinants can be long lasting, or even transgenerational, that is, the epigenetic traits and gene expression patterns can be sometimes inherited by next generations, which are not previously exposed to the causative agents [52].
Considering that epigenetic factors are associated with CNS functioning and meanwhile susceptible to environmental exposure, we next discuss the epigenetic outcome brought by lead exposure and the roles of these changes in the etiology and development of lead neurotoxicity.
The relations of lead exposure with neural epigenetic alterations have long been established. Developmental lead exposure results in a variety of epigenetic changes, characterized by DNA methylation alterations, which can impact gene expression patterns and affect nervous system development [5]. Lead can promptly affect the dynamism of epigenetic determinants and promote the rapid turnover of DNA methylation [4]. Consistent with these findings and statements, lead is known to be an epigenetic modifier [53]. The following are advances of three main epigenetic systems associated with lead neurotoxicity:
Lead exposure can result in the global changes of DNA methylation profiles in CNS, and the detailed orientation of methylome changes varied depending on the studied genetic microenvironment. Singh et al. stated that developmental lead exposure disrupted the hippocampal methylome, and the effect is dependent on the gender, timing, and level of exposure [5]. In particular, the global methylome alterations did not reflect the methylation status of the specific genes. That identified low-level lead exposure as a causative agent of gene-specific DNA methylation patterns in brain [54]. Senut et al. found that lead exposure disrupts global DNA methylation in human embryonic stem cells and alters their neuronal differentiation [4]. An epidemiological study investigated 105 children participants from birth to 78 months and tested peripheral blood DNA to quantify CpG methylation at Differentially Methylated Regions (DMRs) of 22 human imprinted genes. This study provided evidence that early childhood lead exposure resulted in gene-specific DNA methylation differences in the DMRs of PEG3, PLAGL1/HYMAI, and IGF2/H19 [51]. In 2009, Pilsner et al. published the first human study to reveal that maternal bone lead levels were associated with changes in DNA methylation levels in the umbilical cord blood leukocytes of the offspring [55]. In animal studies, DNA methylome-related genes, including DNA methyltransferases, methyl-cytosine-phosphate-guanine (Me-CpG) binding protein-2 (MeCP2), and methionine synthase, were recognized as the potential targets of lead exposure [56, 57]. Sanchez-Martin et al. reported that lead exposure resulted in hypermethylation of three differentially methylated regions in the hippocampus of females, but not males [11]. Overall, lead is a strong environmental force to globally reshape DNA methylation landscape in brain, which is a susceptible organ for epigenetic regulations.
Apart from methylome, the gene-specific alterations of methylation may reflect the detailed influence of lead exposure in CNS. Zawia et al. examined the activity of DNA methyltransferase in the tissues of 23-year-old primates exposed to lead as infants. As a consequence, they found that activity of this methylation enzyme was selective for cytosine nucleotides in a CpG sequence and specific to ones that base-paired to methylated CpG sequence on the other DNA strand [25]. Some genes triggered during memory formation and synaptic plasticity, such as BDNF, showed marked changes in promoter methylation when DNMT activity is suppressed in mice hippocampus, indicating that BDNF can be potentially modulated by specified DNA methylation status [58]. Wu et al. investigated the association between prenatal maternal lead exposure and epigenome-wide DNA methylation. Among female infants, one CpG (cg24637308) showed a strong negative association with lead levels, and this CpG site was thought to be highly expressed in human brain [59]. Our previous study also measured CpG methylation levels in specific CpG-rich promoter regions of DAT1 and DRD4, two dopaminergic-related genes, in the children with higher blood lead levels. According to it, a specific CpG site located upstream of DRD4-coding region was found to be hypermethylated due to lead exposure, and this changes were negatively correlated with the expression levels of DRD4 [39]. The relevant literature pertaining to associations of lead neurotoxicity and DNA methylation was summarized and shown in Table 1.
Animal (Age) | Exposure duration | Epigenetic mechanisms | Pathophysiological outcomes (possible) | References |
---|---|---|---|---|
Human embryonic stem cell | A: day 1 B: day 5 C: days 0–19 D: days 11–19 | DNA methylation status of genes crucial to brain development | Exposure to Pb subtly alters the neuronal differentiation of exposed hESCs | [4] |
Newborns (prenatal) | Prenatal | DNA methylation at LINE-1 repetitive elements; UCB LINE-1 methylation | Epigenetic alterations have detrimental effects on the developing brain, neurological development, and disease | [38] |
Newborns | From birth to 78 months | DMR methylation for PEG3 (A), IGF2/H19 (B), and HYMA/PLAGL1 (C) | Sex-dependent and gene-specific DNA methylation | [51] |
Mice (10 months) | 2 weeks prior mating and during gestation and lactation until PND21 | Average brain methylation: IAP 110:80% | Neurodegeneration, narcolepsy | [60] |
Mice (PND 20 and 700) | Gestational D13 until PND20 | DNA hypermethylation | Gene repression in old age | [61] |
Rats (PND55) | 10 days prior breeding till weaning of 55D | ↓DNMT1 with postnatal 150ppm Pb ↓DNMT1 with postnatal 375ppm Pb ↑DNMT1 with postnatal 750ppm Pb ↓DNMT1 will all perinatal Pb | Defects in neuronal maturation, synaptic plasticity, learning, memory, cognition, and behavior | [57] |
Mice (PND20 and PND700) | Gestational D13 until PND20 | 501 downregulated genes and 647 upregulated genes | Affecting immune responses, metal binding, metabolism, transcription, and transduction | [56] |
Mice (PND1 to PND20) | PND1 to PND21 | ↑Dlx1 methylation ↓Gene expression of Dlx1/2/5/6 ↑Gene expression of Tubb3 | Hyperactivity, weight loss, abnormal behavior | [62] |
Monkeys (23 years) | Birth until 400D | ↓DNMT1 ↑APPmRNA ↑Aβ1-40mRNA ↑Aβ1-42mRNA | Alzheimer’s disease | [16] |
Mice (2 months) | 2 months prior mating and during gestation and lactation until PND2 | Hypermethylation in: Rn4.5s loci in chromosome2 Sfi1 loci in chromosome11 (Rn45s loci inchromosome17) | DNA methylation (sex and tissue specific) | [11] |
Mice (PND0 and PND6) | 2 months prior breeding and throughout lactation | ↓H3K9/14Ac:b/w PND0 & PND6 (HPC) ↓ H3K9Me3:b/w PND0 & PND6 ↓H3K9/14Ac ↓H3K9Me3 ↓H3K9/14Ac: 50% at PND0 with 100ppm Pb ↑H3K9/14Ac: 60% at PND0 with 100ppm Pb | Weight loss, abnormal brain development and cognitive function (sex, age, and brain region specific) | [63] |
Rats | Perinatal to 60D | Acetylated H3 in hippocampus ↑p300 (HAT) mRNA ↑HDAC1 mRNA | Hyperactivity, behavioral disorder, neurological disorder, ADHD (dose specific) | [64] |
Monkeys (3–6,12,23 years) | Birth until 400D | Altered gene expression (22) ↑APP mRNA and protein ↓Dnmt3a and Dnmt1 at 23years ↓MeCP2 at 23years ↑H3K9ac, H4K8ac, H4K12ac ↑H3K4me2 | Neurodegeneration in old age, up and downregulation of genes | [14] |
Mice (Weeks 20) | E1 to E10 | Hypomethylated Chd7 gene ↑Chd7 gene expression (4.7 folds) Altered histone methylation | Autism-like behavior, multiple behavioral abnormalities | [65] |
Mice (PND20, 180,270, 540, and 700) | PND1 to PND20 | ↓DNMT1 protein ↑DNMT3a mRNA at PND20 ↓MeCP2 at PND20 and 270 ↑MAT2A at PND270, 540 and 700 ↓H3K9Ac protein at PND700 ↓H3K4Me2 protein at PND20 | Alzheimer disease | [15] |
Transgenic mice (15) (PND20, 30, 40, and 60) | PND1 to PND20 | Hyperphosphorylation (internal and external brain capsule) ↑ miR34c expression b/w PND20 and 50 ↑ tau mRNA at PND20 ↑CDK5 mRNA at PND40 ↑ Total tau protein at PND20 and 40 ↑CDK5 protein at PND40 and 60 ↑ Phosphorylated tau Ser396 protein at PND20 and 30 | Alzheimer’s disease, tauopathies | [66] |
Mice (PND20, 180 and 700) | PND1 to PND20 | ↑miR-106b at PND20 (1.5 fold) ↓ miR-34c at PND180 (1.6 fold) ↑miR-29b at PND20 (1.6 fold) ↑ miR-132 at PND20 (4.8 fold) ↓miR-124 at PND700 (2 fold) | Alzheimer’s disease, tauopathies | [67] |
Rats (20–22 days) | 8 weeks | ↑miR-211 with 300ppm Pb (1.75 old) ↓ miR-494 with 300ppm Pb (2.04 fold) ↑miR-449a with 300ppm Pb (2.89 fold) ↑miR-34c with 300ppm Pb (4.05 fold) ↑miR-34b with 300ppm Pb (4.48 fold) ↑miR-204 with 300ppm Pb (5.48 fold) ↑miR-448 with 300ppm Pb (30.51 fold) ↓mRNA with 300ppm Pb (Bcl2, Itpr1) ↓mRNA Map2k1 with 300ppm Pb | Neural injury, neurodegeneration, axon and synapse dysfunction, impaired neural development and regeneration, impaired performance, Alzheimer’s disease, Parkinson’s disease and depression | [68] |
Rats (2-4 weeks and 12–14 weeks) | 40D | Apoptotic cells with irregular nuclear membrane, chromatin clumping, and nuclear fragmentation | Apoptosis | [69] |
Mice (10 months) | 2 weeks prior to mating and continued throughout gestation to 3 weeks after birth | ARTN & C5aR1 methylation 32 ppm Pb exposure ) Ankdd1b methylation 2.1 ppm Pb exposure) | Death of neurons, Alzheimer’s disease, migraine, and major depressive disorder | [70] |
Rat (PND55) | PERI: 10 days prior to breeding to PND 21 EPN: birth through weaning (PND 21) LPN: birth through postnatal day 55 | Quantities of methylation changes at gene promotor region and varies according to genders | Schizophrenia, Alzheimer’s disease, memory impairment, etc. | [5] |
Mice (E18, PND0, PND6, and PND60) | 2 months prior to breeding and throughout lactation | Changes of H3K9Ac, H3K4Me3, H3K9Me2, H3K27Me3 level | Cognition deficits, behavioral dysfunction, neurodevelopmental disorders | [71] |
Mice (PND0 and PND6) | Pb acetate for 2 months prior to breeding until sacrifice | Changes of H3K9/14Ac and H3K9Me3 level | Cognitive/behavioral problems during childhood | [63] |
Mice (PND20 and PND50) | PND 1 to PND 20 | ↓MECP2 ↑Dnmt3a mRNA & miR-29b (PND50) ↓DNMT1 mRNA (PND50) ↑miR-148a(PND50) ↑SP1 mRNA(PND20) ↑miR-124(PND50) ↓APP mRNA(PND20) ↑miR-106b(PND50) | Tau-induced cell apoptosis in AD; neurodegeneration | [72] |
Summary of some literature concerning epigenetic changes involved in lead neurotoxicity.
A number of reports suggested that alteration in DNA methylation was largely gender- and tissue-dependent [73]. Early life lead exposure of 3 and 30 ppm led to gender-specific DNA hypermethylation at Rn45a and Sfi1 genes in the hippocampus of female mice only [11]. Another study also stated that maternal lead exposure caused gender-specific epigenetic outcomes for varying degree of vulnerability later in life [74]. These gender differences might be related to the action of sex hormone and the structural discrepancies of body structure resulting in the variance of lead metabolic routes.
CpG methylation was reprogrammed through the action of DNA methylases. Amounting evidence suggested that this pathway was utilized by lead to bring adverse neurological outcome. In a 23-year-old primate with early exposure of lead, protein levels of DNMTs and MeCP2 were significantly decreased. And this attenuation was consistent with hypomethylating effects at multiple genetic loci [14]. Another report found a decreased DNA methyltransferase activity in mouse cortical neuronal cells exposed to lead for 24 h and determined later in life [16]. In a mouse study with developmental lead exposure, DNMT3a in male mice displayed increased expression with 150 and 750 ppm of Pb, while female mice had decreased expression of DNMT3a in response to 150 and 375 ppm of Pb. Moreover, developmental lead exposure can also affect the expression of DNMT1 and MeCP2 in murine hippocampus, which gender and exposure periods were critical contributing factors [57]. Therefore, both expression levels and enzymatic activities of methylation-modifying enzymes can be modulated by lead exposure in CNS.
Except from a conventional methylation form, 5-hydroxymethylated cytosine (5hmC), a new modification and mostly implicated in promoting gene expression, was recently known to be altered by lead exposure in CNS. 5hmCs was extremely abundant in rodent brains, and they are closely associated with critical neurodevelopmental processes such as neuronal differentiation and synaptic function [75]. In light of it, Sen et al. reported that prenatal exposure to lead can alter the hydroxymethylation profile of 5hmC-riched clusters of imprinted genes, which resulted in an altered expression of objective genes in a gender-dependent manner. 5hmC may also serve as potential biomarkers for lead susceptibility to neurological diseases [76].
As a general rule, the changes of DNA methylation levels were often negatively correlated with the transcription levels of the objective genes. But this association was dependent on gender, the exposure periods, and their relative genetic locations. Interestingly, for females, genes regulated by DNA methylation were inclined to encode RNA- and protein-related processes; and for males, the enriched pathways included signaling pathways, stress, and neural responses to stimuli [5].
Compared to DNA methylation, fewer associations between histone modification and lead neurotoxicity were reported. Categorized by posttranslational forms, most studies focused on histone acetylation changes in response to lead exposure. A specific histone acetylation level results from the balanced counteraction of histone acetyltransferases (HATs) and histone deacetylases (HDACs). An acetylated form normally corresponds to a more relaxed chromatin status, leading to an enhanced expression of the target genes, and
Some innovative progresses were made in the primates with early life exposure. Bihaqi et al. observed that apart from DNMTs and MeCP2, lead also caused lifelong alterations of H3K9ac, H3K8ac, and H4K12ac, which levels were increased only in 23-year-old adults, not in 12-year-old primates [14]. In another instance, perinatal lead exposure downregulated H3K9ac levels in aging mice, a proof that key epigenetic regulators can be linked with development of Alzheimer’s disease [15]. Murine hippocampus and frontal cortex were similar in lead-induced epigenetic changes, that is, H3K9/14ac was gradually reduced as exposure prolonged, factored by mixed actions of gender and prenatal stress [63]. The literature pertaining to histone modifications and lead neurotoxicity was shown in Table 1.
Different from histone acetylation, histone methylation gained a stricter site specificity and more stable to maintain gene expression patterns [79]. With the developmental exposure of lead, primates of 400-day olds were subjected to epigenetic examination in brains. H3K4me2 was found to be increased significantly, indicating an activated propensity of related gene expression [14]. In another animal study, H3K9me3 displayed a relatively stable tendency with treatment of lead in mice, and those cases varied depending on the studied brain regions and genders [63]. According to general knowledge gained in this field, H3K4me basically played roles in promoting gene expression, while H3K27me and H3K9me mostly displayed negative regulatory activity. Our previous finding underpinned the importance of H3K27me3 in modulating lead-induced spatial memory deficits [80]. We found that chronic lead exposure perinatally could reduce the global H3K27me3 levels in rat hippocampus, and this alteration led to a genome-wide reprogramming of this repressive epigenetic mark on the target genes. This result gave a picture of how an epigenetic change can give rise to a global genetic response and the ensuing adverse neurological outcomes.
In contrast with acetylation and methylation, very few studies were shown to investigate the interaction of lead neurotoxicity and other forms of histone modifications. In spite of deficiency of relevant literature, this study is supposed to be promising to totally decipher histone codes involved in lead neurotoxicity. H2A ubiquitination was recently found to be associated with DNA damage response, which suggested that site-specific histone ubiquitination organizes the spatiotemporal recruitment of DNA repair factors, and these recruitments facilitated DNA repair pathway choice between homologous recombination and nonhomologous end joining [81].
ncRNAs are epigenetic regulators susceptible to environmental signals. Among diverse forms of ncRNAs, microRNA (miRNA) was most extensively studied concerning their relations with lead neurotoxicity. In rats chronically exposed to lead, at least seven miRNAs were altered considering their expression levels. In details, miR-204, miR-211, miR-448, miR-449a, miR-34b, and miR34c were dramatically upregulated, while miR-494 was downregulated. These miRNAs were implicated in regulating genes involved in neurodegeneration, synaptogenesis, and neuronal injury [68]. Masoud et al. observed that early life lead exposure yielded a transient increase in the expression of AD-related miRNAs, such as miR-106b, miR-29b, and miR-132 [67]. Another rat exposure model with 100 ppm Pb also gave some evidence that some miRNAs, mainly targeting to a histone methyltransferase EZH2, were divergently regulated by lead in pup hippocampus. In response to lead, abundance of miR-137 and miR-101 was elevated, and miR-144d was decreased. The aberrant stimulation miR-137 may have important physiological relevance, as it formed a negative regulatory loop with EZH2, which drove the downregulation of H3K27me3 [80]. Some examples of miRNA changes during lead-induced neurotoxicity were shown in Table 1.
It is insufficient for other forms of ncRNAs remodeled by lead exposure in CNS. In 2018, Nan published an interesting article with relevance to this research field [82]. The authors identified a novel lincRNA (long noncoding RNA), namely lncRNAL20992, as a key responsor toward lead neurotoxicity. lncRNAL20992 was significantly upregulated in a lead-induced neuronal injury model. Four proteins were found to physically interact with lncRNAL20992 to mediate the lead-induced neuronal injury. To date, few associations of piRNAs or circRNAs were discovered with lead-induced neurotoxicity. Interestingly, a 98-nucleotide nuclear RNA with unknown function called Rn4.5s, as well as a RNA precursor Rn45s, showed changes in methylation in the hippocampus of females exposed to 3 ppm of lead [11].
By modifying the global epigenetic landscape, early life lead exposure had not only immediate adverse consequences for brain development but also persistent effects till the later life. This toxic property may increase the susceptibility of organisms to diseases, especially CNS-related diseases [3]. It has been long established that chronic lead contact is an important risk factor for the pathogenesis of Alzheimer’s disease [83]. This finding is significant because AD is the most common form of dementia, which affects aging individual. There were at least 25 million people worldwide affected by this disease in 2003, including at least 4.5 million people in the United States [84]. Similar to other neurodegenerative diseases, AD is a complex and heterogeneous disorder with both environmental and genetic etiology.
There are a variety of molecular mechanisms proposed to mediate the lead-induced pathogenesis of AD. In monkeys, Wu et al. discovered that with lead exposure in infants, the aging monkeys exhibited abnormal expression alterations of AD-related genes and a key transcriptional regulator specificity protein 1 (Sp1). This was manifested by increasing AβPP, b-site AβPP cleaving enzyme (BACE), and Aβ and by decreasing DNA methyltransferase activity [16]. In an epidemiological review toward the Mexican population, it was summarized that early-life lead exposure was a potential risk factor for AD in the Mexican population [85]. While these mechanisms partly explained the key cellular and molecular changes brought by lead exposure, it is still pivotal to figure out the “fetal programming” phenomenon involved in the studied pathogenesis.
Roles of epigenetics are much appreciated due to their similar modes of action with “fetal origin of adult disease,” which characterizes the basic regularities underlying lead-induced pathogenesis of AD [3, 11]. One anticipated way to achieve long-lasting or permanent changes in gene expression is to alter the structural makeup of the DNA bases that led to hypermethylation or hypomethylation consequences. The changes of DNA methylation in promoters or other gene regulatory components are found to be extremely stable and can even transmitted to the next generation. This style of action is consistent with the neurotoxic course of Pb to induce AD and is anticipated to fetal program the key AD-related genes, enabling their long abnormal transcriptions. Compared to CpG methylation, histone modifications are normally unable to elicit permanent regulatory effect till aging period, as evidenced by previous findings that H3K9ac and H3K4me2 followed lifespan-dependent changing curves, whereas variable time points showed different altering orientations [15]. Therefore, CpG methylation might be a competent epigenetic mechanism of choice to be used to explain the long development of AD. In another aspect, susceptible response from specific histone modification may be used to early predict the risk of AD, on the basis of their potential genetic associations.
Given these observations, White et al. proposed the possible pathways by which epigenetic factors mediate Pb-led pathogenesis of AD (Figure 2) [25]. They regarded epigenetics, mainly represented by CpG methylation, as potential key mechanisms that manifested delay consequences of lead exposure and consequent Alzheimer’s disease. According to this hypothesis, early-life lead exposure caused a cascade of molecular changes exemplified by reducing CpG methylations at promoters of key AD-related genes, such as APP and BACE. Assisted by the actions of MeCP2 or SP1, these methylation reductions promoted the gene expression toward the corresponding proteins. Subsequently, Aβ was synthesized and started to accumulate in the later life. When the accumulation reached to a threshold value, AD symptoms started to emerge and progress. This hypothesis gives an intriguing example to implicate epigenetic factors with Alzheimer’s disease induced by early-life lead exposure.
Possible epigenetic mechanism of Alzheimer’s disease induced by early life lead exposure.
In conclusion, epigenetic factors played essential roles in mediating lead-induced neurotoxicity. Comprehensive investigations unveiled the importance of CpG methylations in multiple genetic loci in rodents and primates. CpG methylation on a specific gene promoter might give rise to a long-term suppression of gene expression, in which case formed a phenomenon of “fetal programming” of neurological disease. In addition, changes of histone modifications might reflect a relatively dynamic signal to moderate the ensuing molecular relay and neurotoxic manifestations. As a newly emerging research field, it is anticipated to have several future directions about relevant of epigenetic factors to lead neurotoxicity: (1) new epigenetic mechanisms, such as 5hmC, RNA methylation, and scarcely mentioned ncRNA forms, need to be thoroughly investigated regarding their associations with lead neurotoxicity; (2) most previous studies observed the huge impact of gender on the neurotoxic performances, but very few explanations were provided. Epigenetic differences and causing agents between the genders should be investigated with insight; (3) there are currently some medicine developed to target epigenetic sites, like HDAC inhibitors. However, the sole histone deacetylase is unable to reflect the global epigenetic aspects and to use for intervention with full efficacy. Other specific reversing pharmaceuticals targeting epigenetic factors are warranted to be developed to interfere with development of neurological disease induced by lead exposure.
The work of this chapter was supported by the Fundamental Research Funds for the Central Universities (JZ2020HGTB0053) and the Key Research and Development Project in Anhui (201904e01020001).
The authors declare no conflict of interest.
5hmC | 5-hydroxymethylated cytosine |
AD | Alzheimer’s disease |
BACE | b-site AβPP cleaving enzyme |
BDNF | brain-derived neurotrophic factor |
BLL | blood lead level |
CDC | Centers for Disease Control and Prevention |
CNS | central nervous system |
CpG | Cytosine Guanine dinucleotides |
DAT1 | dopamine transporter 1 |
DMR | Differentially Methylated Region |
DNMT | DNA methyltransferases |
DRD4 | dopamine receptor 4 |
EPSC | excitatory postsynaptic currents |
GABA | γ-aminobutyric acid |
H3K8ac | lysine acetylation at histone H3K8 |
H3K9ac | lysine acetylation at histone H3K9 |
H4K12ac | lysine acetylation at histone H4K12 |
H3K4me | lysine methylation at histone H3K4 |
H3K9me | lysine methylation at histone H3K9 |
H3K27me | lysine methylation at histone H3K27 |
HAT | histone acetyltransferases |
HDAC | histone deacetylase |
lncRNA | long noncoding RNA |
IPSC | inhibitory postsynaptic currents |
MeCP2 | methyl-cytosine-phosphate-guanine (Me-CpG) binding protein-2 |
NMDAR | N-methyl-D-aspartate receptor |
ncRNA | noncoding RNA |
Pb | lead |
piRNA | piwi-interacting RNA |
PTM | posttranslational modifications |
snoRNA | small nucleolar RNA |
SP1 | regulator specificity protein 1 |
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Ciurean, Dagmar Schröter and Thomas Glade",authors:[{id:"163703",title:"Prof.",name:"Thomas",middleName:null,surname:"Glade",slug:"thomas-glade",fullName:"Thomas Glade"},{id:"164141",title:"Ph.D. Student",name:"Roxana",middleName:"Liliana",surname:"Ciurean",slug:"roxana-ciurean",fullName:"Roxana Ciurean"},{id:"164142",title:"Dr.",name:"Dagmar",middleName:null,surname:"Schroeter",slug:"dagmar-schroeter",fullName:"Dagmar Schroeter"}]},{id:"58010",doi:"10.5772/intechopen.72304",title:"Fourth Industrial Revolution: Current Practices, Challenges, and Opportunities",slug:"fourth-industrial-revolution-current-practices-challenges-and-opportunities",totalDownloads:6371,totalCrossrefCites:42,totalDimensionsCites:68,abstract:"The globalization and the competitiveness are forcing companies to rethink and to innovate their production processes following the so-called Industry 4.0 paradigm. It represents the integration of tools already used in the past (big data, cloud, robot, 3D printing, simulation, etc.) that are now connected into a global network by transmitting digital data. The implementation of this new paradigm represents a huge change for companies, which are faced with big investments. In order to benefit from the opportunities offered by the smart revolution, companies must have the prerequisites needed to withstand changes generated by “smart” system. In addition, new workers who face the world of work 4.0 must have new skills in automation, digitization, and information technology, without forgetting soft skills. This chapter aims to present the main good practices, challenges, and opportunities related to Industry 4.0 paradigm.",book:{id:"6291",slug:"digital-transformation-in-smart-manufacturing",title:"Digital Transformation in Smart Manufacturing",fullTitle:"Digital Transformation in Smart Manufacturing"},signatures:"Antonella Petrillo, Fabio De Felice, Raffaele Cioffi and Federico\nZomparelli",authors:[{id:"161682",title:"Prof.",name:"Fabio",middleName:null,surname:"De Felice",slug:"fabio-de-felice",fullName:"Fabio De Felice"},{id:"181603",title:"Dr.",name:"Antonella",middleName:null,surname:"Petrillo",slug:"antonella-petrillo",fullName:"Antonella Petrillo"},{id:"205141",title:"Dr.",name:"Federico",middleName:null,surname:"Zomparelli",slug:"federico-zomparelli",fullName:"Federico Zomparelli"},{id:"208748",title:"Dr.",name:"Raffaele",middleName:null,surname:"Cioffi",slug:"raffaele-cioffi",fullName:"Raffaele Cioffi"}]},{id:"40977",doi:"10.5772/53885",title:"The Emergence of Scientific Reasoning",slug:"the-emergence-of-scientific-reasoning",totalDownloads:4520,totalCrossrefCites:8,totalDimensionsCites:58,abstract:null,book:{id:"654",slug:"current-topics-in-children-s-learning-and-cognition",title:"Current Topics in Children's Learning and Cognition",fullTitle:"Current Topics in Children's Learning and Cognition"},signatures:"Bradley J. 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Therefore, this chapter deals with the philosophical systems and paradigms of scientific research, the epistemology, evaluating understanding and application of various theories and practices used in the scientific research. The key components of the scientific research paradigm are highlighted. Theories on the basis of which this research was focused on identification of the level of development of the management culture in order to implement corporate social responsibility are identified, and the stages of its implementation are described.",book:{id:"5791",slug:"management-culture-and-corporate-social-responsibility",title:"Management Culture and Corporate Social Responsibility",fullTitle:"Management Culture and Corporate Social Responsibility"},signatures:"Pranas Žukauskas, Jolita Vveinhardt and Regina Andriukaitienė",authors:[{id:"179629",title:"Prof.",name:"Jolita",middleName:null,surname:"Vveinhardt",slug:"jolita-vveinhardt",fullName:"Jolita Vveinhardt"}]},{id:"74550",title:"School Conflicts: Causes and Management Strategies in Classroom Relationships",slug:"school-conflicts-causes-and-management-strategies-in-classroom-relationships",totalDownloads:2204,totalCrossrefCites:1,totalDimensionsCites:10,abstract:"Conflicts cannot cease to exist, as they are intrinsic to human beings, forming an integral part of their moral and emotional growth. Likewise, they exist in all schools. The school is inserted in a space where the conflict manifests itself daily and assumes relevance, being the result of the multiple interpersonal relationships that occur in the school context. Thus, conflict is part of school life, which implies that teachers must have the skills to manage conflict constructively. Recognizing the diversity of school conflicts, this chapter aimed to present its causes, highlighting the main ones in the classroom, in the teacher-student relationship. It is important to conflict face and resolve it with skills to manage it properly and constructively, establishing cooperative relationships, and producing integrative solutions. Harmony and appreciation should coexist in a classroom environment and conflict should not interfere, negatively, in the teaching and learning process. This bibliography review underscore the need for during the teachers’ initial training the conflict management skills development.",book:{id:"7827",slug:null,title:"Interpersonal Relationships",fullTitle:"Interpersonal Relationships"},signatures:"Sabina Valente, Abílio Afonso Lourenço and Zsolt Németh",authors:null},{id:"58969",title:"Corruption, Causes and Consequences",slug:"corruption-causes-and-consequences",totalDownloads:27589,totalCrossrefCites:11,totalDimensionsCites:13,abstract:"Corruption is a constant in the society and occurs in all civilizations; however, it has only been in the past 20 years that this phenomenon has begun being seriously explored. It has many different shapes as well as many various effects, both on the economy and the society at large. Among the most common causes of corruption are the political and economic environment, professional ethics and morality and, of course, habits, customs, tradition and demography. Its effects on the economy (and also on the wider society) are well researched, yet still not completely. Corruption thus inhibits economic growth and affects business operations, employment and investments. It also reduces tax revenue and the effectiveness of various financial assistance programs. The wider society is influenced by a high degree of corruption in terms of lowering of trust in the law and the rule of law, education and consequently the quality of life (access to infrastructure, health care). There also does not exist an unambiguous answer as to how to deal with corruption. Something that works in one country or in one region will not necessarily be successful in another. This chapter tries to answer at least a few questions about corruption and the causes for it, its consequences and how to deal with it successfully.",book:{id:"6487",slug:"trade-and-global-market",title:"Trade and Global Market",fullTitle:"Trade and Global Market"},signatures:"Štefan Šumah",authors:[{id:"228073",title:"Mr.",name:"Stefan",middleName:null,surname:"Sumah",slug:"stefan-sumah",fullName:"Stefan Sumah"}]},{id:"55499",title:"Human Resources Management in Nonprofit Organizations: A Case Study of Istanbul Foundation for Culture and Arts",slug:"human-resources-management-in-nonprofit-organizations-a-case-study-of-istanbul-foundation-for-cultur",totalDownloads:2294,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"The aim of this study is to investigate the efficiency and importance of human resources management in nonprofit organizations. The understanding was included to the literature as personnel management at the beginning of the twentieth century and it turned into an approach as human resources management in the 1980s. It could be observed that many organizations, which deem the human as the most critical stakeholder, adopt a traditional way of personnel management in operating human resources. The employees play a key role in the success of an organization. For this reason, subjects such as recruitment, training, development, career management, performance appraisal, occupational health, and safety are the fundamental functions of human resources management. The study examines to what extent these roles are evaluated through a case study. The subject matter of the study is the most powerful culture and art foundation in Turkey. Compared to many other nonprofit organizations, the foundation actively performs a variety of services within a year worldwide. The fact that the total number of employees might rise up to 800, including the field personnel, indicates the need of a good functioning human resources management. The human resources practices of the foundation are examined and evaluated within that scope.",book:{id:"5826",slug:"issues-of-human-resource-management",title:"Issues of Human Resource Management",fullTitle:"Issues of Human Resource Management"},signatures:"Beste Gökçe Parsehyan",authors:[{id:"189113",title:"Dr.",name:"Beste",middleName:null,surname:"Gokce Parsehyan",slug:"beste-gokce-parsehyan",fullName:"Beste Gokce Parsehyan"}]},{id:"59152",title:"Marketing Strategies for the Social Good",slug:"marketing-strategies-for-the-social-good",totalDownloads:1594,totalCrossrefCites:1,totalDimensionsCites:1,abstract:"Social network sites (SNS) have proven to be a good environment to promote and sell goods and services, but marketing is more than creating commercial strategies. Social marketing strategies can also be used to promote behavioral change and help individuals transform their lives, achieve well-being, and adopt prosocial behaviors. In this chapter, we seek to analyze with a netnographic study, how SNS are being employed by nonprofits and nongovernment organizations (NGOs) to enable citizens and consumers to participate in different programs and activities that promote social transformation and well-being. A particular interest is to identify how organizations are using behavioral economic tactics to nudge individuals and motivate them to engage in prosocial actions. By providing an understanding on how SNS can provide an adequate environment for the design of social marketing strategies, we believe our work has practical implications both for academicians and marketers who want to contribute in the transformation of consumer behavior and the achievement of well-being and social change.",book:{id:"6583",slug:"marketing",title:"Marketing",fullTitle:"Marketing"},signatures:"Alicia De La Pena",authors:[{id:"196878",title:"Dr.",name:"Alicia",middleName:null,surname:"De La Pena",slug:"alicia-de-la-pena",fullName:"Alicia De La Pena"}]}],onlineFirstChaptersFilter:{topicId:"4",limit:6,offset:0},onlineFirstChaptersCollection:[{id:"82382",title:"A Cultural Approach in the Synchronous Class in English Teaching and Learning",slug:"a-cultural-approach-in-the-synchronous-class-in-english-teaching-and-learning",totalDownloads:1,totalDimensionsCites:0,doi:"10.5772/intechopen.105553",abstract:"If culture is defined as a way of training to obtain knowledge through educational channels, the concept is associated with educability. Therefore, teaching cognitive, attitudinal, and procedural knowledge directly indicates teaching and learning culture to acquire norms and patterns of sociocultural behavior. The purpose of this study was: to debate about the way interaction among students and teachers in synchronous classes based on life’s materials, topics, and methods, and critical or reflective thinking can be adapted by the teacher to the students’ closest environment to communicate in English as an international language. If a language is taught, spoken, and learned in the country, culture surrounding the context is taught. If this language is not spoken in the place, the knowledge system also transmits norms and values, different from those of the language. So, the students get, culturally and socially, modes of action, principles, and knowledge through international language learning. Thus, teaching and learning English as an international language means the way possible interaction has opportunities for every student’s growth and the way their personality formation gets integral results. English taught and learned as an international language denotes reaching the students’ world and needs to communicate in English as a meaningful international language.",book:{id:"10662",title:"Pedagogy - Challenges, Recent Advances, New Perspectives, and Applications",coverURL:"https://cdn.intechopen.com/books/images_new/10662.jpg"},signatures:"Ned Vito Quevedo Arnaiz, Nemis García Arias and Fredy Pablo Cañizares Galarza"},{id:"82470",title:"The Effect of COVID-19 on the Quality of Life of Care Workers: Challenges for Social Services Leaders",slug:"the-effect-of-covid-19-on-the-quality-of-life-of-care-workers-challenges-for-social-services-leaders",totalDownloads:2,totalDimensionsCites:0,doi:"10.5772/intechopen.105603",abstract:"Stressful situations are likely to impact health and social care workers’ quality of life negatively. Indeed, mental, physical, and emotional health problems have been reported in relation to the effects of the COVID-19 pandemic on the quality of life of health care workers. Instead of health care workers’ reality, and despite the care sector’s relevance, studies of the effects of COVID-19 on the quality of life of care workers have not been sufficiently explored. Recognizing the effect of COVID on the quality of life of care workers will collaborate with leaders of organizations, social work practitioners, and academics in the design of policies that promote better working conditions. Therefore, during 2021, a study was carried out in Chile where 150 social services and care workers were surveyed in Chile using a version of COV19-QoL in Spanish. The impact of COVID on quality of life is described, and the challenges that this reality implies to social service leaders are presented.",book:{id:"11095",title:"Social Work - Perspectives on Leadership and Organisation",coverURL:"https://cdn.intechopen.com/books/images_new/11095.jpg"},signatures:"Magdalena Calderón-Orellana, Alejandra Inostroza and Paula Miranda Sánchez"},{id:"82448",title:"Virus World Vulnerability: A Critical Reading of Gender and Performance in Bo Burnham’s “Inside” (2021)",slug:"virus-world-vulnerability-a-critical-reading-of-gender-and-performance-in-bo-burnham-s-inside-2021",totalDownloads:2,totalDimensionsCites:0,doi:"10.5772/intechopen.105182",abstract:"Through an engagement with the seminal work of Raewyn Connell on masculinities and hegemonic masculinity, this chapter argues for the hegemonic norm as producing behaviour among men that can be traced in multiple male subjectivities. The argument is that men respond to the prevailing masculine norm by enacting self-protective disavowal—a complex psychological process that involves the reordering of reality in the interests of the maintenance of power, and one that is seen in cases of both legitimate and imagined threats to the self and the body. Self-protective disavowal is at the core of the Same Shit phenomenon—the idea that while the experience of masculinity varies across culture and position in the gender order, self-protective disavowal is a constant that leads to predicable patterns among men. The discussion then explores deliberate vulnerability as a kind of anti-protective disavowal in Bo Burnham’s INSIDE, a complex, undefinable ‘special’ released on Netflix in 2021. The chapter considers Burnham’s work as a departure from self-protective disavowal and Same Shit masculinity through deliberate vulnerability and critically evaluates the value of this alternative, especially given the nihilism that reigns over the work and calls into question the validity of uncritically romanticization of alternatives.",book:{id:"10540",title:"Masculinity Studies - An Interdisciplinary Approach",coverURL:"https://cdn.intechopen.com/books/images_new/10540.jpg"},signatures:"Chris McWade"},{id:"82454",title:"Prospects and Pitfalls Experienced by Social Workers Working in a Confounding Environment in a South African Setting",slug:"prospects-and-pitfalls-experienced-by-social-workers-working-in-a-confounding-environment-in-a-south",totalDownloads:2,totalDimensionsCites:0,doi:"10.5772/intechopen.105604",abstract:"While social workers are professionally and aptly placed to facilitate a turn-around environment rife with a conglomeration of challenges such as poverty, ignorance, and diseases, the chapter discusses the developmental prospects and pitfalls that confound their practice in South Africa. Opportunely, social work interventions continue to gain developmental mileage through increased training of social workers, their increased deployment in various versatile domains of social and economic development and increased widening of the scope of social work research, especially current research in fields such as HIV/AIDS and coronavirus. On the other side of the coin, the chapter discusses social work pitfalls attributed to professional curricular gaps as social work continue to follow a western-centric curriculum; the presence of various metaphysical beliefs and myths that weaken or derail social work interventions and a weaker research environment to offer a plausible and timely solution to the prevalent problems. The chapter concludes by calling for a paradigm shift in the social work curriculum as well as its indigenization to productively respond to the South African socio-cultural and geographical milieu.",book:{id:"11095",title:"Social Work - Perspectives on Leadership and Organisation",coverURL:"https://cdn.intechopen.com/books/images_new/11095.jpg"},signatures:"Simon Murote Kang’ethe"},{id:"82425",title:"Financial Reporting and Analysis of Tesla Green Technology in the United States Market",slug:"financial-reporting-and-analysis-of-tesla-green-technology-in-the-united-states-market",totalDownloads:5,totalDimensionsCites:0,doi:"10.5772/intechopen.105065",abstract:"This study aims to discuss and analyze the financial position and performance of the US Tesla green technology company in the United States. This study uses a case study approach, financial data, and website methodologies to collect and analyze the research data. The case study is Tesla, Inc., which is a US electric vehicle and clean energy company based in Austin, Texas. Tesla is a green technology company that produces and designs electric cars, battery energy storage from home to grid-scale, solar roof tiles and solar panels, and related products and services. Tesla is growing fastly by introducing new green products, and it is now one of the world’s most valuable enterprises. It has a high market capitalization of almost US$1 trillion to become the world’s most valuable automaker. This study concludes that Tesla has changed their strategy to become the most worldwide sales of purely battery electric vehicles, capturing 23% of the market and 16% of the plug-in electric battery in the market for 2020. It has also developed a significant installer of photovoltaic systems through its subsidiary Tesla Energy in the United States. One of the largest global battery energy-storage systems suppliers is Tesla Energy, with 3.99 gigawatt-hours installed in 2021.",book:{id:"11251",title:"Banking and Accounting",coverURL:"https://cdn.intechopen.com/books/images_new/11251.jpg"},signatures:"Nizar Mohammad Alsharari"},{id:"82427",title:"Our Globalization Era among Success, Obstacles and Doubts",slug:"our-globalization-era-among-success-obstacles-and-doubts",totalDownloads:13,totalDimensionsCites:0,doi:"10.5772/intechopen.105545",abstract:"In the last decades, the never-ending and unlimited expanding of both international economies and operations became globalization. Among its main features, one could recall the enormous increase of world macro-economic quantities (Gross World Product, Inter-continental Trade, FDI), as well as financial values (public debts and currency printing). The chapter tries to quantify them, by a statistical analysis of historical data (Section 1). Section 2 is dedicated to the strategic problems of firms, in particular the threats and opportunities for (inter) national firms willing to become global, and obstacles are included in Section 3. This given, it deals with the behavior of countries from the political and juridical points of view, and those ones passed form initial perplexities, distaste, or even hostility to a favorable behavior. 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The whole process of submitting an article and editing of the submitted article goes extremely smooth and fast, the number of reads and downloads of chapters is high, and the contributions are also frequently cited.",author:{id:"55578",name:"Antonio",surname:"Jurado-Navas",institutionString:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRisIQAS/Profile_Picture_1626166543950",slug:"antonio-jurado-navas",institution:{id:"720",name:"University of Malaga",country:{id:null,name:"Spain"}}}}]},series:{item:{id:"14",title:"Artificial Intelligence",doi:"10.5772/intechopen.79920",issn:"2633-1403",scope:"Artificial Intelligence (AI) is a rapidly developing multidisciplinary research area that aims to solve increasingly complex problems. In today's highly integrated world, AI promises to become a robust and powerful means for obtaining solutions to previously unsolvable problems. 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Prior to his appointment at Stellenbosch University, he has been at the University of Pretoria, Department of Computer Science (1998-2018), where he was appointed as South Africa Research Chair in Artifical Intelligence (2007-2018), the head of the Department of Computer Science (2008-2017), and Director of the Institute for Big Data and Data Science (2017-2018). 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He is a full professor of signal processing and pattern recognition and is head of the Signals and Communications Department at ULPGC, teaching from 2001 on subjects on signal processing and learning theory. His research lines are biometrics, biomedical signals and images, data mining, classification system, signal and image processing, machine learning, and environmental intelligence. He has researched in 52 international and Spanish research projects, some of them as head researcher. He is co-author of 4 books, co-editor of 27 proceedings books, guest editor for 8 JCR-ISI international journals, and up to 24 book chapters. He has over 450 papers published in international journals and conferences (81 of them indexed on JCR – ISI - Web of Science). He has published seven patents in the Spanish Patent and Trademark Office. He has been a supervisor on 8 Ph.D. theses (11 more are under supervision), and 130 master theses. He is the founder of The IEEE IWOBI conference series and the president of its Steering Committee, as well as the founder of both the InnoEducaTIC and APPIS conference series. He is an evaluator of project proposals for the European Union (H2020), Medical Research Council (MRC, UK), Spanish Government (ANECA, Spain), Research National Agency (ANR, France), DAAD (Germany), Argentinian Government, and the Colombian Institutions. He has been a reviewer in different indexed international journals (<70) and conferences (<250) since 2001. He has been a member of the IASTED Technical Committee on Image Processing from 2007 and a member of the IASTED Technical Committee on Artificial Intelligence and Expert Systems from 2011. \n\nHe has held the general chair position for the following: ACM-APPIS (2020, 2021), IEEE-IWOBI (2019, 2020 and 2020), A PPIS (2018, 2019), IEEE-IWOBI (2014, 2015, 2017, 2018), InnoEducaTIC (2014, 2017), IEEE-INES (2013), NoLISP (2011), JRBP (2012), and IEEE-ICCST (2005)\n\nHe is an associate editor of the Computational Intelligence and Neuroscience Journal (Hindawi – Q2 JCR-ISI). He was vice dean from 2004 to 2010 in the Higher Technical School of Telecommunication Engineers at ULPGC and the vice dean of Graduate and Postgraduate Studies from March 2013 to November 2017. He won the “Catedra Telefonica” Awards in Modality of Knowledge Transfer, 2017, 2018, and 2019 editions, and awards in Modality of COVID Research in 2020.\n\nPublic References:\nResearcher ID http://www.researcherid.com/rid/N-5967-2014\nORCID https://orcid.org/0000-0002-4621-2768 \nScopus Author ID https://www.scopus.com/authid/detail.uri?authorId=6602376272\nScholar Google https://scholar.google.es/citations?user=G1ks9nIAAAAJ&hl=en \nResearchGate https://www.researchgate.net/profile/Carlos_Travieso",institutionString:null,institution:{name:"University of Las Palmas de Gran Canaria",institutionURL:null,country:{name:"Spain"}}},editorTwo:null,editorThree:null},{id:"23",title:"Computational Neuroscience",coverUrl:"https://cdn.intechopen.com/series_topics/covers/23.jpg",isOpenForSubmission:!0,editor:{id:"14004",title:"Dr.",name:"Magnus",middleName:null,surname:"Johnsson",slug:"magnus-johnsson",fullName:"Magnus Johnsson",profilePictureURL:"https://mts.intechopen.com/storage/users/14004/images/system/14004.png",biography:"Dr Magnus Johnsson is a cross-disciplinary scientist, lecturer, scientific editor and AI/machine learning consultant from Sweden. \n\nHe is currently at Malmö University in Sweden, but also held positions at Lund University in Sweden and at Moscow Engineering Physics Institute. \nHe holds editorial positions at several international scientific journals and has served as a scientific editor for books and special journal issues. \nHis research interests are wide and include, but are not limited to, autonomous systems, computer modeling, artificial neural networks, artificial intelligence, cognitive neuroscience, cognitive robotics, cognitive architectures, cognitive aids and the philosophy of mind. \n\nDr. Johnsson has experience from working in the industry and he has a keen interest in the application of neural networks and artificial intelligence to fields like industry, finance, and medicine. \n\nWeb page: www.magnusjohnsson.se",institutionString:null,institution:{name:"Malmö University",institutionURL:null,country:{name:"Sweden"}}},editorTwo:null,editorThree:null},{id:"24",title:"Computer Vision",coverUrl:"https://cdn.intechopen.com/series_topics/covers/24.jpg",isOpenForSubmission:!0,editor:{id:"294154",title:"Prof.",name:"George",middleName:null,surname:"Papakostas",slug:"george-papakostas",fullName:"George Papakostas",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002hYaGbQAK/Profile_Picture_1624519712088",biography:"George A. 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He has (co)authored more than 150 publications in indexed journals, international conferences and book chapters, 1 book (in Greek), 3 edited books, and 5 journal special issues. His publications have more than 2100 citations with h-index 27 (GoogleScholar). His research interests include computer/machine vision, machine learning, pattern recognition, computational intelligence. \nDr. Papakostas served as a reviewer in numerous journals, as a program\ncommittee member in international conferences and he is a member of the IAENG, MIR Labs, EUCogIII, INSTICC and the Technical Chamber of Greece (TEE).",institutionString:null,institution:{name:"International Hellenic University",institutionURL:null,country:{name:"Greece"}}},editorTwo:null,editorThree:null},{id:"25",title:"Evolutionary Computation",coverUrl:"https://cdn.intechopen.com/series_topics/covers/25.jpg",isOpenForSubmission:!0,editor:{id:"136112",title:"Dr.",name:"Sebastian",middleName:null,surname:"Ventura Soto",slug:"sebastian-ventura-soto",fullName:"Sebastian Ventura Soto",profilePictureURL:"https://mts.intechopen.com/storage/users/136112/images/system/136112.png",biography:"Sebastian Ventura is a Spanish researcher, a full professor with the Department of Computer Science and Numerical Analysis, University of Córdoba. 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In the last five years, he has published more than 60 papers in international journals indexed in the JCR (around 70% of them belonging to first quartile journals) and he has edited some Springer books “Supervised Descriptive Pattern Mining” (2018), “Multiple Instance Learning - Foundations and Algorithms” (2016), and “Pattern Mining with Evolutionary Algorithms” (2016). He has also been involved in more than 20 research projects supported by the Spanish and Andalusian governments and the European Union. He currently belongs to the editorial board of PeerJ Computer Science, Information Fusion and Engineering Applications of Artificial Intelligence journals, being also associate editor of Applied Computational Intelligence and Soft Computing and IEEE Transactions on Cybernetics. Finally, he is editor-in-chief of Progress in Artificial Intelligence. 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(Eng.) in Telematics from the Universidad de Colima, Mexico. He obtained both his M.Sc. and Ph.D. from the University of Liverpool, England, in the field of Intelligent Systems. He is a full professor at the Universidad Autonoma de Queretaro, Mexico, and a member of the National System of Researchers (SNI) since 2009. Dr. Aceves Fernandez has published more than 80 research papers as well as a number of book chapters and congress papers. He has contributed in more than 20 funded research projects, both academic and industrial, in the area of artificial intelligence, ranging from environmental, biomedical, automotive, aviation, consumer, and robotics to other applications. He is also a honorary president at the National Association of Embedded Systems (AMESE), a senior member of the IEEE, and a board member of many institutions. His research interests include intelligent and embedded systems.",institutionString:"Universidad Autonoma de Queretaro",institution:{name:"Autonomous University of Queretaro",institutionURL:null,country:{name:"Mexico"}}}]},{type:"book",id:"7726",title:"Swarm Intelligence",subtitle:"Recent Advances, New Perspectives and Applications",coverURL:"https://cdn.intechopen.com/books/images_new/7726.jpg",slug:"swarm-intelligence-recent-advances-new-perspectives-and-applications",publishedDate:"December 4th 2019",editedByType:"Edited by",bookSignature:"Javier Del Ser, Esther Villar and Eneko Osaba",hash:"e7ea7e74ce7a7a8e5359629e07c68d31",volumeInSeries:2,fullTitle:"Swarm Intelligence - Recent Advances, New Perspectives and Applications",editors:[{id:"49813",title:"Dr.",name:"Javier",middleName:null,surname:"Del Ser",slug:"javier-del-ser",fullName:"Javier Del Ser",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. 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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. 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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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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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