Existing 20 ancestry deconvolution tools: ✓ indicates the ability of the software to perform a specified task, ✗ indicates the inapplicability of the task by a particular tool. Unless explicitly specified, LD refers to background LD.
\r\n\tThere are a variety of approaches to reversing biodiversity loss, ranging from economic, to ecological and ethical. The utilitarian approach to conservation, bolstered by the concept of ecosystem services, can be utilized to improve the conservation case by supplementing the burgeoning biodiversity rhetoric. To address this issue, a pluralistic approach to biodiversity is required for conservation and sustainability.
",isbn:"978-1-80356-339-8",printIsbn:"978-1-80356-338-1",pdfIsbn:"978-1-80356-340-4",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,isSalesforceBook:!1,hash:"ab014f8ed1669757335225786833e9a9",bookSignature:"Dr. Gopal Shukla, Dr. Jahangeer Bhat and Dr. Sumit Chakravarty",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11460.jpg",keywords:"Ecosystem Services, Intrinsic Value, Global Trends in Biodiversity Loss, Convention on Biological Diversity, Utilitarian Value, Biodiversity Conservation, Perception, In Situ and Ex Situ Conservation, Nature Conservation, Sustainable Development Goals, Drivers of Degradation, Prioritizing Biodiversity",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"February 17th 2022",dateEndSecondStepPublish:"April 22nd 2022",dateEndThirdStepPublish:"June 21st 2022",dateEndFourthStepPublish:"September 9th 2022",dateEndFifthStepPublish:"November 8th 2022",remainingDaysToSecondStep:"a month",secondStepPassed:!0,currentStepOfPublishingProcess:3,editedByType:null,kuFlag:!1,biosketch:"Dr. Gopal Shukla, prior to becoming an assistant professor, has worked under NAIP (National Agricultural Innovation Project), NICRA ( National Innovations on Climate Resilient Agriculture), and SERB (Science and Engineering Research Board) projects. The focus of his research and development work is forest conservation. He has authored 75 research papers, 10 book chapters and has edited 5 books.",coeditorOneBiosketch:"Dr. Jahangeer is a Guest Associate Editor in Frontiers in the Environmental Science journal and is the first researcher to report the first time growing of Acacia dealbata Link. (Silver Wattle), an invasive species in the high altitudes of the Himalayas. He has 11 years of research and 8 years of teaching experience with a publication record of more than 60, including research articles, review papers, conference papers, and books of national and international repute.",coeditorTwoBiosketch:"Dr. Chakravarty, Ph. D., has a wide experience in forestry training, research, and development. He is currently working as a Professor in Uttar Banga Krishi Viswavidyalaya, Pundibari, Cooch Behar, West Bengal, India. He has conducted research on several aspects of forestry, agroforestry, medicinal plants, and climate change. 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He has been instrumental in developing HE and TVET streams of forestry and allied programmes and worked closely in accreditation with the Fiji Higher Education Commission and forestry stakeholders. Before joining Fiji National University, he worked for HNB Garhwal University, Srinagar, India, and has 11 years of research and 8 years of teaching experience with a publication record of more than 60, including research articles, review papers, conference papers, and books of national and international repute. Dr. Jahangeer reviews research articles for several scientific journals and has handled research projects in his capacity as Principal Investigator and Co-Principal Investigator. His major interests lie in emerging issues in forestry including conservation of biodiversity, traditional knowledge of plants, and sustainable management of forest resources. His focus of research is vegetation ecology, ethnobotany, and evaluation of ecosystem services, forest plant biodiversity, climate change, and socio-cultural issues in forestry. Dr. Jahangeer is currently working at the College of Horticulture and Forestry, Rani Lakshmi Bai Central Agricultural University, Jhansi, India.",institutionString:"Central Agricultural University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"0",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"Central Agricultural University",institutionURL:null,country:{name:"India"}}},coeditorTwo:{id:"94999",title:"Dr.",name:"Sumit",middleName:null,surname:"Chakravarty",slug:"sumit-chakravarty",fullName:"Sumit Chakravarty",profilePictureURL:"https://mts.intechopen.com/storage/users/94999/images/system/94999.jpg",biography:"Dr. Sumit Chakravarty, Ph.D., has wide experience in forestry training, research, and development. 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From chapter submission and review to approval and revision, copyediting and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully commit and concentrate on the chapters they are writing, editing, or reviewing. I assist authors in the preparation of their full chapter submissions and track important deadlines and ensure they are met. I help to coordinate internal processes such as linguistic review, and monitor the technical aspects of the process. As an ASM I am also involved in the acquisition of editors. 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Consequently, there has been a fundamental role for PD animal models in developing new approaches treating this disease, in innovative treatment strategies, and in understanding the nature of the pathogenic processes involved in the dopaminergic neuronal loss [1, 2].
\nSeveral models display many of the distinctive features of the disease; however, none resembles the complex chronic neurodegenerative features observed in human PD. 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 6-hydroxydopamine (6-OHDA) are considered as neurotoxicants that rapidly and selectively kill dopaminergic neurons (in 1–3 days), while in PD patients, the disease is progressive [3].
\nEmborg [4] declares that a representative animal model must present pathology and behavioral manifestations that match the disease, involving its temporal path. The more the similarity of a model is to PD, the bigger the predictive strength for clinical efficacy will be.
\nThe results regarding manganese (Mn) as an experimental PD model have been studied since its toxicity (commonly called manganism) shares neurological symptoms with numerous clinical disorders frequently described as “extrapyramidal motor system dysfunction,” and, in particular, idiopathic PD [5, 6, 7]. Manganism is associated with high brain levels of Mn, primarily in those areas known to contain high concentrations of nonheme iron, particularly the striatum, globus pallidus (GP), substantia nigra compacta (SNc), and subthalamic nuclei [8].
\nThere is some disagreement on the alterations induced by Mn; while some researchers reported that Mn alters nigrostriatal dopaminergic levels and produces a Parkinson-like disorder [9, 10, 11, 12], other authors confirmed that Mn alterations are related to different aspects to those associated to PD in both etiology and pathology [13, 14] especially in the remarkable SNc dopaminergic cell conservation [15, 16, 17, 18, 19]. As stated by Calne et al. [5], Lu et al. [16], and others [20, 21, 22], the most important between these differences is the absence of clinical response to l-DOPA.
\nHowever, studies have reported ostensibly contradictory results on the dopaminergic effects of Mn (see Gwiazda et al. [23] and Guilarte [24] for review), including decrease [9, 25, 26, 27, 28], increase [11, 29], both [30], or no modification [15, 31, 32] in SNc or striatum DA levels in Mn-exposed animals, probably indicating differences in exposure procedures on DA consequences. These inconsistencies might disclose changes in the route of exposure, magnitude, duration, Mn compound or concentration, experimental animals’ species, age, etc., among investigations, revealing the complexity of Mn toxicity and suggesting that the features that cause the toxicity are not entirely recognized.
\nIt appears that lesser dosages of Mn augmented DA and its metabolite concentrations, whereas the inverse was detected with more significant Mn concentrations [30, 32]. Similarly, it has been proposed that higher Mn dosages can drastically accelerate DA and other catecholamine oxidation, which concomitantly intensify reactive oxygen species formation of [33, 34, 35].
\nIt seems that both trivalent and divalent Mn can be carried to the CNS through the brain barriers [36, 37]. Mn2+ is transferred into brain choroidal epithelial and capillary endothelial cells through nramp2 (DMT-1) or by divalent cation transporter DCT-1 [38]. On the other hand, trivalent Mn bound to transferrin is transported across the brain barriers via the receptor-mediated endocytosis [37]. Mn is then liberated into the endothelial cells by endosomal acidification [21], then is transported to the abluminal cell exterior for release into the extracellular fluid. Finally, it is delivered to the glial cells and neurons, for usage and storage [39]. It has been demonstrated that Mn inhibits complex I in the mitochondria altering the oxidative phosphorylation process. Also, it appears that trivalent Mn is more effective in inhibiting complex I than divalent Mn [40, 41, 42, 43] and accelerating ferrous iron oxidation. Mn3+ increased facility to provoke oxidative stress has been established in rats treated with either Mn chloride [MnCl2 (Mn2+)] or Mn acetate [Mn(OAc)3 (Mn3+)] [41]; these researchers state that 1–1000 μM MnCl2 induced increased reactive oxygen species in striatum, while Mn(OAc)3 produced comparable results at significantly lower dosages (1–100 μM). Therefore, the Mn valence and metabolism appear to determine its toxicity.
\nThus, since it has been suggested that trivalent Mn is more effective in producing oxidative stress and divalent Mn requires Mn3+ to induce oxidation and that there is an interaction between the two Mn compounds, this study examines Mn2+/Mn3+ mixture inhalation effects on rats and mice to produce a unique PD experimental model provoking SNc dopaminergic cell death, progressive and bilateral, associating those changes with motor alterations. Moreover, we sought to determine if after Mn inhalation the motor alterations improve with l-DOPA treatment to ensure that the alteration’s origin is dopaminergic.
\nAnimals: 45 CD-1 male mice weighing 33 ± 2 g and 45 male Wistar rats weighing 180 ± 10 g were individually housed in hanging plastic cages under controlled light conditions (12 h light/dark regime) and fed with Purina Rodent Chow and water ad libitum (except the days of reaching task evaluation). The animals were weighed daily. The experiment was done according to the NIH Guide for the Care and Use of Laboratory Animals (No. 80-23 1996), Guide for Care and Use of Laboratory Animals certificated by SAGARPA-Mexico (NOM-062-ZOO-1999, Mexico) and approved by the Institutional Committee of Animal Care (UNAM). We made all attempts to reduce the number of rodents used and their distress.
\nBefore Mn exposure, all rodents were taught and trained for motor performance. Assessment and training were accomplished through the lighted part of the cycle, at the same hour every day. For the reaching task, the animals were kept without food to 90% of average body weight for 24 h and received controlled quantities of food pellets once a day to sustain body weight and deprivation state. Behavior analyses were conducted the days the animals did not inhale. Each animal was tested once a week, a different day for each test.
\nThe mouse reaching box was 19.5 cm × 8 cm and 20 cm high. A 1-cm vertical slot ran up the front of the box. A 0.2-cm-thick plastic shelf was displayed 1.1 cm from the floor on the box front. The rat-reaching box was 30 cm × 15 cm and 20 cm high. As for the mice box, this one has a 1-cm wide and narrow opening that ran up the front of the box. About 20-mg food pellets were positioned near the slot. Animals were habituated for 1 week by introducing them in the cages for 10 min. Pellets were initially reachable on the box floor and then within a short distance on the shelf. Food pellets were progressively raised from the box floor and positioned beyond the shelf (1 cm) until the rodents were obligated to retrieve the pellet with their preferred forelimb. According to Whishaw et al. [44], the pronation of the paw medially allows the mouse/rat to catch the food pellet with the forelimb and not with their tongue. The animals were independently trained and permitted to grasp with their preferred forelimb the pellets [44]. Each animal grasped for 20 food pellets each trial during the evaluating period. A successful reach was scored when the animal was able to retrieve with its forelimb and eat a pellet. When the pellet was knocked off the shelf or pulled into the chamber and dropped through the floor grating were scored as a failure [45]. The qualitative evaluation comprised the analysis of the “reaching performance”: the posture, limb extension, aim, paw supination-pronation during grasping, and the pellet released into the snout.
\nThis test evaluates the rodents’ skills to traverse a narrow beam (3 mm) to reach an enclosed safety platform [46]. The mice apparatus is constructed by an elevating surface of a 10 × 100 cm × 3 mm wood beam 75 cm above the floor with two supports by 15° inclination. Rat’s beam measured 2 m long and was elevated to a height of 1 m above the ground with wood supports with 15° inclination. A home box is situated near the end of the beam. On training days (4 days), each mouse/rat was positioned at the start of the beam with no inclination (four tests each day). When the animals traversed the apparatus in 20 s, they performed two more trials with the beam inclined. Mice were allowed up to 60 s and rats 120 s to traverse the wooden beam. The latency to cross the beam was recorded for each trial.
\nVideo recording: the different trials were recorded with a Sony camcorder. The video camera was placed orthogonally to the reaching box to analyze the animal’s behavior. Demonstrative motionless captures were taken from the video recordings with the Final Cut Pro X for Mac.
\nNeurological evaluation: Tremor and bradykinesia were assessed by inspection of Mn-exposed compared with control animals during the performance of the two tests.
\nAfterward, two groups were formed: one group was exposed to deionized water (control groups; n = 20), while the second group (n = 20) was exposed to the mixture of chloride (MnCl2) 0.04 M and acetate (Mn(OAc)3) 0.02 M (Sigma-Aldrich, Co. Mexico). Inhalations were done as described by Avila-Costa et al. [47]. The animals were positioned in an acrylic chamber. Mn exposure was accomplished in locked acrylic boxes (35 cm × 44 cm and 20 cm high) attached to an ultra-nebulizer (Shinmed, Taiwan), with 10 l/min constant flux. The ultra-nebulizer produces 0.5–5-μm range droplets. A vapor was placed on the other side of the box with a sodium bicarbonate mixture to trap the residual metal. During inhalations, the rats/mice were examined continuously for respiration frequency, regularity, and depth. The inhalation chamber was monitored continuously for oxygen levels, temperature, and Mn concentration.
\nBased on the results found in the behavioral evaluations, we sacrifice the animals after being exposed to 40 (mice) and 72 (rats) inhalations (5/6 months of exposure) under deep anesthesia with sodium pentobarbital lethal dose IP (0.2 mg). Thus, when evident motor alterations were observed, twenty mice/rats were sacrificed (ten controls and ten Mn-exposed), anesthetized with sodium pentobarbital, and perfused via the aorta with phosphate buffer saline (0.1 M pH 7.4) containing 4% paraformaldehyde. The brain was removed and positioned in fixative solution for 2 h and processed for tyrosine hydroxylase (TH) and NeuN immunocytochemistry (five control and five Mn-exposed brains).
\nLater, the rest of the animals continued the Mn inhalation. Five were treated orally with 7.5 mg/kg l-DOPA (Sinemet [Carbidopa-L-DOPA 25/250]) every day during 2 months, five were reserved for the equivalent time but with no treatment, and five controls were kept for the same time and then sacrificed for further analysis; the motor behavior performance was assessed every week.
\nAdditionally, the fresh tissue of other 10 control and 10 exposed animals, after 40 inhalations (mice) and after 72 inhalations (rats), was obtained to determine the concentrations of DA by HPLC in the striatum, SNc, and GP.
\nTissue samples were serially sectioned at a thickness of 50 μm on a vibrating microtome (Pelco 101, Ted Pella Inc., Mexico) within the mesencephalon for TH and GP and striatum for NeuN immunocytochemistry. TH (Chemicon International, Inc., CA, USA, 1:1000) and NeuN immunostaining (Chemicon International, International, Inc., CA, USA, 1:200) with the ABC detection technique (Vector Lab, MI, USA) was performed for the cell analysis. All images were captured using an Optiphot 2 Nikon microscope. Images were analyzed using ImageJ software. The number of TH+ cells was calculated rostrocaudally through the SNc and ventral tegmental area (VTA) in nearby segments. The SNc was manually delineated to trace the region of interest (ROI) at low magnification (4×). The TH-positive cell number was calculated at the level of the third cranial nerve, within a 100-mm counting area at 40× only within this defined ROI [48, 49]. NeuN cell count of striatum and GP was done using 40× objective in seven sections per animal at 0.70 anterior, 0.48 mm posterior to bregma for dorsomedial striatum, and 0.80 anterior and 0.92 mm posterior to bregma for ventrocaudal GP according to [50] for rats and at rostrocaudal levels 0.86 anterior to 0.50 mm posterior to bregma for dorsomedial striatum and 0.62 anterior to 0.98 mm posterior to bregma for ventrocaudal GP according to [51] for mice, in a 11,550 and 3300 mm2 counting area, respectively. It should be noted that both dorsomedial striatum and ventrocaudal GP receive the maximum dopaminergic innervation [52, 53].
\nThe Mn concentration in the inhaling box was calculated by placing a filter at the gap of the inhaling chamber during the whole inhalation time; the flow rate was constant (10 l/min). After each exposure, the filter was detached and weighed; the metal concentration was calculated with a graphite furnace atomic absorption spectrometer (Perkin Elmer Mod. 3110, CT, USA). We analyzed six filters for each inhalation [54]. At the end of the experiment, rat/mice serum Mn levels were also estimated by graphite furnace atomic absorption spectrometry.
\nSNc, striatal, and GP DA contents were obtained after 5 months, for mice, and after 6 months for rats of Mn inhalation as described by [55]. Briefly, five controls and five Mn-exposed mice and five controls and five Mn-exposed rats were anesthetized and decapitated, and with a stereoscopic microscope, the tree structures were obtained. The tissue was homogenized in perchloric acid with 100 μl per brain. Then, the tissue was centrifuged (300 PSI, 2 min, Airfuge centrifuge, Beckman, Fullerton, CA, USA) and the supernatants filtered (0.22-μm membranes, Millipore, Bedford, MA, USA). The resulted tissue was resuspended, and by Bradford method, we performed the protein determination as reported elsewhere [56]. DA levels in 10 μl of supernatant were determined through HPLC reverse phase system attached to an electrochemical detector (BAS; West Lafayette, IN, USA). Results were analyzed using the Peak II integration software (SRI Instruments; Torrance, CA, USA). DA concentration is shown as pg./μg protein.
\nUnpaired t-test was used to analyze the number of TH and NeuN-positive cells. Repeated measures ANOVA analyzed motor behavior tests; post hoc comparisons were performed with Tukey’s test. Group differences were established as statistically significant when p < 0.05. Statistical analysis was done using GraphPad 7 for Mac Software (San Diego, CA).
\nAfter 5 (mice)/6 (rats) months of exposure, neither clinical alterations nor significant weight changes were detected in the exposed animals compared with controls.
\nThe average Mn concentration detected in the chamber filters was of 2676 μg/m3 during the whole experiment. The average Mn concentration in serum of exposed mice was 30 ± 5 μg/l; control mice serum concentration of Mn was 0.05–0.12 μg/l. The average Mn concentration in serum of exposed rats was 45 ± 5 μg/l; control rat’s serum Mn concentration was of 0.05 ± 0.12 μg/l.
\nThe task includes the accomplishment of motor sequences, beginning with smelling a food pellet forward-facing the reaching slot, lifting the arm, adapting position to project the limb across the narrow slot to the food pellet, and taking the food (Figure 1).
\nCharacteristic pictures of a control animal taken during limb moving and withdrawal. The control animals moved their arm throughout the slot and opened their fingers; then, supinated their paw to take the food to the snout; and extended their digits to release the food into the mouth.
Mice and rats were presented with 20 food pellets. Figure 2 displays the success reaches throughout the experiment. Repeated measures ANOVA established a substantial effect of Mn-exposed groups since eight inhalations (p < 0.001). Mice/rats were similar in their skill to recover the pellets before Mn exposure, but Mn inhalation occasioned significant alterations in both number of successful recoveries (p < 0.001) and precision in both mice (Figure 2A) and rats (Figure 2B); however, with l-DOPA treatment, the animals recover their functioning when compared to the non-treated ones, like the control groups’ performance (p < 0.001). Control animals were steady during the entire experiment and were notably better than Mn-exposed animals (Figures 1 and 2AB).
\nReaching success scores (sum of food pellets taken out of 20; mean ± SEM) of control and Mn-exposed mice (A) and control and Mn-exposed rats (B) in the reaching task. The Mn-exposed group is impaired since week 12; note that
The qualitative assessment showed postural swing and deficiencies in limb extension (resulting in several shortened reaches), aim, and paw supination-pronation during grasping and release of the pellet into the slot (Figure 3A–J); both mice and rats exhibited unusual movements when recovering the food after Mn inhalation. The forelimb was frequently totally pronated and moves laterally over the food (Figure 3F, G, and I), or the animal hits at the pellet (Figure 3I); some mice/rats from Mn-exposed groups displayed such behavioral alterations that endured for the complete study.
\nIllustrative still pictures of an exposed to Mn mouse (A–E) and a Mn-exposed rat (F–J). The animal approaches its forelimb by moving the elbow for the hand goes through the gap. As the arm moves closer to the food, the fingers open, and then the mouse pronates its forelimb by elbow adduction and rotates it around the wrist so that the hand is positioned on the top of the food. The pellet is grabbed by flexion of the fingers. The forelimb is withdrawn carrying the food. The animal lies on its hips to eat the pellet, which is secured by the hands. Frames (F–J) Mn-exposed rats displayed alterations characterized by severe postural modifications moving the forelimb obliquely throughout the gap making various small efforts without stretching the forelimb according to the midline of its body. The fingers are simultaneously adducted. The forelimb arises in front of the side or hits laterally, and the fingers do not take the food. The animal often pulls its forelimb across the gap and let fall the food to the floor cage chasing it with the tongue.
The Mn-exposed groups are often incapable of accurately closing the digits around the pellet and dragging it to the slot without lifting the paw (Figure 3F, G, and I). These animals are also not capable of supinating the forelimb entirely and putting the mouth into the gap to recover the food with their tongue (Figure 3J). When the arm is withdrawn throughout the gap, Mn-exposed groups repeatedly turn their body and pursuit the food with the tongue instead of opening their fingers and introducing the food into the snout. The non-reaching forelimb is occasionally placed for support when recovering the food. Post-hoc analysis on the group’s effect showed that at more Mn inhalations, success of retrievals was significantly lesser (Figure 2). These situations amazingly recover with l-DOPA treatment (Figure 2A and B). The treated animals adjust their posture and project the arm toward the food pellet, supinate and pronate the paw to obtain the food, close their digits, and drag the food to the snout; their motor performance with l-DOPA treatment was comparable to control groups (Figures 1 and 2).
\nDuring the last day of evaluation before Mn exposure, we found no significant differences concerning the time in finishing the test for the controls and the Mn-exposed animals (ANOVA, p > 0.05). Figure 4 depicts the mean of total time to traverse the beam. Mn-exposed mice (Figure 4A) and rats (Figure 4B) after 10 weeks of inhalation have a significant increase in the time to cross the beam compared with control groups; moreover, animals exhibit limb weakness, akinesia, postural instability, and action tremor. Mn-exposed mice have a significant reduction in the time taken to traverse the beam after two, four, six, and eight Mn inhalations (Figure 4A) proposing hyperactivity. Afterward there is a significant increase in the time to pass and a visible presence of freezing behavior time (data not shown), compared with control mice. As for the rats (Figure 4B) in the beam-walking test, Mn-exposed animals increased the execution at all-time points. While the control rats maintained an average of 20 s during the entire experiment, the Mn-exposed rats are slow and take more than 120 s to cross the beam after the tenth week (Figure 4B). This effect is completely reversed with l-DOPA treatment. Besides, all exposed animals also exhibited hind-limb weakness, delayed motor initiative (akinesia), postural instability, and action tremor. l-DOPA treatment reverted these motor alterations in both rats and mice.
\nMean latencies to traverse the beam (±SEM) before and after mice (A) and rats’ (B) Mn inhalation and after
As for TH immunohistochemistry, mice (Figure 5A) exposed to 40 inhalations showed 67.58% decreased in the number of TH-immunopositive neurons in SNc compared to the control animals, while there was no loss of neurons in VTA of exposed animals compared to controls (Figure 5A and 6). The rats showed a 75.9% loss in the number of TH immunoreactive neurons after 48 inhalations and, like mice, showed no neuronal loss in the VTA (Figure 5B and 6).
\nTH+ cell number from the SN) and VTA. The data are depicted as the mean ± standard error. A statistically significant diminution in TH+ cells was observed in the SNc (*p < 0.05 unpaired t-test) of Mn-exposed mice (A) and rats (B) compared to controls with no changes in the VTA.
Characteristic TH+ immunostained from coronal sections comprising the SN and VTA of control and Mn-exposed animals showing the ROI which demonstrates the SNc area used for cell calculating. Note that the VTA contains many TH+ cells with no differences among groups and the SNc pronounced cell loss after Mn exposure (upper panel 4×, lower panel 10,000×).
One of the required characteristics for animal models is the neuronal specificity for cerebral nuclei that are affected in humans, so to determine if the Mn mixture affects other brain structures, we performed anti-NeuN immunohistochemistry, a nuclear protein neuronal specific. In this respect, we found no significant loss in the number of neurons in any of the analyzed nuclei (data not shown).
\nFigure 7 shows the change in DA content determined in the striatum (Str), GP, and SNc after 5 months (mice) or after 6 months (rats) of Mn inhalation compared to controls. The average content in the control mice was 96.545 ± 4.8820 and 28.008 ± 12.4500 pg/μg of protein for Mn-exposed mice; hence, DA content declines 71 and 76% for the rat’s striatum.
\nThe decrease in dopamine concentrations in the striatum (str), GP, and SNc after 5 months (mice A) or 6 months (rats B) of Mn inhalation compared to controls. Contents are expressed as percentages, which were in pg/g of protein (*p < 0.001 vs. control group by one-way ANOVA with post hoc comparisons).
This research studied the fact that MnCl2 mixed with Mn(OAc)3 induces synergistic consequences by affecting the dopaminergic system reducing TH+ cell number in the SNc but not in the VTA and reducing DA striatal, GP, and SNc levels, in both mice and rats. We found significant hyperactivity after the first weeks (2–8 inhalations) in mice and, afterward, evident reduction and alterations in locomotor activity; the motor changes improve drastically after l-DOPA treatment in both species. However, rats display different vulnerability to MnCl2/Mn(OAc)3 inhalation as they inhaled three times a week for 6 months. Nevertheless, regardless of the modified procedure, both species display notorious changes in motor behavior and a significant decrease in TH+ cells in the SNc but not in VTA. Moreover, neither of the two species displayed neuronal death neither in the striatum nor the GP.
\nIt has been demonstrated that skilled limb movements, such as the reach to grasp, display very similar motor components in humans and rodents [57, 58]. PD patients are often described as having poor manual skills that worsen as the disease progresses [59, 60]. These patients experience difficulties performing tasks requiring unilateral and bilateral arm movements and sequential and alternating limb movements [58]. In our results, mice and rats took the food from the ledge without raising the forelimb and either place the mouth into the gap to recover the food pellet with the tongue or turn their body and chase the food with the mouth. Those changes could comprise impairments to basal ganglia structures responsible for grasping movements [61]. Our results thus demonstrate that Mn-exposed animals have impairment in their success in retrieving food pellets probably due to dopaminergic cell loss.
\nBoth rats and mice showed extremity coordination disturbances, step length, and motor performance. With longer inhalation times, the Mn-exposed groups display more trouble for climbing the wooden beam. The motor alterations observed here are similar with published results in which C57-treated MPTP exhibited impairments in limb coordination, step length, and motor performance after 2 weeks [62].
\nQualitative examination showed that the groups which inhaled Mn mixture displayed postural instability, akinesia, hind-limb weakness, prolonged freezing behavior, and action tremor. According to this, Autissier et al. [9] described that subchronically orally exposed to Mn mice exhibited akinesia; this alteration was related with low striatal DA levels; Eriksson and coworkers [25] reported that 5 months after Mn exposure the animals developed akinesia, action tremor, and unsteady gait. The exposed animals lacked strength in lower and upper limbs, and the limb movements were uncoordinated. Furthermore, the stereotaxic injection of Mn3+ into the rat SNc altered the rearing behavior and the spontaneous activity [63, 64].
\nRats and mice exposed to Mn showed severe loss of SNc TH-immunopositive cells, but not in VTA, GP, or striatum. Our results disagree with other reports which found no loss of dopaminergic neurons [11, 18, 19, 32, 65, 66] and loss of striatal and GP cells [15, 17, 19]. The disagreements concerning our results and the conclusions that describe no TH+ SNc cell death and GP and striatal cell loss after Mn exposure might be due to at least three causes; first, the mixture of two Mn compounds, which, by far, no report includes such mixture of Mn compounds. Agreeing to Aschner [67], it appears that the Mn toxicity degree is about its oxidation state. As we mentioned above, divalent Mn might be oxidized to trivalent Mn by the superoxide anion [40], and because the electron transport chain in the mitochondria is recognized as the major superoxide producer in the cells, it is understood that the alterations induced by Mn are linked to its oxidation state [40]. It has been proposed that Mn3+ is more effective in producing cell damage [68] and Mn2+ needs the presence of Mn3+ to reach oxidation. Thus it seems that there is synergy between the two Mn states [43]. It also has been said that the brain is an important target of attack for transition metal ions, such as Mn, due to its abundant catecholamine concentration and the rapid oxidative metabolism catalyzed by these metals [69]. In this regard, it has been hypothesized that Mn interacts with catechols specific to dopaminergic neurons to rapidly deplete them and render such cells no longer viable [33, 40]. Thus, it is conceivable that Mn-induced DA oxidation results in the generation of reactive oxygen species, oxidative stress, and secondary cytotoxicity to dopaminergic neurons [40, 70, 71]. Numerous explanations have been proposed to clarify the vulnerability of dopaminergic cells to Mn, such as the lack of cellular antioxidant defenses by the accumulation of the metal [72] and the disruption of mitochondrial oxidative energy metabolism [73]. Second, the concentration of Mn obtained in the inhalation box (2676 mg/m3) and the time of exposure (5 or 6 mo) are sufficient to produce motor and cell alterations. It has been suggested that Mn toxicity results, most often, from the chronic exposure to very high Mn dosage (>1 mg/m3) [7] and after long-term exposure [23]. Third, apparently the exposure method determines the delivery of Mn to the brain [74, 75]. Roels et al. [75] explored Mn levels in rat brains after exposing them to either to MnCl2 or MnO2. These compounds were given intratracheally (inhalation) or intragastrically (oral). This study proposed was to achieve comparable Mn concentrations in the blood and to reach for low oral absorption of Mn vs. the higher rate of absorption from the lung. When the exposition was 1.22 mg MnCl2/kg intratracheally once a week for 4 weeks, there was an increase in blood Mn concentration (68%), which also results in augmented Mn concentrations in the striatum (205%) and cortex (48%) when compared to control group. Oral MnCl2 administration (24.3 mg MnCl2/kg once weekly for 4 weeks) produced about the same blood Mn concentration (68% increase comparing to controls) as intratracheal Mn administration in the same form, but they did not find significant Mn increase in the striatum or cerebral cortex (22% increase versus controls). Therefore, inhaled Mn delivery seems to be more efficient than oral administration in increasing brain Mn levels.
\nMoreover, it is relevant to indicate that, while Mn exposure provoked important SNc dopaminergic cell death, it appears that the VTA dopaminergic cells are not affected. We do not have the facts yet to demonstrate whether this indicates Mn selectivity for the SNc dopaminergic neurons and not for the VTA cells. Nevertheless, it has been proposed that Mn gets into the neurons via the dopamine transporter (DAT) [76, 77] as in the case of some neurotoxins such as MPTP [78], 6-OHDA [79], Maneb, and Paraquat [26], where SNc cells are more vulnerable than VTA cells. It appears that SNc neurons and VTA exhibit different biochemistry, topography, and susceptibility to pathological processes [81], VTA has lesser DAT levels than the SNc [78, 80, 81]. Therefore it is conceivable that Mn gets into SNc cells via the significant volumes of DAT located in these neurons. Nevertheless, further research is required to settle this fact.
\nSeveral studies have shown that Mn accumulates in the basal ganglia, particularly in the GP, the NE, and the SNc which cause neurodegeneration; Mn chronic exposure can induce similar changes to those observed in PD [82]. Patients with this disease present rigidity, tremor, akinesia, and postural changes. These signs reflect the SNc dopaminergic neuronal loss [83]. In this disease, there is a threshold; the motor symptoms appear when DA depletion in the striatum is about 80%, and about 60% of SNc dopaminergic neurons are lost [84]. These results are consistent with our data, which show that after MnCl2/Mn(OAc)3 mixture inhalation, the number of TH-positive SNc neurons decreases to 63% (in mice) and 75% (in rats) and DA content decreases in the studied nuclei, which could explain the motor disturbances observed in the behavioral assessments. Thus, the significant reduction in the quantity of SNc TH+ neurons after MnCl2/Mn(OAc)3 exposure and the decrease of striatal DA concentrations described here explains the evident DA reduction and the parkinsonian symptoms. Therefore, we assume that the motor alterations are exclusively due to dopaminergic changes because l-DOPA was able to reverse those motor disturbances.
\nSome authors described that Mn-induced damage includes the GP [17, 19]; nevertheless, with our data, we can guarantee that the MnCl2/Mn(OAc)3 mixture inhalation also compromises the dopaminergic nigrostriatal pathway. With our results, we prove that l-DOPA treatment significantly recovers the motor performance alterations observed after Mn inhalation, implying that this motor change origin is dopaminergic. Furthermore, the alterations produced by the inhalation of Mn mixture compounds were sufficiently extensive to cause motor deficits such as tremor, rigidity, postural instability, and akinesia. And unlike the complete DA denervation produced by some neurotoxins such as 6-OHDA, which is the most frequently used model, the inhalation of MnCl2/Mn(OAc)3 leaves a considerable portion of the nigrostriatal projection unharmed. As in early and middle stages of PD, the presence of an intact, functioning sub-portion of the nigrostriatal system could allow l-DOPA treatment to be effective.
\nIt is well established that different vulnerability to neurotoxins occur among species. So, the best PD experimental model MPTP, in rats, is not actuality used, and the implications of the data obtained from this model are debatable [85, 86]. Rats injected with MPTP doses comparable to those employed in mice do not show any significant dopaminergic neurodegeneration [86, 87]. Only injections of much higher doses of MPTP (multiple applications of 30–60 mg/kg body weight) cause significant dopaminergic cell loss in rats [88]. Remarkably, these rats must be therapeutically pretreated, with guanethidine, to prevent peripheral catecholamine release and extensive mortality [86]. These findings indicate that rats are somewhat insensitive to MPTP. Consequently, rats are not recommended for MPTP research, since rats fail to develop parkinsonian characteristics, as those observed, e.g., for monkeys and mice [89]. The apparent insensitivity of rats to MPTP toxicity may be related to a species-specific metabolism of MPTP and sequestration of MPP+, which could be different in rats compared to mice and monkeys [89]. And despite that MPTP in nonhuman primates and mice provokes a well animal PD model, a spontaneous recovery of parkinsonian symptoms has been described in both monkeys [90] and mice [91] after MPTP administration, which causes concern to use this model for an assessment of long-term therapeutic effects. However, it has been reported that chronic administration of low doses of MPTP to macaques reproduces all the signs of PD and closely imitates the progressive nature [92]. Nonetheless, rodents are most commonly used over nonhuman primates since rodent models have the advantage that rats and mice are widely available. They have high reproductive rates and require reduced living space, simple feeding, and drinking schedules and low costs [93]. Moreover, because of the economic, logistic, and ethical constraints that are related to experimental research in primates, primate models of PD are used in relatively few laboratories worldwide [94].
\nFurthermore, 6-OHDA model has been extensively used in rats; only scarce studies using mice with 6-OHDA lesions have been published. In these studies, 6-OHDA was injected mainly either intrastriatally [95, 96] or intraventricularly, and the mice were subjected to relatively slight behavioral assessment [97]. Furthermore, Cenci and Lundblad [98] performed the stereotactic unilateral 6-OHDA injection in rats and mice and then treated them with l-DOPA and reported abnormal involuntary movements (AIMs); these researchers indicated that while rat and mice AIMs can be evaluated with the same parameters, there are important differences among the two species. Mice motor behavior is less articulate and faster than rats. It is, therefore, more challenging to determine mice normal and abnormal movements with 6-OHDA model. Additionally, Iancu et al. [99] stereotactically lesioned mice SNc; they got 53 well-lesioned animals out of 110 lesioned. The small amount of well-lesioned mice is probably due to the SNc size since in mice it is extremely small. The slight variances in the inhalation procedure between species that we found here are likely because rat Mn absorption is a fast saturable process probably mediated by a high-affinity system [100]. Consequently, the rats, although with the same Mn concentrations, required more inhalations per week for 6 months instead of 5. However, both species, cytological and behavioral alterations, were very similar.
\nContrasting to MPTP and 6-OHDA PD models, where the alterations occur in a range of days or weeks, while PD in humans develops over decades [90], our PD experimental model induced by Mn inhalation seems to be a suitable model because the dopaminergic cell degeneration is bilateral and progressive and the variances among species are minimum.
\nIt has been established [88] that an acceptable PD experimental model must have these features: (1) an average number of SNc dopaminergic cells at birth followed by a gradual selective loss of these cells in adulthood; (2) merely demonstrable and measurable motor alterations; (3) the model should be established at reasonably short time course to replicate the PD pathogenesis (about 3–6 months), which would allow for therapeutic substances and strategies assessment; and (4) Lewy bodies must be present. Hence, with our Mn inhalation model, we produce three of those characteristics. Nevertheless, further studies are needed to clarify if Mn exposure generates Lewy bodies and determine if the animals recover after the inhalation period.
\nFinally, the results from this research provided essential contributions toward a better understanding of the mechanisms involved in nigrostriatal degeneration in PD because it is highly feasible and adequately simulates the neuroanatomical, neurochemical, and some of the PD behavioral characteristics.
\nIn brief, the results of this research suggest that the motor alterations induced by the inhalation of the combination of MnCl2/Mn(OAc)3 are related to nigrostriatal dopaminergic function, providing new light for the understanding of Mn neurotoxicity as an adequate PD experimental model.
\nThis work was supported by the research grants from PAPIIT-DGAPA–UNAM PAPIIT-DGAPA IN215114, IN219617, and PAPCA-Iztacala UNAM 2016-2113. The authors thank Veronica Rodríguez Mata for her excellent photographic and technical assistance.
\nAuthors declare that there is no conflict of interest.
Today, advances in high-throughput technologies have generated huge amounts of human genomics data in public domains. These data are useful for medical and population genetics to understand the population history, human evolution and demographics, susceptibility to disease, and response to drug. Over time, humanity has experienced the exchange of genetic materials across populations, mainly due to population migrations [1], which have led to wide human genetic variations as results of interbreeding or mating between different populations previously isolated. These genetic variations observed in the human deoxyribonucleic acid (DNA) sequences are caused by inheritance processes, such as mutation and recombination. Generally, the mating process yields the genetic recombination break points, introduces some variations, and creates mixed DNA segments. As a consequence, current human populations are admixed [2, 3] with specific genomes displaying a mosaic of segments originating from different ancestral populations [1, 2, 4], wide phenotypic variations, divergent genetic ancestry, and different traits observed among individuals in worldwide population groups. Thus, it is critical to understand the dynamics related to the origin of these variations, the evolution process, and its consequences in human heredity and health.
\nStudying admixture patterns in human populations consists of characterization of admixture features in human populations, including admixture mapping and date to admixture events. Admixture mapping combines both the identification of genetic variants underlying the ethnic difference in disease risk and inference of ancestry estimates associated with these genetic variants. Estimation of ancestry is commonly known as genetic ancestry inference, which is either global or local ancestry inference. Global ancestry inference estimates the overall proportion contributed by each ancestral population to the admixed genome; while, local ancestry deconvolution (local ancestry inference) estimates the number of copies from a particular population at a given site [5]. Together, admixture mapping and date to admixture events provide a better understanding of the genetic variation features throughout modern human evolution, the demographics, and adaptive processes of human populations. Currently, analyzing admixture patterns has become central to genomics research, contributing to a wide range of biomedical applications. Current advance in technologies is facilitating the movement of people worldwide, thus influencing the complexity of population admixture dynamics and leading to multi-faceted admixture events. On the other hand, the determination of local ancestry through genotyping and microarray datasets has empowered the approaches for dating mutation, selection, and admixture events [6, 7].
\nThe significance of the local ancestry inference topic is viewed through the research interests it has raised over the last two decades. Several models exist for local ancestry deconvolution, including ANCESTRYMAP [8], ADMIXMAP [9], SABER [10], LAMP [11], LAMPLD/LAMPHAP [12], SUPPORTMIX [13], EILA [14], LOTER [15], etc. Figure 1 displays the implementation dynamics of different local ancestry deconvolution models graphically, indicating the time each model was introduced. Local ancestry inference is relevant in personalizing medicines, understanding complex diseases, localizing missing sequences in reference genomes and understanding the population history and demographics. Subsequently, several studies have particularly been focusing on dating past admixture events, relevant to population migrations, heritable genes associated to some diseases, and responses to treatment [16]. The date of admixture in a given population can be predicted by analyzing the ancestral track, break-points, and linkage disequilibrium (LD) [17]. Also, distinction between date of admixture events is made with the use of LD and ancestral tracts in the admixed genomes [17]. Nowadays, there are several models for predicting the age of an admixture event, which are classified into two main groups: LD-based approaches and haplotype-based approaches [17, 18]. These models use information from genomes of several population groups around the world as representative or equivalent ancient populations known to influence the migration and/or admixture processes, yielding observed admixed population patterns worldwide (Figure 2).
\nThe evolution of local ancestry deconvolution since 2003 to 2017.
A partial worldwide admixture painting map. The figure shows several worldwide admixed populations with patterns identified through published paper on population structure from 2008 to 2018. The population migrations within and between continents have resulted in different admixed populations ranging from one- to five-way admixtures.
In this chapter, we survey current models for deconvoluting local ancestry and dating admixture events and explore computational techniques used in these models. We highlight advances made so far in this genomic era and opportunities behind these models and challenges or gaps that still need to be addressed. This informs users and researchers on the current state of research, and orient future trends in designing more effective models, which account for current challenges and produce more accurate and biological relevant estimates. In the subsequent sections, we provide an overview of existing methods used for inferring local ancestry estimates and dating admixture events.
\nIn this section, we survey current models used to elucidate admixture patterns, including local ancestry estimates (deconvolution) and dating admixture events. These models assume that the T genotyped sites are biallelic and the genotype information of the K reference candidate ancestral and admixed populations are considered known. Ancestry at different sites or windows follows a Markov chain. Recombination is assumed to occur at every generation resulting in Poison recombination points with a rate which depends on both the recombination rate, \n
As pointed out previously, existing local ancestry inference models can be categorized into two main groups based on whether the model makes use of admixture/background linkage disequilibrium (LD) or not.
\nLD-based models account for LD in local ancestry deconvolution, and due to the importance of LD in disease mapping, the first local ancestry methods fall into this category. They assume that ancestry along an admixed individual genome follows a first order Markov chain. This means that the immediate past state captures all the information on past states [19]. As a result, LD-based models assume that, at every site, the observed admixed genotypes are generated by the unobserved ancestry, and hence, Hidden Markov Model (HMM) and its extensions are used to infer the unobserved (hidden) states. Thus, to deconvolute ancestry along the admixed genome, these models have three model parameters, namely the initial, transition and observation, or emission probability models. Due to uncertainty and the number of parameters involved, LD-based methods use Markov Chain Monte Carlo (MCMC), forward-backward, or Viterbi algorithms to determine the hidden ancestry sequence for a given individual. Falush et al. and Patterson et al. modeled ancestry switch between ancestry populations at a given site, \n
representing the first marker, and the transition probability between consecutive markers with \n
Admixture LD-based methods are models that account for LD that resulted from the admixture process. They do not model background LD. Admixture LD-based methods include the early methods, for example, STRUCTURE V2 [20], ANCESTRYMAP [8], and ADMIXMAP [9], which are based on the Bayesian framework. Early methods rely on markers that show significant difference in frequency between ancestral populations (AIMs). Admixture LD-based models assume that markers are independent and the global and ancestral allele frequencies are known. They integrate HMM with MCMC, and their switch model and initial and transition models are as in Eqs. (1) and (2), respectively. Since LD-based methods do not model background LD, their observation model depends on only the allele frequency of the ancestry at that site. For instance, assuming K = 2, Patterson et al. defined the emission probability by
where y and \n
SUPPORTMIX [11] models only admixture LD by combining support vector machines (SVMs) and HMM. It was proposed in 2012 to improve on the computational time and address the challenge of a few typed or nonexistent reference panels, which overall improve multi-way local ancestry deconvolution. SUPPORTMIX is the first model to allow the learning of ancestral surrogates given a pool of reference panels. As a result, it is capable to train ancestral populations that are bigger in size than those that are mixed. Since SVMs can handle huge datasets, SUPPORTMIX is faster than early methods. It uses the rich haplotype information. Also proposed in 2012, PCADMIX [24] divides the genome into contiguous windows of SNPs as in SUPPORTMIX. It leverages principal component analysis from proxy ancestral haplotypes to model admixture LD under a standard HMM. Similar to SUPPORTMIX, PCADMIX is fast and requires phased data. Nevertheless, SUPPORTMIX and PCADMIX do not model phase switch errors, and as a result, in 2013, SEQMIX [23] was proposed. Unlike all other admixture LD-based methods, SEQMIX is based on exome sequence, reads data, and uses HMM. SEQMIX models only admixture LD and prunes SNPs in background LD. As a result, to reduce noise and systematic biases from using all SNPs [10] whilst not fully modeling LD (background), admixture and background LD methods emerged [22].
\nSince the biological data often have some dependences that violate the independence assumption in standard HMM, admixture LD-based methods are often not realistic. To relax the independence assumption, the HMM is extended to either Markov HMM, factorial HMM, hierarchical HMM, or two-layer HMM or other multivariate statistical models such as multivariate normal distribution (MVN) and a rich ancestral haplotype data are used unlike early methods. This is the case for SABER [10], SWITCH [25], HAPAA [26], HAPMIX [4], MULTIMIX [27], ALLOY [28], and ELAI [29]. MHMMs were the first HMM extension in local ancestry. They were first implemented in SABER and later in SWITCH. SABER was the first method to model background LD in the genetic ancestry inference. MHMM assumes that the current observed haplotype depends on both the current ancestry and the immediate past observation. The difference in the MHMM and admixture LD HMM-based is that when ancestry switches between sites t − 1 and t, then the MHMM observation model depends on the joint distribution of allele frequencies at the two sites [6, 30], defined as follows [10]:
where \n
where \n
However, SABER has a large parameter set, and does not explicitly model background LD as it models background LD using first order Markov chain [22]; other methods such as SWITCH were proposed. SWITCH takes into recombination even if it does not result in an ancestry switch, emerged. In contrast to SABER, SWITCH conditions the MHMM on recombination. Similar to early methods, probability of recombination depends on the admixture generations, genetic distance between consecutive SNPs, and the recombination rate. Thus, if the transition probability model in SWITCH is marginalized over recombination, then it is similar to Eq. (2) for two-way and Eq. (5) for multi-way. Although SWITCH models background LD and estimates recombination rates, the authors recommended richer MHMM or other different models that would outperform the SWITCH and SABER pairwise models [25]. As a result, methods that use both large- and small-scale HMM, referred to as the HHMM, were introduced.
\nNon-LD methods neither model background nor admixture LD. They either remove SNPs in LD which is the case for LAMP [11] and WINPOP [31], or use all SNPs (linked and unlinked SNPs) without modeling LD; this is the case for EILA [14], RFMIX [32], and LOTER [15]. Since MHMMs have a large number of parameters and do not model LD explicitly, an algorithmic approach that divides genome into windows of SNPs, LAMP [11], emerged in 2008. LAMP is fast and robust, and can infer local ancestry even without proxy ancestral genotypes. This is the case for two-way admixtures. It uses the naive Bayes classifier and a clustering algorithm known as the iterative conditional modes. LAMP estimates the most probable ancestry at a site by applying the majority vote for each SNP [11]. Although accuracy is comprised, LAMP does not suffer from challenges of HMM and extension. As a result, LAMP underperforms in closely related populations, and hence it was extended to WINPOP [31], a dynamic programming algorithm. Unlike LAMP, WINPOP assumes at least one recombination event within each window and varies the window length depending on the genetic distance between populations. Hence, WINPOP and LAMP outperform other methods in closely and distantly related populations, respectively. Both LAMP and WINPOP assume unlinked markers and discards SNPs in LD.
\nAs the admixed sequence data availability increases, Maples et al. proposed a discriminative approach to estimate local ancestry, RFMIX [32]. A discriminative approach estimates the posterior probability directly and not via the joint probability distribution. In contrast to generative ancestry inference models, RFMIX uses the information contained in admixed individuals. This is advantageous in cases of genotyped few reference panels. This is the case for Native Americans [32]. RFMIX uses conditional random fields (CRFs) parametrized on random forests. It outperforms in multi-way admixtures maybe due to modeling phase switch errors. In 2013, EILA [14], a multivariate statistic based method, was proposed particularly to increase inference power through addressing three common challenges in local ancestry. Addressed challenges are the independence of SNP assumption, difficulties in identifying break points, and the use of three genotype values. Instead of raw genotypes, EILA uses a numerical value between 0 and 1. The score determines how close SNPs are to the ancestral populations. Breakpoints are a challenge to identify, but EILA identifies them by fused quantile regression facilitating the use of estimates in admixture dating. Finally, k-means classifiers are used to infer ancestry using all genotyped SNPs [14].
\nRecently, a software package that deconvolves local ancestry in multi-way admixtures for a wide range of species, LOTER [15], was proposed. LOTER can account for phase errors in two-way admixture only. It facilitates the local ancestry inference process and its application in non-model species [15]. Unlike other methods, LOTER needs no biological such as admixture time and recombination rate or statistical parameters such as, number of hidden states and misfit probabilities to deconvolve ancestry [15]. Although it uses the Li and Stephen’s copying model [33] as in LAMPLD/LAMPHAP, LOTER is a nonprobabilistic approach formulated from an optimization problem. Its solution is obtained through dynamic programming.
\nFinally, different existing LD and non-LD-based local ancestry inference models are summarized in Table 1 extracted from Geza et al. [34].
\nSoftware | \nMulti-way | \nAccount LD | \nLD model | \nBiological/statistical parameters | \nReference populations | \nAdmixed populations | \nYear of publication | \n
---|---|---|---|---|---|---|---|
STRUCTURE V2* | \n✓ | \n✓ | \nHMM | \nMarkers, and ancestry proportions | \nUnphased | \nUnphased | \nAugust 2003 | \n
ANCESTRYMAP* | \n✗ | \n✓ | \nHMM | \nPhysical map, recombination and ancestry proportions | \nUnphased | \nUnphased | \nMay 2004 | \n
ADMIXMAP* | \n✓ | \n✓ | \nHMM | \nPhysical map and ancestry proportions | \nUnphased | \nUnphased | \nMay 2004 | \n
SABER | \n✓ | \n✓ | \nMHMM | \nPhysical map or recombination distance | \nPhased/unphased | \nPhased/unphased | \nJuly 2006 | \n
“LAMP” | \n✓ | \n✗ | \n✗ | \nAdmixture generations, LD threshold, and physical map | \nUnphased | \nUnphased | \nFebruary 2008 | \n
HAPAA | \n✓ | \n✓ | \nHHMM | \nAdmixture generations and genetic divergence | \nPhased | \nPhased | \nFebruary 2008 | \n
SWITCH | \n✓ | \n✓ | \nMHMM | \nRecombination rate | \nPhased | \nPhased | \nFebruary 2008 | \n
GEDI-ADMX | \n✓ | \n✓ | \nFixed size FHMM | \nAdmixed and ancestral SNPs (physical map) | \nPhased | \nUnphased | \nMay 2009 | \n
WINPOP | \n✓ | \n✗ | \n✗ | \nRecombination, admixture generations, LD threshold, and physical map | \nUnphased | \nUnphased | \nJune 2009 | \n
HAPMIX | \n✗ | \n✓ | \nHHMM | \nGenetic map mutation rate and admixed and ancestral SNPs | \nPhased | \nUnphased | \nJune 2009 | \n
CHROMOPAINTER | \n✓ | \n✓ | \nCo-ancestry matrix | \nRecombination rate | \nPhased | \nPhased | \nJanuary 2012 | \n
LAMPLD | \n✓ | \n✓ | \nHHMM | \nNumber of hidden states, window size and physical map | \nPhased | \nUnphased | \nMay 2012 | \n
SUPPORTMIX* | \n✓ | \n✓ | \nHMM | \nAdmixture generations and genetic map | \nPhased | \nPhased | \nJune 2012 | \n
PCADMIX* | \n✓ | \n✓ | \nWindows of blocks of SNPs | \nGenetic map and window size | \nPhased | \nPhased | \nAugust 2012 | \n
mSPECTRUM | \n✓ | \n✓ | \n\n | SNPs, mutation and recombination rate | \nPhased | \nPhased | \nAugust 2012 | \n
MULTIMIX | \n✓ | \n✓ | \nMVN | \nGenetic map, legend file and misfitting probabilities | \nPhased/unphased | \nPhased/unphased | \nNovember 2012 | \n
ALLOY | \n✓ | \n✓ | \nNon-homogeneous VLMC | \nMarkers, ancestral proportions, admixture generations, and genetic map | \nPhased | \nPhased | \nFebruary 2013 | \n
RFMIX | \n✓ | \n✗ | \n✗ | \nGenetic map, window size, and admixture generations | \nPhased | \nPhased | \nAugust 2013 | \n
EILA | \n✓ | \n✗ | \n✗ | \nPhysical map | \nUnphased (no missing values) | \nUnphased (no missing values) | \nNovember 2013 | \n
SEQMIX | \n✓ | \n✗ | \n✗ | \nGenetic map | \nUnphased | \nUnphased | \nNovember 2013 | \n
ELAI | \n✓ | \n✓ | \nTwo layer HMM | \nAdmixture generations, lower and upper cluster | \nPhased/unphased | \nPhased/unphased | \nMay 2014 | \n
LOTER | \n✓ | \n✗ | \n✗ | \n— | \nPhased | \nPhased | \nNovember 2017 | \n
Existing 20 ancestry deconvolution tools: ✓ indicates the ability of the software to perform a specified task, ✗ indicates the inapplicability of the task by a particular tool. Unless explicitly specified, LD refers to background LD.
Several models are now available to determine the date of admixture events in a given admixed genome. Breakpoints of haplotypes are used by some models while others focus on the ancestry blocks. Models based on ancestry blocks for dating admixture are formulated using either an empirical criteria or variants associated with a specific population. In order to determine the average length of the admixture block, these methods then assign ancestry on predefined windows using either wavelet transformation or conditional random fields [35]. On the other hand, there are models requiring rapid decrease in haplotype block sizes to estimate the date of the admixture event [36]. This suggests that, in general, models used for dating admixture events can be subdivided in two main classes [17, 18], namely those based on LD and those based on the haplotype distribution, as mentioned earlier.
\nAn admixture event is mainly characterized by the transfer of genes from the ancestral populations to the admixed ones. This leads to the appearance of linkage disequilibrium with regard to the ancestral populations. However, this LD formed often decreases with time. Also, the rate of decay of LD is a function of recombination and the proportion of the admixture [35]. Inversely, many methods employ this rate to calculate the time since the admixture event occurs.
\nIn 2011, Moorjani et al. introduced a method to determine the weighted correlation for a pair of SNPs [36]. This correlation coefficient is further used to measure the LD with ancestral populations [37]. The time of admixture is then determined by analyzing the correlation with respect to the genetic distance, and also fitting using a least squares method the decay of the correlation [35]. This method got improved in 2011 by Loh et al. [18]. The major improvements are in terms of computation. Loh et al. employed instead a fast Fourier transform and other faster techniques to determine the optimal distance to the fitting curve. This method has another advantage that it reduces considerable biases in the estimation of the time of admixture [18, 36]. Later, Loh et al.’s method was improved by Pickrell et al. [38] by introducing the notion of mixture exponential decay in order to take into account the admixture events in the given admixed population history. It mainly focuses on the decay of the LD.
\nLet us consider three ancestral populations \n
The date of admixture between population \n
with \n
Among the haplotype-based approaches, there is the likelihood method introduced in 2009 by Price et al. [4]. It basically determines the number of breakpoints using Hidden Markov Model. It is also able to determine the number of alleles at a particular site inherited from a given ancestor in a population. This is done in two steps. First, the method consists in identifying haplotype from the proxy ancestry populations, and secondly, the origin of each haplotype bock is identified by comparing their likelihood for one ancestral population versus the others. Considering an admixed genome, the likelihood of an observed allele is given by
with \n
where ζ is the total Morgan length, γ the proportion of admixture, and C the observed number of breakpoints [4].
\nOn the other hand, Pugach et al. [17] employed the wavelet transform to design a haplotype block approach. The aim of this method is to derive the time of admixture of a given population using the simple hybrid isolation model. It proceeds in two main steps. First, it obtains a signal of admixture from the admixed data using the principal component technique. The second step consists in deriving the date of admixture using the signal obtained in the first step [17].
\nPool and Nielsen also built a haplotype-based approach. It used precautionary ancestral populations to infer the date of admixture from the genome of an admixed population [39]. It assumed that after a number of generation g, the distribution of the ancestral haplotypes follows exponential distribution given by
where \n
Further methods include that of Gravel developed in 2012 for the identification of multiple ancestral populations in a given admixture dataset [40]. Also, Jin et al. [41] came up with a similar method to explain admixture dynamics. The method incorporates several models including gradual admixture (GA), hybrid isolated (HI), and continuous gene flow (CGF) models [41], which can be extended to GA-Isolation (GA-I) and CGF-Isolation (CGF-I) by considering isolation after admixture [42]. Hellenthal et al. [43] on the other hand built up on the work of Lawson et al. [44] on dating admixture. This method particularly considers the genome of an admixed individual to be a set chunk DNA coming from other individuals. The scheme of this method is mainly made of two stages. The first stage consists in dividing the genome into chunks and matching each of them to the proper ancestral individual. This stage is achieved with the help of Hidden Markov Model. The second stage consists in identifying haplotypes and determining their respective ancestral population [43, 44]. Moreover, the admixture event and its date are derived by fitting the decay of the ancestral haplotype with an exponential distribution curve. Moreover, Ni et al. developed a method based on the observation that the date of admixture events is related to the model used. Their method consists in using the likelihood ratio test to identify the best model for the inference of the date of admixture. Furthermore, they are able to estimate several admixture events with the given optimal model [35].
\nFinally, different existing models and tools for dating admixture events are summarized in Table 2 extracted from Chimusa et al. [35].
\nTool | \nCategory | \nAdmixture model | \nPriori proxy ancestral raw data | \nMulti-way events | \nOnline link | \n
---|---|---|---|---|---|
ROLLOFF | \nLD-based model | \nHI | \nYes | \nNo | \n\nhttps://github.com/DReichLab/AdmixTools/\n | \n
ALDER | \nHI | \nYes | \nNo | \n\nhttp://cb.csail.mit.edu/cb/alder/\n | \n|
MALDER | \nHI | \nYes | \nYes | \n\nhttps://github.com/joepickrell/malder/\n | \n|
CAMer | \nHI, GA, CGF, GA-I, CGF-I | \nYes | \nYes | \n\nhttps://github.com/david940408/CAMer\n | \n|
IMAAPs | \nHI, GA, CGF, GA-I, CGF-I | \nYes | \nYes | \n\nhttp://www.picb.ac.cn/PGG/resource.php\n | \n|
StepPCO | \nHaplotype/ancestry block size distribution-based model | \nHI | \nYes | \nYes | \n\nhttps://bioinf.eva.mpg.de/download/StepPCO/\n | \n
Adware | \n\n | \nHI, Dual-admixture | \nYes | \nYes | \n\nhttps://cran.r-project.org/web/packages/adwave/index.html\n | \n
HAPMIX | \n\n | \nHI | \nYes | \nYes | \n\nhttp://genetics.med.harvard.edu/reichlab/Reich_Lab/Software.html/\n | \n
MultiWaveIner | \n\n | \nHI | \nYes | \nYes | \n\nhttps://github.com/xyang619/MultiWaveInfer/ or \nhttp://www.picb.ac.cn/PGG/resource.php\n | \n
GLOBBERTROTTER | \n\n | \nHI, GA, CGF | \nNo | \nYes | \n\nhttps://github.com/maarjalepamets/human-admixture/\n | \n
Tracts | \n\n | \nHI, GA, CGF | \nNo | \nYes | \n\nhttps://github.com/sgravel/tracts/\n | \n
Ancestry_HMM | \n\n | \nHI | \nNo | \nNo | \n\nhttps://github.com/russcd/\n | \n
Existing dating admixture genomic tools.
Although several models exist to deconvolve local ancestry, most studies that evaluate such models showed that deviations in local ancestry estimates still exist in multi-way admixtures. Deviations in local ancestry also result from genetic drift, miscalling true ancestry, and genotyping errors. However, the signals from these factors affect the whole genome while that of unmodelled natural selection affects particular regions. For example, Chen et al. using four local ancestry inference models to scan for disease-related loci through admixture mapping showed that although all of them are LD based and divide the genome into windows of continuous SNPs, MULTIMIX and LAMPLD estimates differed in almost 20% of the analyzed SNPs. This results from the differences in the biological and statistical parameters they require and the mathematical approaches they use. Another association study by Chimusa et al. [45] also pointed out that admixture mapping is still limited by inaccuracies in multi-way local ancestry deconvolution when they evaluated one LD-based and one non-LD-based local ancestry models, WINPOP and LAMPLD.
\nInaccuracies in local ancestry estimates may result from the use of statistical or biological parameters in the estimation process, which are not always accurate when provided. It could also be due to the dependence of models on reference panels which for some populations are few or even not sampled for others. This is the case for the Native Americans. More so for other admixed populations, their history is not well known. When applied to ancient admixtures, existing methods may yield spurious estimates as they were designed for recent admixtures. Existing methods do not account for natural selection; hence, some deviations exist in regions that are under selection [45]. Also, most of them are benchmarked for three-way admixtures.
\nSince each model was introduced to address a particular challenge that models before it faced, it is clearly expected that no model or tool can achieve the best performance in all admixture scenarios and not trading estimate accuracy with computational speed. Using existing studies by Geza et al. [34], more than 50% of studies that either introduced a model or evaluated methods for association mapping showed that LAMPLD/LAMPHAP outperforms most LD-based methods. And the only LD-based method than outperformed LAMPLD is ELAI; however, this is the only study that assessed ELAI with other models. In cases where LD-based models were compared to non-LD-based models, RFMIX outperformed LAMPLD in three cases highlighted in [34], while another separate study aiming to determine the place of admixture of an admixed population RFMIX also outperformed. This could be because RFMIX can deconvolve ancestry in closely related populations [46]. However, a recent assessment between RFMIX and LOTER resulted in LOTER outperforming in ancient admixtures [15].
\nGenerally, each model is implemented as a tool in local ancestry deconvolution, existing as individual scripts requiring unique inputs and producing unique outputs. This challenges researchers with a limited computational background; thus, there is lack of a unified framework which can require a standard easy to manipulate input files and output results in a way that is easy to process for further application. In conclusion, for informed decisions on models and algorithms, existing models or tools should be assessed within a unified framework. This will allow them to be tested on different admixture scenarios and also incorporating most state-of-the-art LD and non-LD based models.
\nThe evolution of human populations and the history of the mixture of these populations have been deciphered using statistical and computational methods. These methods have been found to perform well when dealing with single point admixture event in two-way admixed populations [35]. However, as any method, they not only have advantages but also pitfalls regarding the estimation of admixture dates in some cases. It is challenging to fit to real admixed populations (for more than 3-way admixture context) in the existing models dating admixture events due to several reasons, including reliance to optimal local ancestry estimates and accurate ancestry breakpoints. This suggests that there is still a need for designing an integrative or a new model to dating admixture events for current multi-way admixed populations to further advance our understanding of human demographics and movement, and facilitate admixture mapping and estimation of the age of a disease locus contributing to disease risk.
\nIn addition, it have been discovered that the mixture exponential decay model over-estimates the date of older admixture events [35] and was suggested to detect at most three admixture events. As mentioned earlier, Ni et al. [47] dealt with the optimization of the method used in dating admixture estimation. They took into account several models but the evaluation of their technique is not effective in the estimation of ancient and multi admixture events [35, 47]. On the other hand, several practical considerations can further limit these approaches including the use of proxy ancestry populations in the estimations which could bias the accuracy of the result. This is the case when dealing for instance with low sample size and inappropriate proxy ancestral populations [35]; the requirement of having accurate LD patterns, ancestry haplotypes distribution, and a big sample size of the admixed population. Thus, there is a need for an adequate model for inferring different dates of admixture events and matching real admixture history using proxy ancestry-based methods [35].
\nCurrently, more than 20 models exist and are implemented as software to deconvolve local ancestry and 12 tools for dating admixture events. In this chapter, we discussed in detail and summarized the most commonly used models, the model assumptions, statistical and biological parameters they require, and existing challenges. This discussion highlights the need for designing more effective models, which account for current challenges and produce more accurate and biologically relevant estimates. Furthermore, it provides useful information for the implementation of practical tools, which consider current medical and population genetic demands. More importantly, this may guide users in the choice of appropriate tools for specific applications and can assist software developers in designing more advanced tools for local ancestry deconvolution and dating admixture events.
\nSome of the authors are supported in part by the National Institutes of Health (NIH) Common Fund [grant numbers U24HG006941 (H3ABioNet) and 1U01HG007459?01 (SADaCC)]. One of the authors is fully funded by the Organization for Women in Science for the Developing World (OWSD) and Swedish International Development Cooperation Agency (Sida). The content of this publication is solely the responsibility of the authors and does not necessarily represent the official views of the funders.
\nThe authors declare that they have no competing interest.
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Shohel"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},subject:{topic:{id:"1076",title:"Chronooncology",slug:"chronooncology",parent:{id:"190",title:"Oncology",slug:"medicine-oncology"},numberOfBooks:2,numberOfSeries:0,numberOfAuthorsAndEditors:71,numberOfWosCitations:35,numberOfCrossrefCitations:21,numberOfDimensionsCitations:52,videoUrl:null,fallbackUrl:null,description:null},booksByTopicFilter:{topicId:"1076",sort:"-publishedDate",limit:12,offset:0},booksByTopicCollection:[{type:"book",id:"5730",title:"Unique Aspects of Anti-cancer Drug Development",subtitle:null,isOpenForSubmission:!1,hash:"9cdd2d8e095ad4f83da2b26cb3e239c7",slug:"unique-aspects-of-anti-cancer-drug-development",bookSignature:"Jolanta Natalia Latosinska and Magdalena Latosinska",coverURL:"https://cdn.intechopen.com/books/images_new/5730.jpg",editedByType:"Edited by",editors:[{id:"77808",title:"Dr.",name:"Jolanta Natalia",middleName:null,surname:"Latosińska",slug:"jolanta-natalia-latosinska",fullName:"Jolanta Natalia Latosińska"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"5767",title:"Natural Products and Cancer Drug Discovery",subtitle:null,isOpenForSubmission:!1,hash:"6d12d5b2fe98bfc2a6411f1b26d8f028",slug:"natural-products-and-cancer-drug-discovery",bookSignature:"Farid A. 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Although there are effective drugs used to treat melanoma, some cell lines have proven resistant to chemotherapy. In this context, several research groups on natural products have investigated the anticancer effect of new natural molecules in the treatment of melanoma. Flavonoids have shown to play an important role in chemoprevention and inhibition of the proliferation, migration, and invasion of melanoma cells. In this chapter, we present a systematic review performed through a literature search over a period of 20 years, using specialized databases. Analysis of all selected manuscripts demonstrated that at least 97 flavonoids have already been investigated for the treatment of melanoma using in vitro or in vivo models. Most of the bioactive flavonoids belong to the classes of flavones (38.0%), flavonols (17.5%), or isoflavonoids (17.5%). Apigenin, diosmin, fisetin, luteolin, and quercetin were considered as the most studied flavonoids for melanoma treatment. In general, flavonoids have shown to be a promising source of molecules with great potential for the treatment of melanoma.",book:{id:"5767",slug:"natural-products-and-cancer-drug-discovery",title:"Natural Products and Cancer Drug Discovery",fullTitle:"Natural Products and Cancer Drug Discovery"},signatures:"Raimundo Gonçalves de Oliveira Júnior, Christiane Adrielly Alves\nFerraz, Mariana Gama e Silva, Érica Martins de Lavor, Larissa Araújo\nRolim, Julianeli Tolentino de Lima, Audrey Fleury, Laurent Picot,\nJullyana de Souza Siqueira Quintans, Lucindo José Quintans Júnior\nand Jackson Roberto Guedes da Silva Almeida",authors:[{id:"70159",title:"Dr.",name:"Lucindo",middleName:null,surname:"Quintans-Júnior",slug:"lucindo-quintans-junior",fullName:"Lucindo Quintans-Júnior"},{id:"72113",title:"Prof.",name:"Jackson",middleName:"Roberto Guedes Da Silva",surname:"Almeida",slug:"jackson-almeida",fullName:"Jackson Almeida"},{id:"203273",title:"Dr.",name:"Jullyana",middleName:null,surname:"de Souza Siqueira Quintans",slug:"jullyana-de-souza-siqueira-quintans",fullName:"Jullyana de Souza Siqueira Quintans"},{id:"203426",title:"Dr.",name:"Laurent",middleName:null,surname:"Picot",slug:"laurent-picot",fullName:"Laurent Picot"},{id:"204628",title:"Mr.",name:"Raimundo",middleName:null,surname:"Oliveira-Junior",slug:"raimundo-oliveira-junior",fullName:"Raimundo Oliveira-Junior"},{id:"204629",title:"MSc.",name:"Christiane",middleName:null,surname:"Ferraz",slug:"christiane-ferraz",fullName:"Christiane Ferraz"},{id:"204630",title:"MSc.",name:"Mariana",middleName:null,surname:"Silva",slug:"mariana-silva",fullName:"Mariana Silva"},{id:"204631",title:"Ms.",name:"Erica",middleName:null,surname:"Lavor",slug:"erica-lavor",fullName:"Erica Lavor"},{id:"204632",title:"Prof.",name:"Julianeli",middleName:null,surname:"Lima",slug:"julianeli-lima",fullName:"Julianeli Lima"},{id:"204633",title:"Prof.",name:"Larissa",middleName:null,surname:"Rolim",slug:"larissa-rolim",fullName:"Larissa Rolim"},{id:"204634",title:"Prof.",name:"Audrey",middleName:null,surname:"Fleury",slug:"audrey-fleury",fullName:"Audrey Fleury"}]},{id:"55925",doi:"10.5772/67797",title:"Endophytic Fungi as Alternative and Reliable Sources for Potent Anticancer Agents",slug:"endophytic-fungi-as-alternative-and-reliable-sources-for-potent-anticancer-agents",totalDownloads:1973,totalCrossrefCites:3,totalDimensionsCites:8,abstract:"In comparison with other natural sources like plants, highly diverse microorganisms are narrowly explored, especially with respect to their limitless potentials as repositories of exceptionally bioactive natural products. Of these organisms, fungi inhabiting tissues of plant in a noninvasive relationship (endophytic fungi) have proven undeniably useful and unmatchable as sources of potent bioactive molecules against several diseases such as cancer and related ailments. In general terms, endophytic fungi are highly prevalent organisms found in the tissue (intracellular or intercellular) of plants and at least for reasonable portion of their lives. It has been proven that virtually every plant, irrespective of habitat and climate, plays host to wide varieties of endophytes. Endophytic fungi produce metabolites produced by different biosynthetic pathways to that of the host plant, and this robustness equips them to synthesize unlimited structural entities and scaffolds of diverse classes. Interestingly too, the cohabitation/culture of these fungi with certain bacteria offers even stronger hopes for anticancer drug discovery. The endless need for potent drugs has necessitated the search of bioactive molecules from several sources, and endophytic fungi appear to be a recipe. This chapter is an attempt to present the current trend of research with these very promising organisms.",book:{id:"5767",slug:"natural-products-and-cancer-drug-discovery",title:"Natural Products and Cancer Drug Discovery",fullTitle:"Natural Products and Cancer Drug Discovery"},signatures:"Edwin O. Omeje, Joy E. Ahomafor, Theophilus U. Onyekaba, Philip\nO. Monioro, Ibekwe Nneka, Sunday Onyeloni, Charles Chime and\nJonathan C. Eboka",authors:[{id:"197824",title:"Dr.",name:"Edwin",middleName:"Ogechukwu",surname:"Omeje",slug:"edwin-omeje",fullName:"Edwin Omeje"},{id:"198038",title:"Dr.",name:"Nneka",middleName:null,surname:"Ibekwe",slug:"nneka-ibekwe",fullName:"Nneka Ibekwe"},{id:"198039",title:"MSc.",name:"Joy",middleName:null,surname:"Ahomafor",slug:"joy-ahomafor",fullName:"Joy Ahomafor"},{id:"198040",title:"Mr.",name:"Sunday",middleName:null,surname:"Onyeloni",slug:"sunday-onyeloni",fullName:"Sunday Onyeloni"},{id:"198041",title:"Mr.",name:"Philip",middleName:null,surname:"Monioro",slug:"philip-monioro",fullName:"Philip Monioro"},{id:"204822",title:"Dr.",name:"Charles",middleName:null,surname:"Chime",slug:"charles-chime",fullName:"Charles Chime"}]},{id:"54388",doi:"10.5772/67650",title:"Computational Studies and Biosynthesis of Natural Products with Promising Anticancer Properties",slug:"computational-studies-and-biosynthesis-of-natural-products-with-promising-anticancer-properties",totalDownloads:1933,totalCrossrefCites:5,totalDimensionsCites:6,abstract:"We present an overview of computational approaches for the prediction of metabolic pathways by which plants biosynthesise compounds, with a focus on selected very promising anticancer secondary metabolites from floral sources. We also provide an overview of databases for the retrieval of useful genomic data, discussing the strengths and limitations of selected prediction software and the main computational tools (and methods), which could be employed for the investigation of the uncharted routes towards the biosynthesis of some of the identified anticancer metabolites from plant sources, eventually using specific examples to address some knowledge gaps when using these approaches.",book:{id:"5767",slug:"natural-products-and-cancer-drug-discovery",title:"Natural Products and Cancer Drug Discovery",fullTitle:"Natural Products and Cancer Drug Discovery"},signatures:"Aurélien F.A. Moumbock, Conrad V. Simoben, Ludger Wessjohann,\nWolfgang Sippl, Stefan Günther and Fidele Ntie‐Kang",authors:[{id:"177615",title:"Prof.",name:"Ludger",middleName:null,surname:"Aloisius Wessjohann",slug:"ludger-aloisius-wessjohann",fullName:"Ludger Aloisius Wessjohann"},{id:"197160",title:"Dr.",name:"Fidele",middleName:null,surname:"Ntie-Kang",slug:"fidele-ntie-kang",fullName:"Fidele Ntie-Kang"},{id:"197406",title:"Mr.",name:"Conrad Veranso",middleName:null,surname:"Simoben",slug:"conrad-veranso-simoben",fullName:"Conrad Veranso Simoben"},{id:"197408",title:"Prof.",name:"Wolfgang",middleName:null,surname:"Sippl",slug:"wolfgang-sippl",fullName:"Wolfgang Sippl"},{id:"199056",title:"Mr.",name:"Aurelien F. A.",middleName:null,surname:"Moumbock",slug:"aurelien-f.-a.-moumbock",fullName:"Aurelien F. A. Moumbock"},{id:"199057",title:"Prof.",name:"Stefan",middleName:null,surname:"Günther",slug:"stefan-gunther",fullName:"Stefan Günther"}]},{id:"55790",doi:"10.5772/intechopen.68506",title:"Phytocompounds Targeting Cancer Angiogenesis Using the Chorioallantoic Membrane Assay",slug:"phytocompounds-targeting-cancer-angiogenesis-using-the-chorioallantoic-membrane-assay",totalDownloads:1794,totalCrossrefCites:2,totalDimensionsCites:6,abstract:"Cancer is the second cause of mortality worldwide. Angiogenesis is an important process involved in the growth of primary tumors and metastasis. New approaches for controlling the cancer progression and invasiveness can be addressed by limiting the angiogenesis process. An increasingly large number of natural compounds are evaluated as angiogenesis inhibitors. The chorioallantoic membrane (CAM) assay represents an in vivo attractive experimental model for cancer and angiogenesis studies as prescreening to the murine models. Since the discovery of tumor angiogenesis, the CAM has been intensively used in cancer research. The advantages of this in vivo technique are in terms of low time-consuming, costs, and a lower number of sacrificed animals. Currently, a great number of natural compounds are being investigated for their effectiveness in controlling tumor angiogenesis. Potential reducing of angiogenesis has been investigated by our group for pentacyclic triterpenes, in various formulations, and differences in their mechanism were registered. This chapter aims to give an overview on a number of phytocompounds investigated using in vitro, murine models and the chorioallantoic membrane assay as well as to emphasize the use of CAM assay in the study of natural compounds with potential effects in malignancies.",book:{id:"5767",slug:"natural-products-and-cancer-drug-discovery",title:"Natural Products and Cancer Drug Discovery",fullTitle:"Natural Products and Cancer Drug Discovery"},signatures:"Stefana Avram, Roxana Ghiulai, Ioana Zinuca Pavel, Marius Mioc,\nRoxana Babuta, Mirela Voicu, Dorina Coricovac, Corina Danciu,\nCristina Dehelean and Codruta Soica",authors:[{id:"141027",title:"Dr.",name:"Cristina",middleName:null,surname:"Dehelean",slug:"cristina-dehelean",fullName:"Cristina Dehelean"},{id:"173283",title:"Dr.",name:"Dorina",middleName:null,surname:"Coricovac",slug:"dorina-coricovac",fullName:"Dorina Coricovac"},{id:"186372",title:"Prof.",name:"Corina",middleName:null,surname:"Danciu",slug:"corina-danciu",fullName:"Corina Danciu"},{id:"186680",title:"Dr.",name:"Roxana",middleName:null,surname:"Ghiulai",slug:"roxana-ghiulai",fullName:"Roxana Ghiulai"},{id:"197894",title:"Prof.",name:"Codruta",middleName:null,surname:"Soica",slug:"codruta-soica",fullName:"Codruta Soica"},{id:"197929",title:"Dr.",name:"Stefana",middleName:null,surname:"Avram",slug:"stefana-avram",fullName:"Stefana Avram"},{id:"202529",title:"Dr.",name:"Ioana Zinuca",middleName:null,surname:"Pavel",slug:"ioana-zinuca-pavel",fullName:"Ioana Zinuca Pavel"},{id:"205584",title:"Mr.",name:"Marius",middleName:null,surname:"Mioc",slug:"marius-mioc",fullName:"Marius Mioc"},{id:"205585",title:"Dr.",name:"Roxana",middleName:null,surname:"Racoviceanu (Babuta)",slug:"roxana-racoviceanu-(babuta)",fullName:"Roxana Racoviceanu (Babuta)"},{id:"205586",title:"Ms.",name:"Mirela",middleName:null,surname:"Voicu",slug:"mirela-voicu",fullName:"Mirela Voicu"}]},{id:"54745",doi:"10.5772/68131",title:"Lycopene: Multitargeted Applications in Cancer Therapy",slug:"lycopene-multitargeted-applications-in-cancer-therapy",totalDownloads:1849,totalCrossrefCites:2,totalDimensionsCites:5,abstract:"Cancer is an uncontrolled growth and division of cells, leading to significant morbidity and mortality and economic burden to the society. Natural products as anticancer molecules have drawn the attention of researchers and have resulted in the development of many successful anticancer drugs, which include camptothecins, epipodophyllotoxins, vinca alkaloids, and taxanes. Another group of compounds with anti-cancer effects include botanicals (phytochemicals) found in the diet. In recent years, a tomato carotenoid lycopene (LYC) has gained attention for its potential health benefits, especially in prevention and treatment of cancer. The studies suggest that the consumption LYC in food or by itself may reduce cancer risk. However, there are insufficient clinical trial data to support the hypothesis. LYC may play a preventive role in a variety of cancers, especially in prostate cancer. It acts by multiple mechanisms including the regulation of growth factor signalling, cell cycle arrest and/or apoptosis induction, metastasis and angiogenesis, as well as by modulating the anti-inflammatory and phase II detoxification enzymes activities. The effects can be attributed to the unique chemical structure of the carotenoid which confers it a strong antioxidant property. In this chapter, we discuss the chemopreventive and anti-cancer properties of LYC, a dietary carotenoid.”",book:{id:"5767",slug:"natural-products-and-cancer-drug-discovery",title:"Natural Products and Cancer Drug Discovery",fullTitle:"Natural Products and Cancer Drug Discovery"},signatures:"Kazim Sahin, Shakir Ali, Nurhan Sahin, Cemal Orhan and Omer\nKucuk",authors:[{id:"39589",title:"Prof.",name:"Kazim",middleName:null,surname:"Sahin",slug:"kazim-sahin",fullName:"Kazim Sahin"}]}],mostDownloadedChaptersLast30Days:[{id:"54281",title:"Towards Metabolic Engineering of Podophyllotoxin Production",slug:"towards-metabolic-engineering-of-podophyllotoxin-production",totalDownloads:1676,totalCrossrefCites:3,totalDimensionsCites:3,abstract:"The pharmaceutically important anticancer drugs etoposide and teniposide are derived from podophyllotoxin, a natural product isolated from roots of Podophyllum hexandrum growing in the wild. The overexploitation of this endangered plant has led to the search for alternative sources. Metabolic engineering aimed at constructing the pathway in another host cell is very appealing, but for that approach, an in-depth knowledge of the pathway toward podophyllotoxin is necessary. In this chapter, we give an overview of the lignan pathway leading to podophyllotoxin. Subsequently, we will discuss the engineering possibilities to produce podophyllotoxin in a heterologous host. This will require detailed knowledge on the cellular localization of the enzymes of the lignan biosynthesis pathway. Due to the high number of enzymes involved and the scarce information on compartmentalization, the heterologous production of podophyllotoxin still remains a tremendous challenge. At the moment, research is focusing on the last step(s) in the conversion of deoxypodophyllotoxin to (epi)podophyllotoxin and 4′-demethyldesoxypodophyllotoxin by plant cytochromes.",book:{id:"5767",slug:"natural-products-and-cancer-drug-discovery",title:"Natural Products and Cancer Drug Discovery",fullTitle:"Natural Products and Cancer Drug Discovery"},signatures:"Christel L. C. Seegers, Rita Setroikromo and Wim J. Quax",authors:[{id:"196901",title:"Prof.",name:"Wim",middleName:null,surname:"Quax",slug:"wim-quax",fullName:"Wim Quax"},{id:"197867",title:"MSc.",name:"Christel L.C.",middleName:null,surname:"Seegers",slug:"christel-l.c.-seegers",fullName:"Christel L.C. Seegers"},{id:"197868",title:"Ms.",name:"Rita",middleName:null,surname:"Setroikromo",slug:"rita-setroikromo",fullName:"Rita Setroikromo"}]},{id:"55831",title:"African Plants with Antiproliferative Properties",slug:"african-plants-with-antiproliferative-properties",totalDownloads:2079,totalCrossrefCites:0,totalDimensionsCites:1,abstract:"Plant-derived compounds have been an integral component in man’s quest to discover ideal anticancer agents. A number of new agents are currently in clinical development with promising selective activity against cancer cell lines and cancer-related molecular targets. This book chapter discusses 14 of such compounds isolated from African plants from 15 plant families. Also contained in this book chapter are compounds from African plants that hold prospect as potential anticancer agents as informed by their in vitro and in vivo preclinical studies. It is, therefore, worthwhile that researchers in the African continent and the world over should keep on working on identifying biomolecules with potential in cancer management.",book:{id:"5767",slug:"natural-products-and-cancer-drug-discovery",title:"Natural Products and Cancer Drug Discovery",fullTitle:"Natural Products and Cancer Drug Discovery"},signatures:"Newman Osafo, Yaw Duah Boakye, Christian Agyare, Samuel\nObeng, Judith Edem Foli and Prince Amankwaah Baffour Minkah",authors:[{id:"182058",title:"Dr.",name:"Christian",middleName:null,surname:"Agyare",slug:"christian-agyare",fullName:"Christian Agyare"},{id:"186987",title:"Dr.",name:"Yaw Duah",middleName:null,surname:"Boakye",slug:"yaw-duah-boakye",fullName:"Yaw Duah Boakye"},{id:"196452",title:"Dr.",name:"Newman",middleName:null,surname:"Osafo",slug:"newman-osafo",fullName:"Newman Osafo"},{id:"201381",title:"Ms.",name:"Judith",middleName:null,surname:"Edem Foli",slug:"judith-edem-foli",fullName:"Judith Edem Foli"},{id:"201382",title:"Mr.",name:"Prince",middleName:"Amankwah Baffour",surname:"Minkah",slug:"prince-minkah",fullName:"Prince Minkah"},{id:"204731",title:"Mr.",name:"Samuel",middleName:null,surname:"Obeng",slug:"samuel-obeng",fullName:"Samuel Obeng"}]},{id:"54388",title:"Computational Studies and Biosynthesis of Natural Products with Promising Anticancer Properties",slug:"computational-studies-and-biosynthesis-of-natural-products-with-promising-anticancer-properties",totalDownloads:1933,totalCrossrefCites:5,totalDimensionsCites:6,abstract:"We present an overview of computational approaches for the prediction of metabolic pathways by which plants biosynthesise compounds, with a focus on selected very promising anticancer secondary metabolites from floral sources. We also provide an overview of databases for the retrieval of useful genomic data, discussing the strengths and limitations of selected prediction software and the main computational tools (and methods), which could be employed for the investigation of the uncharted routes towards the biosynthesis of some of the identified anticancer metabolites from plant sources, eventually using specific examples to address some knowledge gaps when using these approaches.",book:{id:"5767",slug:"natural-products-and-cancer-drug-discovery",title:"Natural Products and Cancer Drug Discovery",fullTitle:"Natural Products and Cancer Drug Discovery"},signatures:"Aurélien F.A. Moumbock, Conrad V. Simoben, Ludger Wessjohann,\nWolfgang Sippl, Stefan Günther and Fidele Ntie‐Kang",authors:[{id:"177615",title:"Prof.",name:"Ludger",middleName:null,surname:"Aloisius Wessjohann",slug:"ludger-aloisius-wessjohann",fullName:"Ludger Aloisius Wessjohann"},{id:"197160",title:"Dr.",name:"Fidele",middleName:null,surname:"Ntie-Kang",slug:"fidele-ntie-kang",fullName:"Fidele Ntie-Kang"},{id:"197406",title:"Mr.",name:"Conrad Veranso",middleName:null,surname:"Simoben",slug:"conrad-veranso-simoben",fullName:"Conrad Veranso Simoben"},{id:"197408",title:"Prof.",name:"Wolfgang",middleName:null,surname:"Sippl",slug:"wolfgang-sippl",fullName:"Wolfgang Sippl"},{id:"199056",title:"Mr.",name:"Aurelien F. A.",middleName:null,surname:"Moumbock",slug:"aurelien-f.-a.-moumbock",fullName:"Aurelien F. A. Moumbock"},{id:"199057",title:"Prof.",name:"Stefan",middleName:null,surname:"Günther",slug:"stefan-gunther",fullName:"Stefan Günther"}]},{id:"55922",title:"Lupan-Skeleton Pentacyclic Triterpenes with Activity against Skin Cancer: Preclinical Trials Evolution",slug:"lupan-skeleton-pentacyclic-triterpenes-with-activity-against-skin-cancer-preclinical-trials-evolutio",totalDownloads:1778,totalCrossrefCites:0,totalDimensionsCites:3,abstract:"Skin cancer is an increasingly frequent pathology, with a dangerous high percentage of malignant melanoma. The use of synthetic chemotherapy raises the problem of severe adverse effects and the development of resistance to treatment. Therefore, the use of natural therapies became the focus of numerous research groups due to their high efficacy and lower systemic adverse effects. Among natural products evaluated as therapeutical agents against skin cancer, betulinic acid was emphasized as a highly selective anti-melanoma agent and is currently undergoing phase II clinical trials as topical application. Several other pentacyclic triterpenes exhibit antiproliferative activities. This chapter aims to present the latest main discoveries in the class of pentacyclic triterenes with antitumor effect and the evolution of their preclinical trials. Furthermore, it includes reports on plant sources containing pentacyclic triterpenes, as well as the main possibilities of their water solubilization and cancer cell targeting. A review on recent data regarding mechanisms of action at cellular and molecular levels complements information on the outstanding medicinal potential of these compounds.",book:{id:"5730",slug:"unique-aspects-of-anti-cancer-drug-development",title:"Unique Aspects of Anti-cancer Drug Development",fullTitle:"Unique Aspects of Anti-cancer Drug Development"},signatures:"Codruţa Şoica, Diana Antal, Florina Andrica, Roxana Băbuţa, Alina\nMoacă, Florina Ardelean, Roxana Ghiulai, Stefana Avram, Corina\nDanciu, Dorina Coricovac, Cristina Dehelean and Virgil Păunescu",authors:[{id:"141027",title:"Dr.",name:"Cristina",middleName:null,surname:"Dehelean",slug:"cristina-dehelean",fullName:"Cristina Dehelean"},{id:"173283",title:"Dr.",name:"Dorina",middleName:null,surname:"Coricovac",slug:"dorina-coricovac",fullName:"Dorina Coricovac"},{id:"186372",title:"Prof.",name:"Corina",middleName:null,surname:"Danciu",slug:"corina-danciu",fullName:"Corina Danciu"},{id:"186678",title:"Dr.",name:"Codruta",middleName:null,surname:"Soica",slug:"codruta-soica",fullName:"Codruta Soica"},{id:"186679",title:"Dr.",name:"Diana",middleName:null,surname:"Antal",slug:"diana-antal",fullName:"Diana Antal"},{id:"186680",title:"Dr.",name:"Roxana",middleName:null,surname:"Ghiulai",slug:"roxana-ghiulai",fullName:"Roxana Ghiulai"},{id:"202526",title:"Dr.",name:"Stefana",middleName:null,surname:"Avram",slug:"stefana-avram",fullName:"Stefana Avram"},{id:"205282",title:"Dr.",name:"Florina",middleName:null,surname:"Ardelean",slug:"florina-ardelean",fullName:"Florina Ardelean"},{id:"205679",title:"Dr.",name:"Florina",middleName:null,surname:"Andrica",slug:"florina-andrica",fullName:"Florina Andrica"},{id:"205680",title:"Dr.",name:"Roxana",middleName:null,surname:"Racoviceanu (Babuta)",slug:"roxana-racoviceanu-(babuta)",fullName:"Roxana Racoviceanu (Babuta)"},{id:"205681",title:"Dr.",name:"Alina",middleName:null,surname:"Moaca",slug:"alina-moaca",fullName:"Alina Moaca"}]},{id:"55925",title:"Endophytic Fungi as Alternative and Reliable Sources for Potent Anticancer Agents",slug:"endophytic-fungi-as-alternative-and-reliable-sources-for-potent-anticancer-agents",totalDownloads:1973,totalCrossrefCites:3,totalDimensionsCites:8,abstract:"In comparison with other natural sources like plants, highly diverse microorganisms are narrowly explored, especially with respect to their limitless potentials as repositories of exceptionally bioactive natural products. Of these organisms, fungi inhabiting tissues of plant in a noninvasive relationship (endophytic fungi) have proven undeniably useful and unmatchable as sources of potent bioactive molecules against several diseases such as cancer and related ailments. In general terms, endophytic fungi are highly prevalent organisms found in the tissue (intracellular or intercellular) of plants and at least for reasonable portion of their lives. It has been proven that virtually every plant, irrespective of habitat and climate, plays host to wide varieties of endophytes. Endophytic fungi produce metabolites produced by different biosynthetic pathways to that of the host plant, and this robustness equips them to synthesize unlimited structural entities and scaffolds of diverse classes. Interestingly too, the cohabitation/culture of these fungi with certain bacteria offers even stronger hopes for anticancer drug discovery. The endless need for potent drugs has necessitated the search of bioactive molecules from several sources, and endophytic fungi appear to be a recipe. This chapter is an attempt to present the current trend of research with these very promising organisms.",book:{id:"5767",slug:"natural-products-and-cancer-drug-discovery",title:"Natural Products and Cancer Drug Discovery",fullTitle:"Natural Products and Cancer Drug Discovery"},signatures:"Edwin O. Omeje, Joy E. Ahomafor, Theophilus U. Onyekaba, Philip\nO. Monioro, Ibekwe Nneka, Sunday Onyeloni, Charles Chime and\nJonathan C. Eboka",authors:[{id:"197824",title:"Dr.",name:"Edwin",middleName:"Ogechukwu",surname:"Omeje",slug:"edwin-omeje",fullName:"Edwin Omeje"},{id:"198038",title:"Dr.",name:"Nneka",middleName:null,surname:"Ibekwe",slug:"nneka-ibekwe",fullName:"Nneka Ibekwe"},{id:"198039",title:"MSc.",name:"Joy",middleName:null,surname:"Ahomafor",slug:"joy-ahomafor",fullName:"Joy Ahomafor"},{id:"198040",title:"Mr.",name:"Sunday",middleName:null,surname:"Onyeloni",slug:"sunday-onyeloni",fullName:"Sunday Onyeloni"},{id:"198041",title:"Mr.",name:"Philip",middleName:null,surname:"Monioro",slug:"philip-monioro",fullName:"Philip Monioro"},{id:"204822",title:"Dr.",name:"Charles",middleName:null,surname:"Chime",slug:"charles-chime",fullName:"Charles Chime"}]}],onlineFirstChaptersFilter:{topicId:"1076",limit:6,offset:0},onlineFirstChaptersCollection:[],onlineFirstChaptersTotal:0},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:0,limit:8,total:null},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:9,numberOfPublishedChapters:87,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:98,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:27,numberOfPublishedChapters:287,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:9,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:11,numberOfPublishedChapters:139,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:8,numberOfPublishedChapters:129,numberOfOpenTopics:0,numberOfUpcomingTopics:2,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!1},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:107,numberOfOpenTopics:3,numberOfUpcomingTopics:1,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:10,numberOfPublishedChapters:103,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2632-0517",doi:"10.5772/intechopen.73681",isOpenForSubmission:!0}],sshSeriesList:[{id:"22",title:"Business, Management and Economics",numberOfPublishedBooks:1,numberOfPublishedChapters:12,numberOfOpenTopics:2,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:0,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!1},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:0,numberOfPublishedChapters:10,numberOfOpenTopics:4,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{id:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. The whole process of submitting an article and editing of the submitted article goes extremely smooth and fast, the number of reads and downloads of chapters is high, and the contributions are also frequently cited.",author:{id:"55578",name:"Antonio",surname:"Jurado-Navas",institutionString:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRisIQAS/Profile_Picture_1626166543950",slug:"antonio-jurado-navas",institution:{id:"720",name:"University of Malaga",country:{id:null,name:"Spain"}}}},{id:"6",text:"It is great to work with the IntechOpen to produce a worthwhile collection of research that also becomes a great educational resource and guide for future research endeavors.",author:{id:"259298",name:"Edward",surname:"Narayan",institutionString:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259298/images/system/259298.jpeg",slug:"edward-narayan",institution:{id:"3",name:"University of Queensland",country:{id:null,name:"Australia"}}}}]},series:{item:{id:"10",title:"Physiology",doi:"10.5772/intechopen.72796",issn:"2631-8261",scope:"Modern physiology requires a comprehensive understanding of the integration of tissues and organs throughout the mammalian body, including the cooperation between structure and function at the cellular and molecular levels governed by gene and protein expression. While a daunting task, learning is facilitated by identifying common and effective signaling pathways mediated by a variety of factors employed by nature to preserve and sustain homeostatic life. \r\nAs a leading example, the cellular interaction between intracellular concentration of Ca+2 increases, and changes in plasma membrane potential is integral for coordinating blood flow, governing the exocytosis of neurotransmitters, and modulating gene expression and cell effector secretory functions. Furthermore, in this manner, understanding the systemic interaction between the cardiovascular and nervous systems has become more important than ever as human populations' life prolongation, aging and mechanisms of cellular oxidative signaling are utilised for sustaining life. \r\nAltogether, physiological research enables our identification of distinct and precise points of transition from health to the development of multimorbidity throughout the inevitable aging disorders (e.g., diabetes, hypertension, chronic kidney disease, heart failure, peptic ulcer, inflammatory bowel disease, age-related macular degeneration, cancer). With consideration of all organ systems (e.g., brain, heart, lung, gut, skeletal and smooth muscle, liver, pancreas, kidney, eye) and the interactions thereof, this Physiology Series will address the goals of resolving (1) Aging physiology and chronic disease progression (2) Examination of key cellular pathways as they relate to calcium, oxidative stress, and electrical signaling, and (3) how changes in plasma membrane produced by lipid peroxidation products can affect aging physiology, covering new research in the area of cell, human, plant and animal physiology.",coverUrl:"https://cdn.intechopen.com/series/covers/10.jpg",latestPublicationDate:"May 14th, 2022",hasOnlineFirst:!0,numberOfPublishedBooks:11,editor:{id:"35854",title:"Prof.",name:"Tomasz",middleName:null,surname:"Brzozowski",slug:"tomasz-brzozowski",fullName:"Tomasz Brzozowski",profilePictureURL:"https://mts.intechopen.com/storage/users/35854/images/system/35854.jpg",biography:"Prof. Dr. Thomas Brzozowski works as a professor of Human Physiology and is currently Chairman at the Department of Physiology and is V-Dean of the Medical Faculty at Jagiellonian University Medical College, Cracow, Poland. His primary area of interest is physiology and pathophysiology of the gastrointestinal (GI) tract, with the major focus on the mechanism of GI mucosal defense, protection, and ulcer healing. He was a postdoctoral NIH fellow at the University of California and the Gastroenterology VA Medical Center, Irvine, Long Beach, CA, USA, and at the Gastroenterology Clinics Erlangen-Nuremberg and Munster in Germany. He has published 290 original articles in some of the most prestigious scientific journals and seven book chapters on the pathophysiology of the GI tract, gastroprotection, ulcer healing, drug therapy of peptic ulcers, hormonal regulation of the gut, and inflammatory bowel disease.",institutionString:null,institution:{name:"Jagiellonian University",institutionURL:null,country:{name:"Poland"}}},editorTwo:null,editorThree:null},subseries:{paginationCount:4,paginationItems:[{id:"10",title:"Animal Physiology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/10.jpg",isOpenForSubmission:!0,annualVolume:11406,editor:{id:"202192",title:"Dr.",name:"Catrin",middleName:null,surname:"Rutland",slug:"catrin-rutland",fullName:"Catrin Rutland",profilePictureURL:"https://mts.intechopen.com/storage/users/202192/images/system/202192.png",biography:"Catrin Rutland is an Associate Professor of Anatomy and Developmental Genetics at the University of Nottingham, UK. She obtained a BSc from the University of Derby, England, a master’s degree from Technische Universität München, Germany, and a Ph.D. from the University of Nottingham. She undertook a post-doctoral research fellowship in the School of Medicine before accepting tenure in Veterinary Medicine and Science. Dr. Rutland also obtained an MMedSci (Medical Education) and a Postgraduate Certificate in Higher Education (PGCHE). She is the author of more than sixty peer-reviewed journal articles, twelve books/book chapters, and more than 100 research abstracts in cardiovascular biology and oncology. She is a board member of the European Association of Veterinary Anatomists, Fellow of the Anatomical Society, and Senior Fellow of the Higher Education Academy. Dr. Rutland has also written popular science books for the public. https://orcid.org/0000-0002-2009-4898. www.nottingham.ac.uk/vet/people/catrin.rutland",institutionString:null,institution:{name:"University of Nottingham",institutionURL:null,country:{name:"United Kingdom"}}},editorTwo:null,editorThree:null},{id:"11",title:"Cell Physiology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/11.jpg",isOpenForSubmission:!0,annualVolume:11407,editor:{id:"133493",title:"Prof.",name:"Angel",middleName:null,surname:"Catala",slug:"angel-catala",fullName:"Angel Catala",profilePictureURL:"https://mts.intechopen.com/storage/users/133493/images/3091_n.jpg",biography:"Prof. Dr. Angel Catalá \r\nShort Biography Angel Catalá was born in Rodeo (San Juan, Argentina). He studied \r\nchemistry at the Universidad Nacional de La Plata, Argentina, where received aPh.D. degree in chemistry (Biological Branch) in 1965. From\r\n1964 to 1974, he worked as Assistant in Biochemistry at the School of MedicineUniversidad Nacional de La Plata, Argentina. From 1974 to 1976, he was a Fellowof the National Institutes of Health (NIH) at the University of Connecticut, Health Center, USA. From 1985 to 2004, he served as a Full Professor oBiochemistry at the Universidad Nacional de La Plata, Argentina. He is Member ofthe National Research Council (CONICET), Argentina, and Argentine Society foBiochemistry and Molecular Biology (SAIB). His laboratory has been interested for manyears in the lipid peroxidation of biological membranes from various tissues and different species. Professor Catalá has directed twelve doctoral theses, publishedover 100 papers in peer reviewed journals, several chapters in books andtwelve edited books. Angel Catalá received awards at the 40th InternationaConference Biochemistry of Lipids 1999: Dijon (France). W inner of the Bimbo PanAmerican Nutrition, Food Science and Technology Award 2006 and 2012, South AmericaHuman Nutrition, Professional Category. 2006 award in pharmacology, Bernardo\r\nHoussay, in recognition of his meritorious works of research. Angel Catalá belongto the Editorial Board of Journal of lipids, International Review of Biophysical ChemistryFrontiers in Membrane Physiology and Biophysics, World Journal oExperimental Medicine and Biochemistry Research International, W orld Journal oBiological Chemistry, Oxidative Medicine and Cellular Longevity, Diabetes and thePancreas, International Journal of Chronic Diseases & Therapy, International Journal oNutrition, Co-Editor of The Open Biology Journal.",institutionString:null,institution:{name:"National University of La Plata",institutionURL:null,country:{name:"Argentina"}}},editorTwo:null,editorThree:null},{id:"12",title:"Human Physiology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/12.jpg",isOpenForSubmission:!0,annualVolume:11408,editor:{id:"195829",title:"Prof.",name:"Kunihiro",middleName:null,surname:"Sakuma",slug:"kunihiro-sakuma",fullName:"Kunihiro Sakuma",profilePictureURL:"https://mts.intechopen.com/storage/users/195829/images/system/195829.jpg",biography:"Professor Kunihiro Sakuma, Ph.D., currently works in the Institute for Liberal Arts at the Tokyo Institute of Technology. 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