IntechOpen was founded by scientists, for scientists, in order to make book publishing accessible around the globe. Over the last two decades, this has driven Open Access (OA) book publishing whilst levelling the playing field for global academics. Through our innovative publishing model and the support of the research community, we have now published over 5,700 Open Access books and are visited online by over three million academics every month. These researchers are increasingly working in broad technology-based subjects, driving multidisciplinary academic endeavours into human health, environment, and technology.
\\n\\n
By listening to our community, and in order to serve these rapidly growing areas which lie at the core of IntechOpen's expertise, we are launching a portfolio of Open Science journals:
All three journals will publish under an Open Access model and embrace Open Science policies to help support the changing needs of academics in these fast-moving research areas. There will be direct links to preprint servers and data repositories, allowing full reproducibility and rapid dissemination of published papers to help accelerate the pace of research. Each journal has renowned Editors in Chief who will work alongside a global Editorial Board, delivering robust single-blind peer review. Supported by our internal editorial teams, this will ensure our authors will receive a quick, user-friendly, and personalised publishing experience.
\\n\\n
"By launching our journals portfolio we are introducing new, dedicated homes for interdisciplinary technology-focused researchers to publish their work, whilst embracing Open Science and creating a unique global home for academics to disseminate their work. We are taking a leap toward Open Science continuing and expanding our fundamental commitment to openly sharing scientific research across the world, making it available for the benefit of all." Dr. Sara Uhac, IntechOpen CEO
\\n\\n
"Our aim is to promote and create better science for a better world by increasing access to information and the latest scientific developments to all scientists, innovators, entrepreneurs and students and give them the opportunity to learn, observe and contribute to knowledge creation. Open Science promotes a swifter path from research to innovation to produce new products and services." Alex Lazinica, IntechOpen founder
\\n\\n
In conclusion, Natalia Reinic Babic, Head of Journal Publishing and Open Science at IntechOpen adds:
\\n\\n
“On behalf of the journal team I’d like to thank all our Editors in Chief, Editorial Boards, internal supporting teams, and our scientific community for their continuous support in making this portfolio a reality - we couldn’t have done it without you! With your support in place, we are confident these journals will become as impactful and successful as our book publishing program and bring us closer to a more open (science) future.”
\\n\\n
We invite you to visit the journals homepage and learn more about the journal’s Editorial Boards, scope and vision as all three journals are now open for submissions.
\\n\\n
Feel free to share this news on social media and help us mark this memorable moment!
After years of being acknowledged as the world's leading publisher of Open Access books, today, we are proud to announce we’ve successfully launched a portfolio of Open Science journals covering rapidly expanding areas of interdisciplinary research.
\n\n\n\n
IntechOpen was founded by scientists, for scientists, in order to make book publishing accessible around the globe. Over the last two decades, this has driven Open Access (OA) book publishing whilst levelling the playing field for global academics. Through our innovative publishing model and the support of the research community, we have now published over 5,700 Open Access books and are visited online by over three million academics every month. These researchers are increasingly working in broad technology-based subjects, driving multidisciplinary academic endeavours into human health, environment, and technology.
\n\n
By listening to our community, and in order to serve these rapidly growing areas which lie at the core of IntechOpen's expertise, we are launching a portfolio of Open Science journals:
All three journals will publish under an Open Access model and embrace Open Science policies to help support the changing needs of academics in these fast-moving research areas. There will be direct links to preprint servers and data repositories, allowing full reproducibility and rapid dissemination of published papers to help accelerate the pace of research. Each journal has renowned Editors in Chief who will work alongside a global Editorial Board, delivering robust single-blind peer review. Supported by our internal editorial teams, this will ensure our authors will receive a quick, user-friendly, and personalised publishing experience.
\n\n
"By launching our journals portfolio we are introducing new, dedicated homes for interdisciplinary technology-focused researchers to publish their work, whilst embracing Open Science and creating a unique global home for academics to disseminate their work. We are taking a leap toward Open Science continuing and expanding our fundamental commitment to openly sharing scientific research across the world, making it available for the benefit of all." Dr. Sara Uhac, IntechOpen CEO
\n\n
"Our aim is to promote and create better science for a better world by increasing access to information and the latest scientific developments to all scientists, innovators, entrepreneurs and students and give them the opportunity to learn, observe and contribute to knowledge creation. Open Science promotes a swifter path from research to innovation to produce new products and services." Alex Lazinica, IntechOpen founder
\n\n
In conclusion, Natalia Reinic Babic, Head of Journal Publishing and Open Science at IntechOpen adds:
\n\n
“On behalf of the journal team I’d like to thank all our Editors in Chief, Editorial Boards, internal supporting teams, and our scientific community for their continuous support in making this portfolio a reality - we couldn’t have done it without you! With your support in place, we are confident these journals will become as impactful and successful as our book publishing program and bring us closer to a more open (science) future.”
\n\n
We invite you to visit the journals homepage and learn more about the journal’s Editorial Boards, scope and vision as all three journals are now open for submissions.
\n\n
Feel free to share this news on social media and help us mark this memorable moment!
\n\n
\n'}],latestNews:[{slug:"intechopen-supports-asapbio-s-new-initiative-publish-your-reviews-20220729",title:"IntechOpen Supports ASAPbio’s New Initiative Publish Your Reviews"},{slug:"webinar-introduction-to-open-science-wednesday-18-may-1-pm-cest-20220518",title:"Webinar: Introduction to Open Science | Wednesday 18 May, 1 PM CEST"},{slug:"step-in-the-right-direction-intechopen-launches-a-portfolio-of-open-science-journals-20220414",title:"Step in the Right Direction: IntechOpen Launches a Portfolio of Open Science Journals"},{slug:"let-s-meet-at-london-book-fair-5-7-april-2022-olympia-london-20220321",title:"Let’s meet at London Book Fair, 5-7 April 2022, Olympia London"},{slug:"50-books-published-as-part-of-intechopen-and-knowledge-unlatched-ku-collaboration-20220316",title:"50 Books published as part of IntechOpen and Knowledge Unlatched (KU) Collaboration"},{slug:"intechopen-joins-the-united-nations-sustainable-development-goals-publishers-compact-20221702",title:"IntechOpen joins the United Nations Sustainable Development Goals Publishers Compact"},{slug:"intechopen-signs-exclusive-representation-agreement-with-lsr-libros-servicios-y-representaciones-s-a-de-c-v-20211123",title:"IntechOpen Signs Exclusive Representation Agreement with LSR Libros Servicios y Representaciones S.A. de C.V"},{slug:"intechopen-expands-partnership-with-research4life-20211110",title:"IntechOpen Expands Partnership with Research4Life"}]},book:{item:{type:"book",id:"4537",leadTitle:null,fullTitle:"Updates on Cancer Treatment",title:"Updates on Cancer Treatment",subtitle:null,reviewType:"peer-reviewed",abstract:"In spite of advances in the cancer research field, cancer treatment still challenges researchers and clinicians, as proven by the still impressive and increasing number of worldwide cancer-related deaths. 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The aim of the referred projects was to develop biotechnological strategies to overcome these diseases, seeking to identify diagnostic, risk, and/or prognostic biomarkers. His scientific network includes Brazilian institutions (INCa, UFRJ, UFSCar, UFRN, UNESP) and foreign institutions (Technion, La Sabana University, The Johns Hopkins University and UTHSCSA). 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1. Introduction
Development of alternative weed control methods is needed to help decrease reliance on herbicide use. Biological weed control is an alternative option for weed problems, particularly in agriculture and forestry. It is based on the use of natural enemies, particularly insects and pathogens to control weeds, as a sustainable, low cost and more environmentally acceptable method of weed control. One of the approaches to biological weed control using pathogens, mainly fungi, is inundative, bioherbicide approach.
Bioherbicides are phytopathogenic microorganisms or microbial phytotoxins useful for biological weed control applied in similar ways to conventional herbicides [1–3]. The active ingredient in a bioherbicide is, however, a living microorganism. Most commonly the organism is a fungus; hence the term mycoherbicide is often used in these cases [4]. Although the use of fungi and bacteria as inundative biological control agents (bioherbicides) has been recognized as a significant technological weed control alternative [5–9], it can be argued that it serves a more important role as a complementary component in successful integrated management strategies [10], and not as a replacement for chemical herbicides and other weed management tactics [11]. Actually, in many situations, bioherbicides can be used as the sole option for the management of one or two target weeds, i.e. as a minor supplement to conventional chemical herbicides [12].
However, according to many authors, bioherbicides offer many advantages in comparison with synthetic herbicides. They include:
a high degree of specificity of target weed;
no effect on non-target and beneficial plants or man;
absence of residue build-up in the environment; and
effectiveness for managing herbicide-resistant (HR) weed populations [7,9,12–16].
Except numerous advantages of bioherbicides, some circumstances have been noted to restrain the progress of bioherbicides into profitable outputs. These include:
biological restrictions (host changeability, host scope resistance mechanisms and interaction with other microorganisms that affect efficacy) [17];
environment restrictions (epidemiology of bioherbicides reliant on optimal environmental conditions) [18–20];
technical restrictions (wholesale production and formulation development of reliable and effective bioherbicide) [17,21]; and
commercial restrictions (market capacity, patent protection, confidence and adjustment) [21–23].
2. Biological weed control
Biological control is the deliberate use of natural enemies to reduce the population of a target weed to below a desired threshold [24,25] and can be divided into two main approaches:
classical approach, in which a natural enemy is exported from its native range to an introduced (weedy, invasive) range of a plant, [24,26,27], and
bioherbicide approach, in which a natural enemy is used within its native range to control a native or naturalized weed [28–30].
2.1. Classical (inoculative) approach
The biocontrol approach using an imported pathogen to control a native or naturalized weed with minimal manipulations has been termed the inoculative or classical biocontrol method [31]. The classical approach is directed mainly towards the control of exotic weeds, which have spread in the introduced area in the absence of natural enemies. Control is achieved by the importation and release of highly host-specific pathogens virulent to the target weed in its native region [32]. These agents feed on the weed, reproduce and gradually suppress the weed as their population grows.
A highly successful biological control programme was implemented in Hawaii in the 1970s when a white smut fungus (Entyloma ageratinae sp. nov.) was introduced from Jamaica to control the exotic weed mistflower (Ageratina riparia (Regel) K. & R.), which was invading Hawaiian indigenous forest. The effect was rapid, with 95 per cent control after 3–4 years [33]. Western Australian golden wattle (Acacia saligna (Labill.) H.L. Wendl.) is regarded as the most important invasive weed that threatens the Cape Fynbos Floristic Region of South Africa, a unique ecosystem. In about 8 years, the introduction of the rust disease (Uromycladium tepperianum Sacc.) from Australia had become widespread in the province and tree density was decreased by 90–95% [34].
Another widely acclaimed example of biological control success is the use of a rust fungus (Puccinia chondrillina Bubak & Syd.) to control rush skeleton (Chondrilla juncea L.) in Australia. The rust fungus was introduced from the Mediterranean. Puccinia chondrillina was also introduced into the western United States to control a Chondrilla juncea L. biotype. However, unlike in Australia, the rust was only partially successful [35]. An example of successful classical biological control is that of rust fungus (Puccinia carduorum Jacky), imported from Turkey and released into the northeastern United States (Virginia and Maryland) in 1987 to control musk thistle (Carduus thoermeri Weinm.). The rust fungus has spread widely from its original introduction to the western states of Wyoming and California [36–38]. Baudoin et al. [36] found that Puccinia carduorum reduces musk thistle density by rushing agedness of rust-infected musk thistle and diminishes seed production by 20– 57%. Rust fungus (Puccinia jaceae var. solstitialis), imported from Bulgaria and Turkey, was released in California, United States, in 2003 for biological control of yellow starthistle (Centaurea solstitialis L.). The host range tests on this pathogen were extensive [39,40].
Trujillo et al. [41] have introduced septoria leaf spot (Septoria passiflorae Syd.) for the biological control of the exotic weed banana poka (Passiflora tripartita (Juss.) Poir var. tripartita Holm-Nie. Jörg. & LAW), at different forest sites in Hawaii, which resulted in over 50 per cent biomass reduction of the weed 3 years after inoculation.
Klamathweed beetle (Chrysolina quadrigemina Suffrian), introduced from Australia, proved especially effective for common St. Johnswort (Hypericum perforatum L.) weed control on California rangeland. Populations of the beetles quickly grew and spread. After 5 years, millions were collected from original release sites for redistribution throughout the Pacific Northwest. Ten years after the first release, H. perforatum populations in California were reduced to less than 1% of their original size [25]. Another example of successful classical biological control is the introduction of the black dot spurge beetle (Aphthona nigriscutis Foudras) from Hungary as a biological control agent for leafy spurge (Euphorbia esula L.). Release of these insects has resulted in a 99 per cent reduction in spurge stand density in one area and a corresponding 30-fold increase in grass biomass in pasture and rangeland after 4 years [42,43].
2.2. Bioherbicide (inundative) approach
Opposite to classical (inoculative) approach, the bioherbicide (inundative) approach uses indigenous plant pathogens that are isolated from weeds and are cultured to produce large quantity of infective material [28]. These are utilized at amounts that will provoke tremendous levels of infection, leading to elimination of the target weed before economic damages happen [29]. A development of this strategy involves application of weed pathogens in a manner similar to herbicide applications. Bioherbicide inoculum is susceptible to unfavourable environmental conditions after spraying, and viability needs to be maintained for as long as is necessary to achieve infection following application [30]. Once in the field, the inundative application of inoculum is timed to coincide with the most favourable environmental conditions and susceptible growth stage of the weed, so that a disease epidemic occurs and the weed population is suppressed [44,45]. Once the weed problem has been removed, natural constraints ensure that the pathogen population returns to a low level once again.
The bioherbicide (inundative) approach has been successfully implemented for a number of important agricultural, invasive and exotic weeds. Many examples dedicated to positive bioherbicide implementation are elaborated in the Section “Bioherbicide case studies”.
3. History of bioherbicides
Utilization of plant pathogens for weed control was first reported in the early 1900s, but the concept of using bioherbicides to control weeds attracted wide interest among weed scientists and plant pathologists after the Second World War. The earliest experiments simply involved fungus Fusarium oxysporum Schlecht. against prickly pear cactus (Opuntia ficus-indica (L.) Mill.) in Hawaii. In the 1950s, the Russians mass-produced the spores of Alternaria cuscutacidae Rudakov and applied them to the parasitic weed dodder (Cuscata spp.). In 1963, the Chinese mass-produced a different fungus (Colletotrichum gloeosporioides f. sp. cuscutae) for the same weed (Cuscata spp.). They called their mycoherbicide “LuBao” and an improved formulation is still in use today. Official date of bioherbicide control of weeds commenced in the late 1960s with an ambitious programme to find out a pathogen or pathogens for sorrels or docks (Rumex spp.) in the United States [46] and blackberries (Rubus spp.) in Chile [47]. From the 1970s there has been a considerable number of prosperous bioherbicide projects [8,24,48]. The number of scientific articles on bioherbicide research has enlarged excessively since the early 1980s. The number of weeds aimed for control as well as the number of potential pathogen candidates studied has increased. Registered and unregistered uses of bioherbicides have also increased considerably. In addition, the numbers of US patents published for the bioherbicidal technology and bioherbicide handling have increased, perhaps anticipating an increased dependence on bioherbicides in the future [49].
4. Bioherbicide case studies
Considering the research effort expended in this area, some bioherbicides are commercialized (Devine®, Collego®, BioMal®, Camperico®, Myco–TechTM®, Woad Warrior®, Smolder®, Dr. bioSedge®, Biochon®, StampOut® [13,22,28,50–55] and many are underway to develop and register. Plant pathologists and weed scientists have identified approximately 200 plant pathogens that are candidates for development as commercial bioherbicides [48,56]. Some examples are presented below.
Culture filtrates of Plectosporium tabacinum (van Beyma) M. E. Palm, W. Gams et Nirenberg, isolated from naturally infected cleavers plants, provided 80–90% control of Galium spp. under field conditions. [57]. Fusarium oxysporum (PSM 197), a potential mycoherbicide for controlling Striga spp. in West Africa, showed significant reductions in the total number of emerged plants of S. asiatica (91.3%), S. gesneroides (81.8%) and S. hermonthica (94.3%) [58]. Hemp sesbania (Sesbania\n\t\t\t\texaltata [Raf.] Rydb. ex A. W. Hill), one of the 10 most troublesome weeds in soybean in Arkansas, Louisiana and Mississippi [59] was 90% controlled with the isolates of the fungus Colletotrichum truncatum [14–16]. The level of control was similar to those achieved with the synthetic herbicide acifluorfen in the same crop [15]. A Myrothecium verrucaria (Alb. & Schwein.) Ditmar:Fr. (MV) bioherbicidal isolate IMI 361690 provided >85% control of Chenopodium amaranticolor Coste & Reynier, Senna obtusifulia L., Sesbania exaltata (Raf.) Cory and Datura stramonium L. [60]. Other MV isolates have bioherbicidal activity for the control of Carduus acanthoides L. and Euphorbia esula L. [61,62]. Trichothecenes produced by an MV isolate from Italy could inhibit seed germination of the parasitic plant Orobanche ramosa [63]. Recently, MV was shown to be highly virulent against Portulaca oleracea, Portulaca portulacastrum, Euphorbia maculata and Euphorbia prostrata in commercial tomato (Lycopersicon esculentum L.) fields in the southeastern United States [64]. Phomopsis amaranthicola, an indigenous plant pathogen, provided up to 100% control of several Amaranthus species [65–67]. Host range testing of this organism has not shown infection of soybean, corn, sorghum or wheat. Mintz et al. [68] evaluated another fungal pathogen, Aposphaeria amaranthi Ell. & Barth. (later renamed as Microsphaeropsis amaranthi (Ell. & Barth.) [69], as a potential bioherbicide for several Amaranthus species (A. retroflexus, A. spinosus, A. hybridus and A. albus). In this context, in field experiments, eight Amaranthus species treated with Microsphaeropsis amaranthi and a mixture of Microsphaeropsis amaranthi and Phomopsis amaranthicola had severe disease ratings of 15 days after treatment (DAT), and mortality ranged from 74% to 100% [70]. Drechslera avenacea is a potential bioherbicide for Avena fatua control in dryland wheat crops in southern Australia. Maximum disease severity (DS) (1.1 lesions per mm2 of leaf tissue) was recorded following the application of 1×105 spores per mL and exposure of weeds to a 12- to 16-h dew period at 20–25°C [71]. The fungus Pyricularia setariae applied at the concentration of 105 spores mL-1 reduced fresh weight of Setaria viridis (L.) Beauv. by 34% 7 DAT when compared with controls, whereas a concentration of 107 spores mL-1 reduced fresh weight by 87%. More importantly, Pyricularia setariae caused 80% fresh weight reduction of Setaria viridis (L.) Beauv. biotype resistant to sethoxydim, compared with 17% achieved with sethoxydim [72]. Sesbania exaltata [Raf.] Rydb. ex A.W. Hill was effectively controlled by 85, 90 and 93% of Colletotrichum truncatum (Schwein.) Andrus & Moore at inoculum concentrations of 2.5, 5.0 and 10.0 x 106 spores mL-1, respectively [73]. Taraxacum officinale was controlled by 70–80% and 90% by biocontrol strains of Phoma macrostoma applied as granular fungal inoculums to soil at the rate of 63g/m2 and 125g/m2, respectively [74]. The fungus Phoma macrostoma exhibits control of broadleaved weeds Taraxacum officinale and Cirsium arvense while showing no effect on grasses or cereal crops and is now being developed as a biological herbicide for weeds in turfgrass (lawns, golf courses, public grounds), agriculture (cereal crops) and agro-forestry (reforestation nurseries) [75]. Kadir et al. [76] have demonstrated the efficacy of Dactylaria higginsii as a bioherbicide agent for Cyperus rotundus L. in field trials. They have also reported that Dactylaria higginsii disease could help reduce interference from Cyperus rotundus L. and improve yield in greenhouse-grown tomato [77]. Morales-Payan et al. [78] estimated the bioherbicidal efficacy of Dactylaria higginsii in several field trials in Florida and Puerto Rico. According to their results, application of Dactylaria higginsii at 8 and 18 days after emergence (DAE) or 8, 18 and 25 DAE reduced the yield of pepper to 24 and 31%, respectively, compared to weed-free control plots. Similarly, Semidey et al. [79] have reported that onion yield was higher in plots sprayed three times with Dactylaria higginsii as compared to the yield from one or two applications. The potential of Dactylaria higginsii as a substitute to methyl bromide fumigation in an integrated approach to Cyperus rotundus L. control in a tomato production system was examined by Rosskopf et al. [80]. The results obtained showed that weed seedlings between 3 and 5 weeks of age were the most susceptible to the disease. Besides the use of fungi as bioherbicides, several strains of soil bacteria as pre-emergent biological control agents against annual grassy weeds have been identified and field-tested. Up to 85–90% control of green foxtail (Setaria viridis (L.) P. Beauv.) and wild oat (Avena fatua L.) was achieved using a granular formulation called "pesta" [81–83]. The leading bacterial candidate for biological control of the grass weeds is a Pseudomonas fluorescens, strain BRG100, which delays the emergence of the weeds and significantly inhibits root growth. Charudattan et al. [84] reported on potential virus-based bioherbicide tobacco mild green mosaic virus (TMGMV), which caused 83–97% mortality of Solanum viarum plants of different sizes and ages.
5. Interaction between bioherbicides and synthetic herbicides
The idea of combining bioherbicides with synthetic herbicides or adjuvants has been the issue of substantial research work. Moreover, it has been revealed that mixtures of some bioherbicides and synthetic herbicides can be synergistic [85,86], culminating from reduced weed defence reactions caused by the herbicides, consequently making the weeds more sensitive to pathogen attack [87,88]. Christy et al. [86] reported a synergy between trimethylsulfonium salt of glyphosate and Xanthomonas campestris against several weed species. Other synergistic interactions involving chemical herbicides and bioherbicides have been discovered and some were granted patents in the United States [85,89]. According to Caulder and Stowell [85,89], acifluorfen and bentazon were the most effective synergists and provided significant control in several weed/pathogen combinations: (Senna obtusifolia, formerly Cassia obtusifolia [L.] Irwin & Barneby) and Alternaria cassiae Jurair & Khan; Aeschynomene virginica [L.] Britton, Sterns & Poggenb. and Colletotrichum gloesporioides; Sesbania exaltata (Raf.) Cory and Colletotrichum truncatum; and Desmodium\n\t\t\t\ttortuosum [SW.] DC. and Fusarium lateritium Nees. A sublethal dose of glyphosate (50 mmol L-1) suppressed the biosynthesis of a phytoalexin derived from the shikimate pathway in Senna obtusifolia (L.) H. S. Irwin & Barneby, infected by Alternaria cassiae Jurair & Khan, reducing the resistance of the weed to fungal infection and disease development [90]. Similarly, 12 DAT, Brunnichia ovata [Walt.] Shinners and Campsis radicans [L.] Seem. ex Bureau were controlled by 88 and 90%, respectively, through a synergistic interaction between the fungus Myrothecium verrucaria (Alb. & Schwein.) Ditmar: Fr. and the herbicide glyphosate. Neither glyphosate nor M. verrucaria controlled these weeds at commercially acceptable levels (≥80%) [73]. According to Boyette et al. [91], timing of glyphosate application in relation to combined treatment with the bioherbicide M. verrucaria can improve the control of Pueraria lobata (Willd.) Ohwi, Brunnichia ovata [Walt.] Shinners and Campsis radicans [L.] Seem. ex Bureau. Heiny [92] revealed that Phoma proboscis Heiny at 1 x 107 spores mL-1 mixured with reduced rates of 2,4-D plus MCPP controlled field bindweed (Convolvulus\n\t\t\t\tarvensis L.) more effectively than the herbicide mixture alone and as effectively as the pathogen at a 10-fold higher rate. Application of various crop oils [68,93–97] and invert emulsions [15,98–100] improved efficacy and performance of many bioherbicides and biocontrol fungi. For instance, according to Hoagland et al. [10] treatment of fungus Myrothecium verrucaria (MV) strain originally isolated from sicklepod (Senna obtusifolia L.) mixture with the surfactant Silwet L-77 caused 100% mortality of Pueraria lobata (Willd.) Ohwi seedlings under greenhouse conditions, and 90–100% control of older Pueraria lobata (Willd.) Ohwi plants in naturally infested and experimental plots, respectively.
6. Bioherbicide limitations
In spite of considerable research in bioherbicides, there are only a few commercially available products worldwide. This lack of availability is mainly due to limitations in bioherbicide development, which need to be overcome to ensure the future commercial success of bioherbicides [22, 101]. Limitations in bioherbicide development can be classified as either environmental (temperature and, particularly, humidity as major factors influencing the efficacy of bioherbicides), biological (mainly host variability and resistance), or technological–commercial (mass production and formulation, which often blocked bioherbicide development) [17,22,102].
7. Environmental limitations
Environmental limitations are a constraint to the effective use of many biological agents, including bioherbicides. Environmental factors influence formulation performance of bioherbicides as inoculum production is dependent on sporulation of the formulation. This process, although rapid, might continue over several weeks subsequent to applications and might encounter variable environmental conditions [18,21,22]. In the application of bioherbicides, environmental conditions prevailing in the phyllosphere of plants are frequently hostile for biological control agents [103,104]. A requirement of more than 12 h of dew period for severe infection by a pathogen has been reported for several potential bioherbicides [105–108] and this may limit the efficacy of the bioherbicide in the field. Temperature generally has not been considered to be as critical as moisture for mycoherbicide [109], although field efficacy of Colletotrichum orbiculare in controlling Xanthium spinosum L. is reduced by high-temperature conditions after inoculation of plants [110]. However, dew period length requirement and temperature typically interact [111]. Low temperatures may greatly extend dew period length requirements for bioherbicides developed for use in crops, such as winter wheat.
Nutrient balance can play an important part in sporulation of fungi. Studies with Colletotrichum truncatum have shown how carbon concentration and carbon to nitrogen (C:N) ratio influence propagule production [112]. Moreover, a defined amino acid composition of the N source improved the production of conidia [113]. In addition, spore fitness in terms of germination and appressoria formation rate and subsequent disease production [114] was influenced by C:N ratios.
Soil environment, moisture and the nutrient status of the soil can influence the physiology of target plants and, therefore, their interaction with aerial applied bioherbicides [21]. Pre-emergence application has been considered as an alternative approach to overcome some of the environmental stresses imposed upon propagules applied onto the foliage or soil surface [115]. Bioherbicides consisting of propagules of soil-borne pathogens, which normally infect at or below the soil surface, appear to be more protected from environmental extremes and may persist and give residual control [116,117]. In this context, Jackson et al. [113] reported for 95% control of the emerging Sesbania exaltata (Raf.) Rydb. ex A. W. Hill seedlings when Colletotrichum truncatum (Schw.) Andrus and Moore was incorporated into the soil.
There are many environmental limitations to applying bioherbicides and maintaining their efficacy in water as well [118]. Auld and McRae [4] stated that for control of aquatic weeds a biocontrol agent would need to possess a high ecological capability to contend with varying conditions between surface and bottom, as well as across even small bodies of water. Oxygen concentration, temperature, light intensity and salinity are just four of the variables to contend with.
8. Biological limitations
From a biological viewpoint, a good bioherbicide acts relatively quickly and has acceptable efficacy in control of weeds. Unfortunately, Charudattan [8] stated that many of the discovered weed pathogens may provide partial control of only one weed species, even under ideal conditions. This host particularity is related to the fundamental bio-physiology of the pathogen and to host changeability [119,120] and resistance as well [17]. In other words, within a population of weed species there will usually be a range of genetically diverse biotypes [121] that may include some resistant biotypes, just as there may be a range of biotypes of microorganisms [122], for instance within fungal species, with slightly different host ranges [14,123,124], so that there is potential to mix and vary the biotypes of a species used as a bioherbicide. Non-target plant protection in relation to the potential use of Chondrostereum purpureum (Pers ex Fr.) Pouzar (silverleaf disease) to control black cherry (Prunus serotina Erhr.) in coniferous forests by modelling the dispersal of spores and therefore quantitatively assessing the risks to susceptible fruit trees outside the forest was noted by De Jong et al. [125]. Concerns have been raised regarding the potential for sexual or asexual gene exchange between bioherbicide strains and strains attacking distantly related crop plants [109,126,127].
9. Technological–commercial limitations
Several technological limitations have been identified that could prevent the widespread use of bioherbicides [21]. Pathogenic strains, formulation method and the interaction of these two parameters significantly affect the shelf life of the formulations at room temperature [21,128]. High concentrations and the alteration of formulations are needed to increase bioherbicide activity [129]. Compatibility testing of formulation components that range from registered agricultural products to novel substances, such as sunscreens, humectants and starches, can consume a great deal of time and resources [130].
The most challenging aspect of formulating bioherbicides is to overcome the dew requirement that exists for several of them. Attempts to overcome this limitation have included developing various water-retaining materials; invert and vegetable oil emulsion formulations [15,94,131] and granular pre-emergence formulations [132] are considered as a promising approach to make pathogens less dependent on available water for initial infections to occur [133,134]. In addition, appropriate formulations can also reduce the dosage of inoculum required to kill weeds [135], thus potentially reducing the cost of bioherbicides.
Experiments conducted with a number of potential bioherbicides have demonstrated that an invert emulsion allowed infection to occur in the absence of available water [15,133,136] and reduced the need to apply high dosages of inoculum [135]. Invert emulsions consist of a continuous oil phase that contains water droplets. Connick and Boyette [137] have developed an invert emulsion formulation exhibiting lower viscosity and greater water-retention properties. Auld [93] reported that application of low concentrations of vegetable oils with an emulsifying adjuvant enhances efficacy of Colletotrichum orbiculare in inciting disease on Xanthium spinosum L. in the absence of dew in greenhouse conditions. However, according to the same author, oil emulsions were not effective in the field conditions. An invert emulsion has been shown to overcome dew requirements and reduce the spore concentrations required [15]. But, unfavourable characteristic is containing of more than 30% oil which makes these formulations expensive and very viscous, typically requiring special spraying equipment such as air-assist nozzles, and because of the high oil content it is likely to produce phytotoxic effects on non-target plants [135,138]. Invert emulsions have been shown to cause phytotoxicity in some cases and to predispose a variety of plants to opportunistic pathogens as well [99].
From the other side, the main restriction in the application of solid (dry) forms of bioherbicide is that they must await suitable, moist conditions for fungal growth and infection [139]. Moreover, during this waiting period the living active ingredients must survive in the field. In addition, ant theft has been a problem with some formulations [140].
The simplest liquid formulations of bioherbicides are water suspensions of spores often with a small amount of wetting agent. These are generally used as standards against which to compare more complex formulations. However, under ideal conditions for fungal infection, simple aqueous suspensions can be successful in the field [110]. Pathogenicity of an aqueous mycelial inoculum of Alternaria eichhorneae Nag Raj & Ponnapa in a controlled environment experiment was improved with hydrophilic polymers such as gellan gum, alginates and the polyacrylamide [141]. Although several polymers retained considerably more water after 6–8 h than the water-suspension controls, no increase in efficacy of the fungus Colletotrichum orbiculare was found [142]. Vegetable oil emulsions that contain 10% oil and 1% of an emulsifying agent reduced dew dependence in controlled environment studies using C. orbiculare in control of Xanthium spinosum L. [93]. Unfortunately, in the field conditions, the efficacy of these formulations was variable [143].
A novel bioherbicide formulation uses a complex emulsion – water-in-oil-in-water (WOW) emulsion [144]. It contains at least one lipophilic surfactant, at least one hydrophilic surfactant, oil and water. Although used in the pharmaceutical [145], cosmetic [146] and food industries [147], WOW emulsions do not appear to have been widely used in agricultural or horticultural technology. Although numerous improvements of liquid formulations of bioherbicides have been made, genetic manipulation of fungi offers a broad extent of opportunities to adjust formulations and to ameliorate bioherbicide characteristics [148].
Taking into account the above-mentioned restrictions, the production of bioherbicides by profit-oriented companies would involve additional expenditure without guaranteed income. The amount of abundant development and production of phytopathogenic microorganisms or their phytotoxins for bioherbicides in immerse or in solid-state systems, which would alter from one bioherbicide to another, is relatively high [149]. In addition, the small market capacity of considerable competent bioherbicide aspirants reveals that market capacity could be a restraint for developing such herbicides. Because of that, firms are suspicious that development and registration expenditures will be paid back [21,22].
10. Conclusion
The bioherbicide access to weed control is attaining impetus. New bioherbicides will be applicable in inundate lands, badlands as well as in control of parasite weeds or HR weeds. Research on synergism between pathogens and herbicides for their incorporation in effective weed management, applied science, fungal metabolites and biotechnology utilization, principally genetic engineering is needed. Bioherbicides will not deal with all of the environmental and weed control issues related with synthetic herbicides, nor will they alter the present or future depository of synthetic herbicides. To a certain degree, their appearance will presumably be complementary components in lucrative weed management systems, and in the revelation of different phytotoxins with new performances and new molecular sites of action. Advanced research on this field is imperative in order to entirely find out mutual interactions of phytopathogenic microorganisms, crops and weeds, and to identify new plant pathogens or their phytotoxins promising effective for the new-generation bioherbicides.
\n',keywords:"Bioherbicide (inundative) approach, advantages, restrictions",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/49228.pdf",chapterXML:"https://mts.intechopen.com/source/xml/49228.xml",downloadPdfUrl:"/chapter/pdf-download/49228",previewPdfUrl:"/chapter/pdf-preview/49228",totalDownloads:3748,totalViews:1346,totalCrossrefCites:3,totalDimensionsCites:8,totalAltmetricsMentions:0,introChapter:null,impactScore:2,impactScorePercentile:77,impactScoreQuartile:4,hasAltmetrics:0,dateSubmitted:"November 28th 2014",dateReviewed:"September 15th 2015",datePrePublished:null,datePublished:"December 2nd 2015",dateFinished:"October 5th 2015",readingETA:"0",abstract:"Bioherbicides are biologically based control agents useful for biological weed control. Hence, bioherbicides have been identified as a significant biological control strategy. Bioherbicides have many advantages such as clearly defined for target weeds, no side effect on beneficial plants or human health, a lack of pesticide residue build-up in the environment, and effectiveness for control of some herbicide-resistant weed biotypes. More importantly, it has been demonstrated that mixtures of some bioherbicides and synthetic herbicides can be more effective. Apart from many bioherbicide benefits, some factors have been noted to restrict the development of bioherbicides into profitable products. They involved environmental, biological and technical–commercial restrictions.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/49228",risUrl:"/chapter/ris/49228",book:{id:"4787",slug:"herbicides-physiology-of-action-and-safety"},signatures:"Zvonko Pacanoski",authors:[{id:"175043",title:"Associate Prof.",name:"Zvonko",middleName:null,surname:"Pacanoski",fullName:"Zvonko Pacanoski",slug:"zvonko-pacanoski",email:"zvonko_lav@yahoo.com",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/175043/images/6134_n.jpg",institution:{name:"SS. Cyril & Methodius Seminary",institutionURL:null,country:{name:"United States of America"}}}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Biological weed control",level:"1"},{id:"sec_2_2",title:"2.1. Classical (inoculative) approach",level:"2"},{id:"sec_3_2",title:"2.2. Bioherbicide (inundative) approach",level:"2"},{id:"sec_5",title:"3. History of bioherbicides",level:"1"},{id:"sec_6",title:"4. Bioherbicide case studies",level:"1"},{id:"sec_7",title:"5. Interaction between bioherbicides and synthetic herbicides",level:"1"},{id:"sec_8",title:"6. Bioherbicide limitations",level:"1"},{id:"sec_9",title:"7. Environmental limitations",level:"1"},{id:"sec_10",title:"8. Biological limitations",level:"1"},{id:"sec_11",title:"9. Technological–commercial limitations",level:"1"},{id:"sec_12",title:"10. Conclusion",level:"1"}],chapterReferences:[{id:"B1",body:'Goeden RD. Projects on Biological Control of Russian Thistle and Milk Thistle in California: Failures That Contributed to the Science of Biological Weed Control. In: Spencer N, Noweierski R, Eds. Abstracts of the 10th International Symposium on Biological Control of Weeds. Montana State University, Bozeman, MT, USA; 1999.'},{id:"B2",body:'Boyetchko SM, Rosskopf EN, Caesar AJ, Charudattan R. Biological Weed Control with Pathogens: Search for Candidates to Applications. In: Khachatourians GG., Arora DK., eds. 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Risk Analysis for Biological Control: A Dutch Case Study in Biocontrol of Prunus serotina by the Fungus Chondrostereum purpureum. Plant Disease 1990;74(3) 189–194.'},{id:"B126",body:'TeBeest DO, Cisar CR, Spiegel FW. Partial Characterization of Progeny from a Cross Between Colletotrichum gloeosporioides f. sp. aeschynomene and C. gloeosporioides from Carya. Plant Protection Quarterly 1992;7(4) 171.'},{id:"B127",body:'Weidemann GJ. Risk Assessment: Determining Genetic Relatedness and Potential Asexual Gene Exchange in Biocontrol Fungi. Plant Protection Quarterly 1992;7(4) 166–168.'},{id:"B128",body:'Hebbar KP, Lumsden RD, Lewis JA, Poch SM, Bailey BA. Formulation of Mycoherbicidal Strain of Fusarium oxysporum. Weed Science 1998;46(4) 501–507.'},{id:"B129",body:'Patzoldt WL, Tranel PJ, Alexander AL, Schmizer PR. A common ragweed population resistant to cloransulam-methyl. Weed Science 2001;49(4) 485–490.'},{id:"B130",body:'Bayer KN, Wolf TM, Caldwell BC, Baiely KL. Assays for Predicting Mycoherbicide Formulation Compatibility. In: Spencer N., Noweierski R., eds. Abstracts of the 10th International Symposium on Biological Control of Weeds. Montana State University, Bozeman, MT, USA, 4–9 July 1999.'},{id:"B131",body:'Boyette CD, Jackson MA, Quimby PCJr, Connick WJJr, Zidak NK, Abbas HK. Biological Control of the Weed Hemp Sesbania with Colletotrichum truncatum. In: Spencer N., Noweierski R., eds. Abstracts of the 10th International Symposium on Biological Control of Weeds. Montana State University, Bozeman, MT, USA, 4–9 July 1999.'},{id:"B132",body:'Watson AK, Wymore X. Identifying Limiting Factors in the Biocontrol of Weeds. In: Baker RR., Dunn PE., eds. New Direction in Biological Control: Alternatives for Suppressing Agricultural Pests and Diseases (ed. by). Alan R. Liss, New York, NY; 1990. p305–316.'},{id:"B133",body:'Daigle DJ, Connick WJ. Formulation and Application Technology for Microbial Weed Control. In: Hoagland RE., ed. Microbes and Microbial Products as Herbicides, ACS Symp. Ser. 439. American Chem. Soc., Washington, DC; 1990. p 288–304.'},{id:"B134",body:'Womack JG, Burge MN. Mycoherbicide Formulation and the Potential for Bracken Control. Pesticide Science 1993;37(4) 337–341.'},{id:"B135",body:'Amsellem Z, Sharon A, Gressel J, Quimby PC Jr. Complete Abolition of High Inoculum Threshold of Two Mycoherbicides (Alternaria\n\t\t\t\t\tcassiae and A. crassa) When Applied in Invert Emulsion. Phytopathology 1990;80(10) 925–929.'},{id:"B136",body:'Yang SM, Johnson DR, Dowler WM, Connick WJJr. Infection of Leafy Spurge by Alternaria alternata and A. angustiovoidea in the Absence of Dew. Phytopathology 1993;83(9) 953–958.'},{id:"B137",body:'Connick WJJr, Boyette CD. Host Range and Virulence of Colletotrichum truncatum, a Potential Mycoherbicide for Hemp Sesbania (Sesbania exaltata). Plant Disease 1991;75(1) 62–64.'},{id:"B138",body:'Womack JG, Eccleston GM, Burge MN. A Vegetable Oil Based Invert Emulsion for Mycoherbicide Delivery. Biological Control 1996;6(1) 23–28.'},{id:"B139",body:'Chittick AT, Ash GJ, Kennedy RA, Harper JDI. Microencapsulation: An Answer to the Formulation Quandary? VI international Bioherbicide Group Workshop, Canberra, Australia; 2003.'},{id:"B140",body:'Gracia-Garza JA, Fravel DR, Bailey BA, Hebbar PK. Dispersal of Formulations of Fusarium oxysporum f. sp. erythroxyli and F.\n\t\t\t\t\toxysporum f. sp. melonis by Ants. Phytopathology 1998;88(3) 185–189.'},{id:"B141",body:'Shabana YM, Baka ZA, Abdel-Fattah GM. Alternaria eichhorniae, a Biological Control Agent for Waterhyacinth: Mycoherbicidal Formulation and Physiological and Ultrastructural Host Responses. European Journal of Plant Pathology 1997;103(2) 99–111.'},{id:"B142",body:'Chittick AT, Auld BA. Polymers in Bioherbicide Formulation: Xanthium spinosum and Colletotrichum as a Model System. Biocontrol Science and Technology 2001;11(6) 691–702.'},{id:"B143",body:'Klein TA, Auld BA, Fang W. Evaluation of Oil Suspension Emulsions of Colletotrichum orbiculare as a Mycoherbicide in Field Trials. Crop Protection 1995; 14(3) 193–197.'},{id:"B144",body:'Auld BA. Bioherbicidal Formulations. Australian Provisional Patent Application 2002952094. Patent Office, IP Australia, Canberra; 2002.'},{id:"B145",body:'Marti-Mestres G, Niellond F. Emulsions in Health Care Applications – An Overview. Journal of Dispersion Science and Technology 2002;23(1-3) 419–439.'},{id:"B146",body:'De Luca M, Grossoird JL, Medard JM, Vaution C. A Stable W/O/W Multiple Emulsion. Cosmetics Toiletries 1990;105: 65–69.'},{id:"B147",body:'Cindio B, Grasso G, Cacace D. Water-in-Oil-in Water Double Emulsions for Food Applications: Yield Analysis and Rheological Properties. Food Hydrocolloids 1991;4(5) 339–353.'},{id:"B148",body:'Pilgeram AL, Carsten LD, Sands DC. Genetic Improvement of Bioherbicides. In: Osiewacz AD., ed. The Mycota, X Industrial Applications. Springer-Verlag, Berlin, Germany; 2002. p367–374.'},{id:"B149",body:'Ghosheh HZ. Constraints in Implementing Biological Weed Control: A Review. Weed Biology and Management 2005;5(3) 83–92.'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Zvonko Pacanoski",address:"zvonkop@zf.ukim.edu.mk; zvonko_lav@yahoo.com",affiliation:'
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1. Introduction
Every cell is defined by its membrane. This amphiphilic molecular matrix is highly organized and complex in terms of its lipid and protein components. Ion channels have evolved to mediate ion transport throughout membranes always in favor of electrochemical gradients from free-living bacteria to mammal neurons [1, 2]. In doing so, these membrane proteins are part of complex physiological networks which include signal transduction processes, cellular communication, or the propagation of electrical signals [3]. The voltage-gated ion channel (VGIC) superfamily comprises dozens of variations on a common theme—(i) a voltage sensor domain (VSD) and (ii) a pore domain (PD) [4]. This modular architecture has in turn evolved into activation mechanisms as diverse as the detection of changes in the potential across the membrane, the binding of diverse chemical ligands, local membrane stretching, or subtle changes in temperature or the pH. In consequence, those physical-chemical variables are often interrelated modulating the ion channel gating but not clearly defined as exclusive stimuli for a determined protein [5]. In voltage sensing, the VSD performs important conformational rearrangements moving through the membrane-electric field and coupling this motion to the opening of the permeation pathway at the PD. To do this, four transmembrane segments (S1–S4) at the VSD respond sensing the electric field by translocating the so-called gating charges and by reorganization of the dipole moments into an aqueous crevice around the S4 segments, so that at any membrane potential, the charged side-chains of basic residues (mainly Arg and Lys) are essentially both hydrated and ionized either above or below the plane of the lipid bilayer (i.e. depolarized or hyperpolarized, respectively) [6].
In that sense, the VSD is clearly a mobile and intrinsically flexible element. A more detailed analysis of this mobility has revealed the relative flexibility of the different regions into this domain and clearly demonstrate that helices S1, S2, and the N-terminal part of S3 (S3a) are relatively more static than the so-called VSD paddle (S3b-S4) which loop linker show enhanced flexibility at higher temperatures in molecular simulations [7]. In those in silico studies, it is also evident that the segment S4 undergoes hinge bending and swiveling about its central axis, motion facilitated by the conformational instability of the S3a helix [7, 8]. The intrinsic flexibility of the S3a region facilitates movement of the segment S3b-S4, which in turn exhibits an even higher flexibility profile due to its composition rich in residues with small side-chain (Gly, Ser, Thr) and basic residues (Figure 1). Notably, these predictions have been experimentally confirmed elsewhere [9, 10] and some reports also indicate that abnormal S4 movements cause pathological effects related for example to the development of epilepsy [11]. Therefore, it is becoming increasingly clear that the VSD is a flexible dynamic structure with evident relevance in physiological disorders.
Figure 1.
Flexibility plot for the VSD of Kv1.2-Kv2.1 paddle chimera (PDB code: 2r9r) calculated using the method previously reported by us [5]. a. Cartoons showing the hyperpolarized (left) and depolarized (right) conformations of the VSD. b. Plots showing B-factors normalized to a Gumbel distribution according to our previous studies. Segment S3b-S4, involved in channel activation and the electromechanical coupling exhibits higher flexibility than the rest of the voltage sensor (S1–S3a).
The mechanisms of gating in ion channels have been intensively studied. On activation, outward S4 motion is associated with specific interactions with conserved negative countercharges (Asp and Glu) in transmembrane segments S1, S2, and S3 by forming sequential salt bridges with the positively charged residues in S4 inside an aqueous pore (Figure 2). Such interactions facilitate the translocation of the S4 segment in an energetically unfavorable membrane environment promoting the sequential salt-bridge formation and the electromechanical activation of the S4-S5 linker, which directly couples voltage sensor movement to the activation gate [12]. These negative countercharges are well-conserved in S1, S2, and S3 transmembrane segments in Kv channels (Figure 3). Besides, several VSD countercharge mutations associated with disease phenotypes including neural, cardiac, or skeletal muscle disorders have also been identified [14]. Despite channelopathies often affect ion channel gating, many of these pathologies have yet to be functionally or biophysically characterized. In this regard and given the diverse physiological and pathophysiological functions played by members of the VGIC superfamily, the VSD becomes a promising target for rational drug design.
Figure 2.
The gating charge transfer center (CTC) in the voltage sensors of Kv channels. a. Ribbon representation of the four segments (S1–S4) making one VSD of the human ether-a-go-go-related gene (hERG) channel (PDB code: 7cn0). b. Close-up view of the CTC highlighting the gating charges on the S4 segment. Side-chains of the positively charged residues on S4 (labeled as R and K) and negative residues D456 and D460 interact forming salt bridges. The hydrophobic residue F463 controls the energy barrier of the final gating transition. Figures containing structures were prepared with Pymol (http://www.pymol.org/).
Figure 3.
Sequence logos from the three main subfamilies of voltage-gated potassium channels using the webserver WebLogo (http://weblogo.threeplusone.com/). The bars below the sequence logos represent the extent of transmembrane segments S1–S4. The consensus sequences generated are represented statistically, showing the relative conservation of each residue at that position. The height of each letter in every position indicates the maximum theoretical entropy for protein sequences (measured in bits) [13] which is determined by the number of aligned sequences and the degree of ambiguity in the alignments for each residue. Blue stars indicate basic residues involved in voltage sensing on S4. Green circles indicate conserved negative countercharges in S2 and S3. Red hexagon depicts a well-conserved aromatic residue that controls the transfer of the more inner gating charge, shaping the electric field inside the voltage sensor. Conserved residues addressed in this study are color-coded as: Red (hydrophobic); green (acidic); blue (basic); orange (small side-chain); pink (flexible side-chain); and black (rigid side-chain).
2. The voltage sensor domain as a pharmacological target
There are many reports on the interactions of different intracellular ligands with ion channels and particularly important is the well-understood interaction of ligands with the cytosolic tail domain (CTD) in large-conductance calcium-activated potassium channels (BKCa), which contain several binding sites. Also relevant are the studies of the interaction of cGMP or cAMP with the cyclic nucleotide-binding domain (CNBD) in cyclic nucleotide-gated (CNG) and hyperpolarization-activated (HCN) channels. Structural and functional information has shown that frequently the ligand-binding sites in those channels are clustered located at the interface between the cytosolic domain and the VSD, acting synergistically to activate the gate at the PD [15, 16]. In other studies, ligands have been found directly coupled to the VSD influencing the channel activation, opening, closing, or inactivating the pore, such as some protein toxins from tarantula do [17, 18] or the binding of vanilloids, monoterpenoids, and related compounds to the S1–S4 domain in the transient receptor potential (TRP) channels [19].
From a structural perspective, the study of interactions between specific chemical ligands and the VSD in ion channels opens the possibility to rationally design both agonist and antagonist drugs. Let us have a look at three specific cases—(1) the voltage- and lipid-gated potassium channel KCNQ2 (Figure 4), (2) the cold/menthol activated TRPM8 channel (Figure 5), and (3) the capsaicin receptor TRPV1 (Figure 6). Studies on the KCNQ2 (Kv7.2) potassium channel show that the aromatic amide ztz240, a derivative of niclosamide, binds to the open configuration of the VSD. This interaction directly couples such a chemical ligand with a binding pocket of 170 Å3 located between some specific residues at segments S2 (Glu130, Ile134, Phe137) and S4 (Arg207 and Arg210), i.e. precisely in the gating charge pathway of this ion channel [20]. This raises the possibility to design drugs using the channel gating pore in voltage-dependent channels as a therapeutic target [21]. In this case, ztz240 and some derived chemotypes have demonstrated important anti-epileptic activity, which might be valuable for the treatment of epilepsy (see below). Remarkably, this interaction in the gating charge pathway of KCNQ2, considering the induced-fit model, demonstrates that this pocket may accommodate different activators [20].
Figure 4.
Structure of the human Kv7.2 (KCNQ2) channel (PDB accessions codes 7cr0 (apostate) and 7cr1 (in complex with ztz240). a. Ribbon representation of side view showing the VSDs exposed to the lipid bilayer (not shown here). b. Surface representation showing the ligand-binding pocket as a box. c. the unliganded structure of the VSD (highlighted in pale green) is superimposed with the one in complex with ligand (highlighted in smudge green). d. Three-dimensional stick representation of the Kv7.2 pocket in complex with ligand ztz240 (dark brown). The distances traveled by the side-chain conformational rotamers are shown as dashes. The overlapping residues correspond to the side-chains involved in ligand binding.
Figure 5.
Structure of the TRPM8 ion channel from the collared flycatcher (Ficedula albicollis) (PDB codes 6bpq (apostate) and 6nr3 (in complex with icilin, PI(4,5)P2, and Ca2+). a. Ribbon representation of side view. b. Surface representation showing the ligand-binding pocket as a box. c. The unliganded structure of the VSLD is highlighted in light blue and superimposed with the one in complex with icilin (semi-dark blue). d. Overlay of both structures to visualize the side-chain conformation changes (see Figure 3 for details).
Figure 6.
Structure of the TRPV1 channel from rat (PDB codes 7lp9 (apostate, 4°C), 7lpe (in complex with capsaicin, 48°C), and 7lpa (in complex with capsaicin, 4°C). a. Side view of the tetramer in ribbon representation. b. Surface representation showing the ligand-binding pocket as a box. c. The unliganded structure of the VSLD is highlighted in light orange and superimposed with the one in complex with capsaicin (bright orange). d. Overlay of structures at 4°C (apostate) and 48°C (in presence of capsaicin) to visualize two different rotamers by residue (see Figure 3 for details). Inset: Superposition of Arg557 side-chain obtained at 4°C for apo- and holo-structures.
In the case of TRPM8, an analog binding pocket has been described as highly adaptable to accommodate diverse chemical structures in distinct orientations. Both agonists and antagonists are dynamically recognized in this promiscuous pocket making the whole S1–S4 domain conformationally dynamic and transmitting these rearrangements to the TRP helix, but without inducing important changes in its overall structure [22]. Menthol, the main compound of mint, is the clue activator to understand how TRPM8 channels are ligand-activated. It binds to the cavity formed between S1 and S4 by a so-called “grab and stand” mechanism. The hydroxyl group of menthol works as a hand to specifically grab with Arg842 (segment S4) through a hydrogen bond, while its isopropyl “legs” stand on residues on S4 through electrostatic interactions. Thus, menthol binding induced widespread conformational rearrangements in the S1–S4 domain which open the S6 bundle gate to allow ion permeation [23].
On the other hand, since TRPV1 channels participate in several pathways of neuronal inflammatory signaling, it also represents an attractive therapeutic target for the treatment of neuroinflammation, neurodegenerative diseases, and chronic pain. Feng et al. [24] have studied diverse diarylurea compounds by molecular docking and dynamics, finding that specific residues located in the interface between the VSD and the PD are implicated in several van der Waals interactions. Particularly important are residues Tyr511, Leu518, Leu547, Thr550, Asn551, Arg557, and Leu670. Besides these observations, residues at the base of the interface between the VSD and the PD (segments S3, S4, S5, and the S4-S5 linker) are important binding sites for N-(3-fluoro-4-methylsulfonamidomethylphenyl)urea. Docking analysis of this compound with human TRPV1 has revealed that hydrogen bonding and π–π interactions with Tyr511 (segment S3) and hydrophobic interactions with two pockets in the S3 and S4 segments (residues Met514, Leu515 and Leu547, Thr550, respectively) are critical for its activity. Flexible docking studies have also revealed that N-benzyl phenylsulfonamide derivatives of 2-(3-fluoro-4- methylsulfonamidophenyl)propanamide specifically bind to the same pockets, being again critical for the potent activity of these antagonists [25, 26]. Notably, conformational analyses have revealed that the S1–S4 domain in TRPV channels remains relatively static during opening [27, 28, 29].
These three examples are mechanistically different, but they all share something in common, and this is the specific association of their respective ligands at the VSD, as well as their direct association with the potential difference across the membrane. However, even though TRP channels have frequently been treated as strictly ligand-dependent, it is increasingly clear that their voltage sensitivity could be underestimated [30]. These reports support the idea that the increasingly available detailed structural information, as well as detailed functional studies, greatly simplifies the search for chemical modulators with agonistic or antagonistic action. In consequence, the identification of potential ligand-binding sites in the VSD makes the rational design of new drugs, the goal of several research efforts.
2.1 Side-chain flexibility and ligand accommodation
Proteins are intrinsically flexible. This property derives from the two bonds associated with the carbon α (Cα), which can freely rotate and contribute to the flexibility of the main backbone. The torsion angles Phi (Φ) and Psi (ψ) represent the rotation around the Cα-N bond and the one around the Cα-carbonyl bond, respectively. However, this rotational capacity also depends on the steric and conformational effects of the associated side-chains. In these terms, one classical structural parameter to estimate the mobility of each atom into a protein structure is the so-called B-factor, which reflects the degree of thermal motion and static disorder. This parameter, also called the Debye−Waller factor, represents the atomic displacement of the macromolecule and is used in protein crystallography to describe the attenuation of X-ray or neutron scattering caused by thermal motion, which reflects the uncertainty in atom positions [31, 32]. Therefore, proteins are intrinsically rigid or flexible ultimately based on their primary sequence.
From this perspective, in addition to their known physical and chemical properties, if their relative location parameters are considered, amino acids can also be classified in terms of their contribution to the flexibility of a given segment within a protein. The amino acids that are considered rigid generally consist of those that exhibit bulky side-chains, generally cyclic or aromatic, those that have heavy heteroatoms, and are generally hydrophobic. On the other hand, amino acids considered flexible are those having polar side-chains, have charges, or whose side group is only a proton, i.e. glycine [33]. Proline deserves a separate discussion, as this amino acid has been considered both rigid and flexible in terms of its kinking effect on alpha helices [34].
Typically, flexibility in proteins has been visualized in terms of local and global motions, which include—(i) the multiple conformations that a certain residue can acquire in the polypeptide chain, (ii) local-scale fluctuations in the conformation of the side chains with respect to the backbone, and (iii) massive movements of subdomains with respect to another part of the protein [35]. In this last regard, a pioneer study of protein crystal structures shows that intrinsic flexibility can be distinguished in terms of hinge motions and shear displacements between close-packed segments of the protein [36]. It is becoming clearer that studying protein flexibility and the multiple side-chain conformations during molecular docking is very relevant since it may contribute to a favorable change in the Gibbs binding free energy by optimizing the van der Waals interactions between the protein and the ligand. This favors a change in enthalpy and minimizes the decrease in entropy [37, 38], albeit protein flexibility also depends on several other factors, including heat capacity, conformational entropy, salt bridge networks, electrostatic interactions, and the hydrophobic effect [39]. In any case, the study of side-chain flexibility in ion channels and how it contributes to ligand accommodation could be critical to understand molecular recognition events and predict ligand binding. This could open novel therapeutic strategies for the treatment of diverse neuropathic disorders.
2.2 Three cases of study: Kv7.2, TRPM8, TRPV1
Since flexible regions in proteins can be predicted from the primary sequence through the evaluation of the normalized B-factor for a determined structure [40], we have implemented an easy algorithm in Excel based on the procedure carried out by Smith and cols. [32, 33]. In general terms, B-factor normalization, Bn, depends on (1) the atomic thermal factor, B, reported on the PDB, (2) the sample mean value of B-factors, Bm, for a dataset of protein structures, and (3) the standard deviation of the sample distribution of such factors, Bσ, for a determined structure [41]. In sum, normalized B-factors are indicative of each local residue flexibility that can be calculated as:
Bn=B−BmBσE1
Based on these theoretical principles, we implemented an algorithm to predict local side-chain flexibility, which correlates the composition of amino acids in a protein sequence in the context of its N- and C-terminal neighbors. The program assigns a weighted normalized B-factor value based on a stiffness classification for each amino acid, in accordance with previously published results [33]. This software, so-called FlexiProt, includes Trp, Tyr, Phe, Cys, Ile, Val, His, Leu, and Met as rigid amino acids and the rest of them, i.e. Gly, Thr, Arg, Ser, Asn, Gln, Asp, Pro, Glu, and Lys as flexible. The program incorporates a graphical generator of local flexibility profiles, based on primary sequence, to help the user better visualize this disorder parameter for its subsequent structural evaluation. Flexiprot is friendly and interactive since although it runs automatically, it allows at all times the possibility of evaluating local subsequences for a better prediction of the internal flexibility parameter, based on structural aspects associated with the theoretical degrees of freedom of the side-chains.
Through this type of sequence analysis, we show in Figure 7 the local flexibility profiles of three distinct channels for the segments S3 to S4—(1) human KCNQ2 (hKv7.2), (2) mouse TRPM8 (mTRPM8), and (3) rat TRPV1 (rTRPV1). As in the Kv1.2-2.1 paddle chimera (Figure 1), in these three cases, local flexibility for segment S4 is always higher than the one for segment S3. However, the profile of the S3 segment in the TRPV1 channel is significantly stiffer than the other two, which have similar flexibility profiles for the same segment, although the S4 segment of the voltage-dependent channel Kv7.2 is considerably more flexible compared to their thermosensitive counterparts. This notorious flexibility is mainly determined by the highly conserved Arg residues, responsible for transporting the gating charges in the voltage sensor during the activation mechanism of these proteins [5]. Considering the new structures available for this channel in the presence of the ztz240 modulator, whose binding site is precisely in the intimacy of the voltage sensor, it becomes interesting to analyze the role of side-chain flexibility for each of the interacting residues and that has been mentioned elsewhere [20, 42]. Figure 4 show this interaction in two conformational states for the VSD of the Kv7.2 channel, in the absence and presence of the state-dependent modulator ztz240. For a segment of 145 residues that encompass the integrity of the VSD, a root-mean-square deviation (RMSD) of 1.159 Å is indicative of a fine accommodation for this drug without representing a significant conformational change of this protein domain. It is clearly noted that the intrinsically flexible residues Arg207 and Arg 210 at the S4 segment undergo an important conformational rearrangement that allows the ligand to be adequately accommodated through van der Waals interactions. The analysis of the structures also indicates that these residues are displaced 3.0 and 3.3 Å respectively. Another important residue, implicated in the potentiation of the activity of ztz240 is Glu130, an amino acid considered even more flexible than Arg [33], which is found as a countercharge in the S2 segment and whose side group moves 2.4 Å during the interaction. In contrast to these data, two other amino acids also important for the interaction, Ile134 and Phe137—amino acids of a rigid nature—show a rearrangement of 2.3 Å and 1.8 Å, respectively. These data suggest that the significant local flexibility of the S4 segment in this channel strongly contributes to ligand accommodation with minor effects on the large movements that the VSD experience during activation and that some of the main residues interact with this ligand move in a range of 1.8–3.3 Å.
Figure 7.
Predicted flexibility for segments S3 and S4 in human Kv7.2, TRPM8 (mouse), and TRPV1 (rat). Flexibility (defined by B-factor values) using the FlexiProt algorithm according to Ref. [5] shows a higher flexibility profile for segment S4 compared to S3. Predictions also indicate that the three channels follow the flexibility ranking TRPV1 < TRPM8 < Kv7.2. Asterisk indicates the start of the first turn of the α-helix at the N-terminal part of segment S3a. mBf: mean B-factor.
In TRPM8, a channel described also as sensitive to voltage [43, 44], a similar effect to Kv7.2/ztz240 is observed. According to recent structural studies of this channel, icilin, a compound derived from tetrahydropyrimidine-2-one and more potent than menthol as the agonist, binds to the voltage-sensor-like domain (VSLD) mainly through van der Waals interactions to residues Tyr745 (S1), Glu782 (S2) Asn799 (S3), Asp802 (S3), Arg841 (S4), and His844 (S4) [28, 45, 46]. Analogously to that seen in the Kv7.2 channel, the significant flexibility exhibited by the S3 and S4 segments in the TRPM8 channel contributes to a fine accommodation of icilin through conformational rearrangements of these amino acids in a range from 2 to 4.6 Å (Figure 5D). These displacements occur in the context of an RMSD of 0.89 Å over 123 Cα atoms which integrate the VSLD of this cold-sensitive channel. Similarly, the interaction of the antagonist TC-I 2014 in the same cavity of the VSLD [28] induces small rearrangements of the corresponding side-chains implicated in ligand sensitivity, with displacements of around 1–3 Å and an average RMSD of 0.427 Å (data not shown). Taken together, these observations suggest that the high flexibility profile in the S3 and primarily the S4 segments of these transmembrane domains facilitates a fine repositioning of the participating side-chains, which are implicated in ligand accommodation.
The case of the transient receptor potential vanilloid subtype 1 channel is slightly different. Figure 6 shows the interaction of capsaicin with the VSLD of TRPV1. Thanks to the recently released structural data of TRPV1 channels in presence of this ligand, a more detailed exploration of such interactions as a function of the associated local flexibility contribution of the VSLD contributes to a better understanding of this process. For a segment of 166 residues encompassing the whole VSLD and part of the TRPbox, an RMSD of 0.63 Å suggest an almost null conformational change for this part of the protein in the course of the closed-to-open transition during the ligand interaction, as it has been previously reported [25]. In this case, residues Val518, Met547, Thr550, and Asn551 move their side-chains less than 1 Å when they interact with capsaicin, whereas Tyr511 and Arg557 experience a significant displacement of 7.8 Å and 5.1 Å, respectively. These observations are consistent with the low predicted local flexibility for segment S3 in this channel (Figure 7, Table 1) [5]. Furthermore, they are also in good agreement with the vision that the VSLD acts as a rigid body during TRPV1 activation [25].
Flexibility parameters for the studied channels upon ligand interaction.
mBf, mean B-factor (1/mBf).
Our analysis shows that in this case, the low flexibility profile of the S3 segment contributes to creating a rigid crevice. This structure accommodates the catechol/vanilloid ring of capsaicin at the base of the VSLD where the bulky side-chain of Tyr511 residue rearranges with a displacement of almost 8 Å during a transition from 4 to 48°C. It is very significant that this tyrosine, which frequently is classified as a rigid side-chain with low conformational entropy, in the context of the structure of this channel, carries out a significant rearrangement even greater than Arg557, which has been frequently quantified as much more flexible [33, 47]. Besides, the side-chain of Arg557 at S4 undergoes a conformational rearrangement of 5.1 Å during the interaction but an almost null displacement (0.8 Å) if this is carried out at 4°C (Figure 6D, inset). Indeed, despite its low flexibility, tyrosine has been considered very effective for mediating molecular recognition maybe because changing the orientation of its side-chain from gauche negative (g−) to trans (t) conformation is equivalent to moving the hydroxyl group around 9 Å, which is the length of an average drug molecule [48, 49]. On the other hand, the motion of Arg557 is associated with the formation of a hydrogen bond with the Glu570 residue on the S4-S5 linker, leading to its swivel [50]. This also confirms that arginine often participates in molecular recognition events. The terminal positively charged guanidinium group of this residue affords multiple geometries due to its long side-chain can retain substantial residual conformational entropy occupying several rotameric states, while maintaining specific interactions through its charged functional group [51]. In sum, we hypothesize that, in contrast with the mechanism dependent on the large local (S3–S4) flexibility of the voltage-dependent Kv7.2 channel or the cold/menthol-activated TRPM8 channel, these large conformational changes in specific residues compensate for the low mobility that the whole transmembrane domain (i.e. the VSLD), as a rigid body, undergoes during TRPV1 activation.
3. Side-chain flexibility and the dynamic nature of protein-ligand interactions
Despite the large increase in deposition of crystallographic, NMR, and cryo-electron microscopy structures in recent years, little dynamic information regarding the conformational degrees of freedom of protein structures is currently available. In silico local flexibility theoretical prediction together with molecular dynamics algorithms are likely to be useful in helping to solve this limitation. Diverse computational strategies have been developed to explore the side-chain rotameric states as a function of the primary sequence, backbone structure, and ligand interaction by molecular docking in specific protein motifs [52, 53, 54]. Besides, the prediction of protein flexibility [32, 33, 40, 41], as well as its identification and visualization [55], have been a constant goal in protein research. Side-chain flexibility represents an intrinsic property of amino acids, as it correlates with configurational entropy differences and indeed is related to the generation of dynamic rotamers, which are defined as a particular combination of side-chain dihedral angles [38].
Given the dynamic and multifactorial nature of flexibility in proteins, trying to predict the binding mode of any ligand is an inspiring challenge. However, the use of predictive tools, dynamic simulations, and specific experimental tests will facilitate a better understanding of the molecular mechanisms underlying ligand-dependent modulation of ion channels. This could be of great impact on the rational design and discovery of novel drugs. Therefore, in the case of the study of the VSD as a ligand-binding motif, side-chain flexibility is especially relevant and must be always considered in light of the induced-fit model and conformational selection mechanisms [56]. In these terms, since side-chain and also frequently the backbone are subject to rearrangements upon ligand interaction (see our previous analysis above), we suggest that any experimental approach to develop novel drugs should be designed from the perspective of a dynamic target. In this sense, the study by Li and cols. is very relevant since they identify a hydrophobic pocket inside the charge transfer center (CTC) of the Kv7.2 channel which can accommodate different chemical ligands [20]. This enables such openers to regulate ion channel activation and offers new therapeutic strategies for the treatment of several hyperexcitability disorders, such as epilepsy and neuropathic pain. Since the VSD exhibits important conformational freedom during the gating process, it is important to note that this class of ligands preferentially binds to specific conformational states. The compound ztz240, for example, is accommodated to a hydrophobic pocket only when the VSD is in its activated conformation. This interaction stabilizes the activated state of the channel, thus contributing to its antiepileptic activity [57]. Therefore, it is conceivable to consider the so-called gating pore as an important target for ion channel research given its potential adaptability to new openers or inhibitors.
In the Figure 8 included at the end of this study, the workflow for the development of drugs with therapeutic potential is shown sequentially. In silico and structural studies, from the perspective of the “induced fit” model and the “conformational selection” hypothesis [58, 59], both contribute to a better understanding of the dynamic aspects of the protein/ligand interactions. In these terms, the role of side-chain flexibility becomes pivotal, and methods to predict it, such as the one performed herein, as well as methods to visualize it, such as those reported elsewhere [55] are indispensable analysis tools. By the appropriate selection of chemical candidates with pharmacological potential, ion channels with defined mutations can be experimentally evaluated, shedding some light on the involvement of specific residues in ligand accommodation and their effects on voltage sensor regulation. Furthermore, thanks to the correct study of the flexibility profiles for a given segment, it is also possible to evaluate the nature of these interactions, providing additional information about the degrees of freedom necessary for an adequate ligand accommodation. With this background, experimental testing in animal models and eventual clinical studies becomes an achievable goal for the treatment of neurological disorders and problems of acute pain.
Figure 8.
Compounds that act on the voltage sensor could be a good alternative for the development of new analgesic drugs and provide a complement to pain therapy. After synthesis of a compound with pharmacological potential, ion channel mutagenesis (1) and associated electrophysiological tests (2) are performed. The study of the activation/inactivation properties of ionic channels with therapeutic interest (3) is decisive for establishing correlations between the adaptability of the molecular target and the candidate drug (4). Considering side-chain intrinsic flexibility and the degree of pocket disorder during these molecular recognition events allows the identification of residues crucial for drug activity. Finally, the new active compounds are tested for their in vivo validation using animal models (5). This strategy could be applied to the discovery of several modulators capable of dealing with diverse neurological disorders (6).
From this perspective, the predictive analysis of local flexibility that we have performed here on three different ion channels clearly shows how the characteristic ligands of each protein are accommodated in the binding sites generating important conformational changes in the side-chains of specific residues. In a very revealing way, we found that the Kv7.2 channel and the TRPM8 have a VSD and a VSLD with high S3-S4 flexibility profiles (mBf of 1.44/1.48 for S3 and 1.68/1.59 for S4, respectively) (Table 1). These domains show small local conformational changes according to the corresponding RMSD values calculated (1.16 Å and 0.89 Å respectively), while on the other hand, a channel such as TRPV1, whose flexibility profile is rather rigid (mBf = 1.39 for S3 and 1.55 for S4) exhibits a still minor conformational change (RMSD = 0.63 Å for the equivalent segment) during the interaction with its specific ligand. Likewise, the conformational changes that we observe in the participating side-chains are also revealing, since the rotamers generated during the ligand interaction in flexible VSDs (Kv7.2 and TRPM8) are the result of rotations less than 3 Å on average, while in the case of the rigid S1-S4 segment of the TRPV1 channel, the conformational changes of the side-chains are less than 1 Å but two residues, in particular, Tyr511 (S3) and Arg557 (S4), undergo rotations of 7.8 Å and 5.1 Å, respectively, which suggest a different mechanism for ligand accommodation. This is even more revealing when it is considered that the conformational changes observed in the side-chain of Arg557 were obtained at 48°C [48] while the conformational rotamer for that residue at 4°C is less than 1 Å and that corresponding to Tyr 511 is even higher (8.2 Å) with a side-chain angle rotation of ~101°, which also suggest that motion of this residue is critical for ligand binding (Figure 6D).
After this analysis, we speculate that two different mechanisms for ligand accommodation in ion channels exist, which seem to be dependent on the conformational freedom of the VSD. These mechanisms could be interpreted as VSDs that have higher degrees of freedom, i.e. flexible and more prone to fine induced-fit mechanisms, which adapt better to the ligand through small displacements of multiple participating side-chains. On the other hand, more rigid VSDs follow the classical lock and key model for enzyme-substrate interactions, in which the ligand is accommodated directly but with important conformational changes in certain very specific residues. The conformational freedom of these specific residues would compensate for the low mobility observed in the rest of the structure.
4. Conclusions
Flexible regions in proteins are critical elements for the recognition of macromolecular interactions and induced molecular flexibility is essential to understand the principles of molecular recognition between ligand and receptor. However, the nature of side-chain flexibility is elusive and dynamic processes involving this flexible component are among the most difficult to characterize. Given its direct participation in the activation of voltage-dependent channels, the voltage-sensing domain is a very attractive target from the therapeutic point of view. As side-chain flexibility represents an intrinsic property of amino acids which is correlated with configurational entropy differences, it is now known that rotamer changes in specific residues during ligand interaction are finely synchronized [38]. Our analysis has confirmed this claim. According to our predictive algorithm, the local flexibility in S3–S4 segments which are implied to ligand binding in three different channels, correlated well with the adaptability of specific residues through the generation of side-chain rotamers during each interaction. However, what is intriguing is the fact that segments exhibiting high flexibility profiles (i.e. Kv7.2 and TRPM8) are correlated with small-scale changes and the generation of side-chain rotamers that are more homogeneously and subtly accommodated among the participating residues during ligand binding, while those which are slightly more rigid (i.e. TRPV1) remain practically immobile during the interaction, except for one or two residues that undergo a very pronounced conformational rearrangement to accommodate the drug. Since it is assumed that these new conformations are energetically favorable states [60], in terms of drug design these observations might not be trivial when considering the induced-fit model [58, 59] in combination with the conformational selection hypothesis [61]. In agreement with them, the dynamic binding of drugs to a specific protein target may lead to chemoselectivity, high ligand affinity as well as the favoring of long residence times in the binding site. There are many potential interactions if those factors are considered and reasonably well understood. In these terms, the identification of side-chain rotamer rearrangements upon ligand binding in combination with the use of the global RMSD comparison between two protein conformers is more informative. Thus, the incorporation of predictive tools of side-chain flexibility in protein/ligand interactions is key to infer dynamic aspects in molecular docking. Besides, the experimental evaluation of new drugs from this perspective becomes pivotal in the rational design of therapeutic strategies to control several physiological disorders and face emerging channelopathies.
Acknowledgments
The authors wish to thank the Division of Postgraduate Studies and Research (DEPI) of the Technological Center of Mexico, Veracruz campus, for the facilities for conducting this study.
Notes
FlexiProt 2.0 is a software designed for the prediction of flexibility profiles in primary sequences. Today, our group is working to share it in the public domain. For more information or in case of interest, contact the corresponding author at: daniel.bm@veracruz.tecnm.mx.
\n',keywords:"voltage sensor, side-chain flexibility, side-chain rotamers, RMSD, induced-fit docking, conformational selection",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/80157.pdf",chapterXML:"https://mts.intechopen.com/source/xml/80157.xml",downloadPdfUrl:"/chapter/pdf-download/80157",previewPdfUrl:"/chapter/pdf-preview/80157",totalDownloads:106,totalViews:0,totalCrossrefCites:0,dateSubmitted:"December 12th 2021",dateReviewed:"December 20th 2021",datePrePublished:"January 21st 2022",datePublished:null,dateFinished:"January 21st 2022",readingETA:"0",abstract:"After ligand binding, many ion channels undergo rearrangements at the voltage sensor domain (VSD) that often modulate their gating activity with important physiological repercussions. Since the VSD is dynamic, it is interesting to establish a correlation between the potential mobility of this element in terms of its intrinsic flexibility and its ability to accommodate several ligands by induced-fit mechanisms. We presume that these associations are not causal since the flexibility of the VSD could have an important impact on the ligand coupling event. Many significantly flexible ion channels show a general architecture and composition compatible with important conformational changes and capable of accommodating chemically diverse agonists. In this contribution, the structural bases of this subtle and probably unexpected relationship between the VSD flexibility and its influence during the dynamic coupling of the ligand are exposed. Thus, given its physiological relevance, the study of ion channel malfunction can be associated with ligand accommodation events to the VSD, which could depend on its local flexibility. This could contribute to a better understanding of the molecular bases of a variety of physiological disorders. In consequence, considering these effects during the protein/ligand interaction could be determinant to the rational design of novel drugs.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/80157",risUrl:"/chapter/ris/80157",signatures:"Abigail García-Morales, Aylin López-Palestino and Daniel Balleza",book:{id:"10838",type:"book",title:"Ion Channels - From Basic Properties to Medical Treatment",subtitle:null,fullTitle:"Ion Channels - From Basic Properties to Medical Treatment",slug:null,publishedDate:null,bookSignature:"Ph.D. Zuzana Sevcikova Tomaskova",coverURL:"https://cdn.intechopen.com/books/images_new/10838.jpg",licenceType:"CC BY 3.0",editedByType:null,isbn:"978-1-80355-550-8",printIsbn:"978-1-80355-549-2",pdfIsbn:"978-1-80355-551-5",isAvailableForWebshopOrdering:!0,editors:[{id:"232970",title:"Ph.D.",name:"Zuzana",middleName:null,surname:"Sevcikova Tomaskova",slug:"zuzana-sevcikova-tomaskova",fullName:"Zuzana Sevcikova Tomaskova"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:null,sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. The voltage sensor domain as a pharmacological target",level:"1"},{id:"sec_2_2",title:"2.1 Side-chain flexibility and ligand accommodation",level:"2"},{id:"sec_3_2",title:"2.2 Three cases of study: Kv7.2, TRPM8, TRPV1",level:"2"},{id:"sec_5",title:"3. Side-chain flexibility and the dynamic nature of protein-ligand interactions",level:"1"},{id:"sec_6",title:"4. Conclusions",level:"1"},{id:"sec_7",title:"Acknowledgments",level:"1"},{id:"sec_7",title:"Notes",level:"1"}],chapterReferences:[{id:"B1",body:'Balleza D, Quinto C, Elias D, Gómez-Lagunas F. A high-conductance cation channel from the inner membrane of the free-living soil bacteria Rhizobium etli. Archives of Microbiology. 2010;192(7):595-602. DOI: 10.1007/s00203-010-0587-3'},{id:"B2",body:'Labarca P, Bacigalupo J. Ion channels from chemosensory olfactory neurons. Journal of Bioenergetics and Biomembranes. 1988;20(5):551-569. 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Automation of the diagnosis process will enable accurate diagnosis of the disease and hence holds the promise of delivering reliable health-care to resource-scarce areas. Machine learning technologies have been used for automated diagnosis of malaria. We present some of our recent progresses on highly accurate classification of malaria-infected cells using deep convolutional neural networks. First, we describe image processing methods used for segmentation of red blood cells from wholeslide images. We then discuss the procedures of compiling a pathologists-curated image dataset for training deep neural network, as well as data augmentation methods used to significantly increase the size of the dataset, in light of the overfitting problem associated with training deep convolutional neural networks. We will then compare the classification accuracies obtained by deep convolutional neural networks through training, validating, and testing with various combinations of the datasets. These datasets include the original dataset and the significantly augmented datasets, which are obtained using direct interpolation, as well as indirect interpolation using automatically extracted features provided by stacked autoencoders. This chapter ends with a discussion of further research.",book:{id:"6346",slug:"machine-learning-advanced-techniques-and-emerging-applications",title:"Machine Learning",fullTitle:"Machine Learning - Advanced Techniques and Emerging Applications"},signatures:"W. David Pan, Yuhang Dong and Dongsheng Wu",authors:[{id:"214067",title:"Dr.",name:"W. David",middleName:null,surname:"Pan",slug:"w.-david-pan",fullName:"W. 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The machine-learning framework entails capturing and maintaining a rich set of information and transforming it into a structured knowledge base for different uses in various fields. In the field of education, teachers can save time in their non-classroom activities by adopting machine learning. For example, teachers can use virtual assistants who work remotely from the home for their students. This kind of assistance helps to enhance students’ learning experience and can improve progression and student achievement. Machine learning fosters personalized learning in the context of disseminating education. Advances in AI are enabling teachers to gain a better understanding of how their students are progressing with learning. This enables teachers to create customized curriculum that suits the specific needs of the learners. When employed in the context of education, AI can foster intelligence moderation. It is through this platform that the analysis of data by human tutors and moderators is made possible.",book:{id:"6346",slug:"machine-learning-advanced-techniques-and-emerging-applications",title:"Machine Learning",fullTitle:"Machine Learning - Advanced Techniques and Emerging Applications"},signatures:"Ibtehal Talal Nafea",authors:[{id:"216001",title:"Dr.",name:"Ibtehal",middleName:null,surname:"Nafea",slug:"ibtehal-nafea",fullName:"Ibtehal Nafea"}]},{id:"68953",title:"Machine Translation and the Evaluation of Its Quality",slug:"machine-translation-and-the-evaluation-of-its-quality",totalDownloads:1535,totalCrossrefCites:1,totalDimensionsCites:4,abstract:"Machine translation has already become part of our everyday life. This chapter gives an overview of machine translation approaches. Statistical machine translation was a dominant approach over the past 20 years. It brought many cases of practical use. It is described in more detail in this chapter. 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However, the necessary equipment to accurately measure the criteria pollutants is expensive. Since the countries with more serious problems of air pollution are the less wealthy, this study proposes an affordable method based on machine learning to estimate the concentration of PM2.5. The capital city of Ecuador is used as case study. Several regression models are built from features of different levels of affordability. The first result shows that cheap data collection based on web traffic monitoring enables us to create a model that fairly correlates traffic density with air pollution. Building multiple models according to the hourly occurrence of the pollution peaks seems to increase the accuracy of the estimation, especially in the morning hours. The second result shows that adding meteorological factors allows for a significant improvement of the prediction of PM2.5 concentrations. Nevertheless, the last finding demonstrates that the best predictive model should be based on a hybrid source of data that includes trace gases. 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She obtained her Ph.D. in Veterinary Sciences from the University of Trás-os-Montes e Alto Douro, Portugal. After almost 32 years of teaching at the University of Trás-os-Montes and Alto Douro, she recently moved to the University of Évora, Department of Veterinary Medicine, where she teaches in the field of Animal Reproduction and Clinics. Her primary research areas include the molecular markers of the endometrial cycle and the embryo–maternal interaction, including oxidative stress and the reproductive physiology and disorders of sexual development, besides the molecular determinants of male and female fertility. She often supervises students preparing their master's or doctoral theses. 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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. 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In 1992, Dr. Babinszky obtained a Ph.D. in Animal Nutrition from the University of Wageningen. His main research areas are swine and poultry nutrition. He has authored more than 300 publications (papers, book chapters) and edited four books and fourteen international conference proceedings.",institutionString:"University of Debrecen",institution:{name:"University of Debrecen",country:{name:"Hungary"}}},{id:"201830",title:"Dr.",name:"Fernando",middleName:"Sanchez",surname:"Davila",slug:"fernando-davila",fullName:"Fernando Davila",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/201830/images/5017_n.jpg",biography:"I am a professor at UANL since 1988. My research lines are the development of reproductive techniques in small ruminants. We also conducted research on sexual and social behavior in males.\nI am Mexican and study my professional career as an engineer in agriculture and animal science at UANL. Then take a masters degree in science in Germany (Animal breeding). Take a doctorate in animal science at the UANL.",institutionString:null,institution:{name:"Universidad Autónoma de Nuevo León",country:{name:"Mexico"}}},{id:"309250",title:"Dr.",name:"Miguel",middleName:null,surname:"Quaresma",slug:"miguel-quaresma",fullName:"Miguel Quaresma",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/309250/images/9059_n.jpg",biography:"Miguel Nuno Pinheiro Quaresma was born on May 26, 1974 in Dili, Timor Island. He is married with two children: a boy and a girl, and he is a resident in Vila Real, Portugal. He graduated in Veterinary Medicine in August 1998 and obtained his Ph.D. degree in Veterinary Sciences -Clinical Area in February 2015, both from the University of Trás-os-Montes e Alto Douro. He is currently enrolled in the Alternative Residency of the European College of Animal Reproduction. He works as a Senior Clinician at the Veterinary Teaching Hospital of UTAD (HVUTAD) with a role in clinical activity in the area of livestock and equine species as well as to support teaching and research in related areas. He teaches as an Invited Professor in Reproduction Medicine I and II of the Master\\'s in Veterinary Medicine degree at UTAD. Currently, he holds the position of Chairman of the Portuguese Buiatrics Association. He is a member of the Consultive Group on Production Animals of the OMV. He has 19 publications in indexed international journals (ISIS), as well as over 60 publications and oral presentations in both Portuguese and international journals and congresses.",institutionString:"University of Trás-os-Montes and Alto Douro",institution:{name:"University of Trás-os-Montes and Alto Douro",country:{name:"Portugal"}}},{id:"38652",title:"Prof.",name:"Rita",middleName:null,surname:"Payan-Carreira",slug:"rita-payan-carreira",fullName:"Rita Payan-Carreira",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRiFPQA0/Profile_Picture_1614601496313",biography:"Rita Payan Carreira earned her Veterinary Degree from the Faculty of Veterinary Medicine in Lisbon, Portugal, in 1985. She obtained her Ph.D. in Veterinary Sciences from the University of Trás-os-Montes e Alto Douro, Portugal. After almost 32 years of teaching at the University of Trás-os-Montes and Alto Douro, she recently moved to the University of Évora, Department of Veterinary Medicine, where she teaches in the field of Animal Reproduction and Clinics. Her primary research areas include the molecular markers of the endometrial cycle and the embryo–maternal interaction, including oxidative stress and the reproductive physiology and disorders of sexual development, besides the molecular determinants of male and female fertility. She often supervises students preparing their master's or doctoral theses. She is also a frequent referee for various journals.",institutionString:null,institution:{name:"University of Évora",country:{name:"Portugal"}}},{id:"283019",title:"Dr.",name:"Oudessa",middleName:null,surname:"Kerro Dego",slug:"oudessa-kerro-dego",fullName:"Oudessa Kerro Dego",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/283019/images/system/283019.png",biography:"Dr. Kerro Dego is a veterinary microbiologist with training in veterinary medicine, microbiology, and anatomic pathology. Dr. Kerro Dego is an assistant professor of dairy health in the department of animal science, the University of Tennessee, Institute of Agriculture, Knoxville, Tennessee. He received his D.V.M. (1997), M.S. (2002), and Ph.D. (2008) degrees in Veterinary Medicine, Animal Pathology and Veterinary Microbiology from College of Veterinary Medicine, Addis Ababa University, Ethiopia; College of Veterinary Medicine, Utrecht University, the Netherlands and Western College of Veterinary Medicine, University of Saskatchewan, Canada respectively. He did his Postdoctoral training in microbial pathogenesis (2009 - 2015) in the Department of Animal Science, the University of Tennessee, Institute of Agriculture, Knoxville, Tennessee. Dr. Kerro Dego’s research focuses on the prevention and control of infectious diseases of farm animals, particularly mastitis, improving dairy food safety, and mitigation of antimicrobial resistance. Dr. Kerro Dego has extensive experience in studying the pathogenesis of bacterial infections, identification of virulence factors, and vaccine development and efficacy testing against major bacterial mastitis pathogens. Dr. Kerro Dego conducted numerous controlled experimental and field vaccine efficacy studies, vaccination, and evaluation of immunological responses in several species of animals, including rodents (mice) and large animals (bovine and ovine).",institutionString:"University of Tennessee at Knoxville",institution:{name:"University of Tennessee at Knoxville",country:{name:"United States of America"}}},{id:"251314",title:"Dr.",name:"Juan Carlos",middleName:null,surname:"Gardón Poggi",slug:"juan-carlos-gardon-poggi",fullName:"Juan Carlos Gardón Poggi",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/251314/images/system/251314.jpeg",biography:"Juan Carlos Gardón Poggi received University degree from the Faculty of Agrarian Science in Argentina, in 1983. Also he received Masters Degree and PhD from Córdoba University, Spain. He is currently a Professor at the Catholic University of Valencia San Vicente Mártir, at the Department of Medicine and Animal Surgery. He teaches diverse courses in the field of Animal Reproduction and he is the Director of the Veterinary Farm. He also participates in academic postgraduate activities at the Veterinary Faculty of Murcia University, Spain. His research areas include animal physiology, physiology and biotechnology of reproduction either in males or females, the study of gametes under in vitro conditions and the use of ultrasound as a complement to physiological studies and development of applied biotechnologies. Routinely, he supervises students preparing their doctoral, master thesis or final degree projects.",institutionString:null,institution:{name:"Valencia Catholic University Saint Vincent Martyr",country:{name:"Spain"}}},{id:"309529",title:"Dr.",name:"Albert",middleName:null,surname:"Rizvanov",slug:"albert-rizvanov",fullName:"Albert Rizvanov",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/309529/images/9189_n.jpg",biography:'Albert A. Rizvanov is a Professor and Director of the Center for Precision and Regenerative Medicine at the Institute of Fundamental Medicine and Biology, Kazan Federal University (KFU), Russia. He is the Head of the Center of Excellence “Regenerative Medicine” and Vice-Director of Strategic Academic Unit \\"Translational 7P Medicine\\". Albert completed his Ph.D. at the University of Nevada, Reno, USA and Dr.Sci. at KFU. He is a corresponding member of the Tatarstan Academy of Sciences, Russian Federation. Albert is an author of more than 300 peer-reviewed journal articles and 22 patents. He has supervised 11 Ph.D. and 2 Dr.Sci. dissertations. Albert is the Head of the Dissertation Committee on Biochemistry, Microbiology, and Genetics at KFU.\nORCID https://orcid.org/0000-0002-9427-5739\nWebsite https://kpfu.ru/Albert.Rizvanov?p_lang=2',institutionString:"Kazan Federal University",institution:{name:"Kazan Federal University",country:{name:"Russia"}}},{id:"210551",title:"Dr.",name:"Arbab",middleName:null,surname:"Sikandar",slug:"arbab-sikandar",fullName:"Arbab Sikandar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/210551/images/system/210551.jpg",biography:"Dr. Arbab Sikandar, PhD, M. Phil, DVM was born on April 05, 1981. He is currently working at the College of Veterinary & Animal Sciences as an Assistant Professor. He previously worked as a lecturer at the same University. \nHe is a Member/Secretory of Ethics committee (No. CVAS-9377 dated 18-04-18), Member of the QEC committee CVAS, Jhang (Regr/Gen/69/873, dated 26-10-2017), Member, Board of studies of Department of Basic Sciences (No. CVAS. 2851 Dated. 12-04-13, and No. CVAS, 9024 dated 20/11/17), Member of Academic Committee, CVAS, Jhang (No. CVAS/2004, Dated, 25-08-12), Member of the technical committee (No. CVAS/ 4085, dated 20,03, 2010 till 2016).\n\nDr. Arbab Sikandar contributed in five days hands-on-training on Histopathology at the Department of Pathology, UVAS from 12-16 June 2017. He received a Certificate of appreciation for contributions for Popularization of Science and Technology in the Society on 17-11-15. He was the resource person in the lecture series- ‘scientific writing’ at the Department of Anatomy and Histology, UVAS, Lahore on 29th October 2015. He won a full fellowship as a principal candidate for the year 2015 in the field of Agriculture, EICA, Egypt with ref. to the Notification No. 12(11) ACS/Egypt/2014 from 10 July 2015 to 25th September 2015.; he received a grant of Rs. 55000/- as research incentives from Director, Advanced Studies and Research, UVAS, Lahore upon publications of research papers in IF Journals (DR/215, dated 19-5-2014.. He obtained his PhD by winning a HEC Pakistan indigenous Scholarship, ‘Ph.D. fellowship for 5000 scholars – Phase II’ (2av1-147), 17-6/HEC/HRD/IS-II/12, November 15, 2012. \n\nDr. Sikandar is a member of numerous societies: Registered Veterinary Medical Practitioner (life member) and Registered Veterinary Medical Faculty of Pakistan Veterinary Medical Council. The Registration code of PVMC is RVMP/4298 and RVMF/ 0102.; Life member of the University of Veterinary and Animal Sciences, Lahore, Alumni Association with S# 664, dated: 6-4-12. ; Member 'Vets Care Organization Pakistan” with Reference No. VCO-605-149, dated 05-04-06. :Member 'Vet Crescent” (Society of Animal Health and Production), UVAS, Lahore.",institutionString:"University of Veterinary & Animal Science",institution:{name:"University of Veterinary and Animal Sciences",country:{name:"Pakistan"}}},{id:"311663",title:"Dr.",name:"Prasanna",middleName:null,surname:"Pal",slug:"prasanna-pal",fullName:"Prasanna Pal",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/311663/images/13261_n.jpg",biography:null,institutionString:null,institution:{name:"National Dairy Research Institute",country:{name:"India"}}},{id:"202192",title:"Dr.",name:"Catrin",middleName:null,surname:"Rutland",slug:"catrin-rutland",fullName:"Catrin Rutland",position:null,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",country:{name:"United Kingdom"}}},{id:"283315",title:"Prof.",name:"Samir",middleName:null,surname:"El-Gendy",slug:"samir-el-gendy",fullName:"Samir El-Gendy",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRduYQAS/Profile_Picture_1606215849748",biography:"Samir El-Gendy is a Professor of anatomy and embryology at the faculty of veterinary medicine, Alexandria University, Egypt. Samir obtained his PhD in veterinary science in 2007 from the faculty of veterinary medicine, Alexandria University and has been a professor since 2017. Samir is an author on 24 articles at Scopus and 12 articles within local journals and 2 books/book chapters. His research focuses on applied anatomy, imaging techniques and computed tomography. Samir worked as a member of different local projects on E-learning and he is a board member of the African Association of Veterinary Anatomists and of anatomy societies and as an associated author at local and international journals. Orcid: https://orcid.org/0000-0002-6180-389X",institutionString:null,institution:{name:"Alexandria University",country:{name:"Egypt"}}},{id:"246149",title:"Dr.",name:"Valentina",middleName:null,surname:"Kubale",slug:"valentina-kubale",fullName:"Valentina Kubale",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/246149/images/system/246149.jpg",biography:"Valentina Kubale is Associate Professor of Veterinary Medicine at the Veterinary Faculty, University of Ljubljana, Slovenia. Since graduating from the Veterinary faculty she obtained her PhD in 2007, performed collaboration with the Department of Pharmacology, University of Copenhagen, Denmark. She continued as a post-doctoral fellow at the University of Copenhagen with a Lundbeck foundation fellowship. She is the editor of three books and author/coauthor of 23 articles in peer-reviewed scientific journals, 16 book chapters, and 68 communications at scientific congresses. Since 2008 she has been the Editor Assistant for the Slovenian Veterinary Research journal. She is a member of Slovenian Biochemical Society, The Endocrine Society, European Association of Veterinary Anatomists and Society for Laboratory Animals, where she is board member.",institutionString:"University of Ljubljana",institution:{name:"University of Ljubljana",country:{name:"Slovenia"}}},{id:"258334",title:"Dr.",name:"Carlos Eduardo",middleName:null,surname:"Fonseca-Alves",slug:"carlos-eduardo-fonseca-alves",fullName:"Carlos Eduardo Fonseca-Alves",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/258334/images/system/258334.jpg",biography:"Dr. Fonseca-Alves earned his DVM from Federal University of Goias – UFG in 2008. He completed an internship in small animal internal medicine at UPIS university in 2011, earned his MSc in 2013 and PhD in 2015 both in Veterinary Medicine at Sao Paulo State University – UNESP. Dr. Fonseca-Alves currently serves as an Assistant Professor at Paulista University – UNIP teaching small animal internal medicine.",institutionString:null,institution:{name:"Universidade Paulista",country:{name:"Brazil"}}},{id:"245306",title:"Dr.",name:"María Luz",middleName:null,surname:"Garcia Pardo",slug:"maria-luz-garcia-pardo",fullName:"María Luz Garcia Pardo",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/245306/images/system/245306.png",biography:"María de la Luz García Pardo is an agricultural engineer from Universitat Politècnica de València, Spain. She has a Ph.D. in Animal Genetics. Currently, she is a lecturer at the Agrofood Technology Department of Miguel Hernández University, Spain. Her research is focused on genetics and reproduction in rabbits. The major goal of her research is the genetics of litter size through novel methods such as selection by the environmental sensibility of litter size, with forays into the field of animal welfare by analysing the impact on the susceptibility to diseases and stress of the does. Details of her publications can be found at https://orcid.org/0000-0001-9504-8290.",institutionString:null,institution:{name:"Miguel Hernandez University",country:{name:"Spain"}}},{id:"350704",title:"M.Sc.",name:"Camila",middleName:"Silva Costa",surname:"Ferreira",slug:"camila-ferreira",fullName:"Camila Ferreira",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/350704/images/17280_n.jpg",biography:"Graduated in Veterinary Medicine at the Fluminense Federal University, specialist in Equine Reproduction at the Brazilian Veterinary Institute (IBVET) and Master in Clinical Veterinary Medicine and Animal Reproduction at the Fluminense Federal University. She has experience in analyzing zootechnical indices in dairy cattle and organizing events related to Veterinary Medicine through extension grants. I have experience in the field of diagnostic imaging and animal reproduction in veterinary medicine through monitoring and scientific initiation scholarships. I worked at the Equus Central Reproduction Equine located in Santo Antônio de Jesus – BA in the 2016/2017 breeding season. I am currently a doctoral student with a scholarship from CAPES of the Postgraduate Program in Veterinary Medicine (Pathology and Clinical Sciences) at the Federal Rural University of Rio de Janeiro (UFRRJ) with a research project with an emphasis on equine endometritis.",institutionString:null,institution:null},{id:"41319",title:"Prof.",name:"Lung-Kwang",middleName:null,surname:"Pan",slug:"lung-kwang-pan",fullName:"Lung-Kwang Pan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/41319/images/84_n.jpg",biography:null,institutionString:null,institution:null},{id:"125292",title:"Dr.",name:"Katy",middleName:null,surname:"Satué Ambrojo",slug:"katy-satue-ambrojo",fullName:"Katy Satué Ambrojo",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/125292/images/system/125292.jpeg",biography:"Katy Satué Ambrojo received her Veterinary Medicine degree, Master degree in Equine Technology and doctorate in Veterinary Medicine from the Faculty of Veterinary, CEU-Cardenal Herrera University in Valencia, Spain.Dr. Satué is accredited as a Private University Doctor Professor, Doctor Assistant, and Contracted Doctor by AVAP (Agència Valenciana d'Avaluació i Prospectiva) and currently, as a full professor by ANECA (since January 2022). To date, Katy has taught 22 years in the Department of Animal Medicine and Surgery at the CEU-Cardenal Herrera University in undergraduate courses in Veterinary Medicine (General Pathology, integrated into the Applied Basis of Veterinary Medicine module of the 2nd year, Clinical Equine I of 3rd year, and Equine Clinic II of 4th year). Dr. Satué research activity is in the field of Endocrinology, Hematology, Biochemistry, and Immunology in the Spanish Purebred mare. She has directed 5 Doctoral Theses and 5 Diplomas of Advanced Studies, and participated in 11 research projects as a collaborating researcher. She has written 2 books and 14 book chapters in international publishers related to the area, and 68 scientific publications in international journals. Dr. Satué has attended 63 congresses, participating with 132 communications in international congresses and 19 in national congresses related to the area. Dr. Satué is a scientific reviewer for various prestigious international journals such as Animals, American Journal of Obstetrics and Gynecology, Veterinary Clinical Pathology, Journal of Equine Veterinary Science, Reproduction in Domestic Animals, Research Veterinary Science, Brazilian Journal of Medical and Biological Research, Livestock Production Science and Theriogenology, among others. Since 2014 she has been responsible for the Clinical Analysis Laboratory of the CEU-Cardenal Herrera University Veterinary Clinical Hospital.",institutionString:null,institution:null},{id:"201721",title:"Dr.",name:"Beatrice",middleName:null,surname:"Funiciello",slug:"beatrice-funiciello",fullName:"Beatrice Funiciello",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/201721/images/11089_n.jpg",biography:"Graduated from the University of Milan in 2011, my post-graduate education included CertAVP modules mainly on equines (dermatology and internal medicine) and a few on small animal (dermatology and anaesthesia) at the University of Liverpool. After a general CertAVP (2015) I gained the designated Certificate in Veterinary Dermatology (2017) after taking the synoptic examination and then applied for the RCVS ADvanced Practitioner status. After that, I completed the Postgraduate Diploma in Veterinary Professional Studies at the University of Liverpool (2018). My main area of work is cross-species veterinary dermatology.",institutionString:null,institution:null},{id:"291226",title:"Dr.",name:"Monica",middleName:null,surname:"Cassel",slug:"monica-cassel",fullName:"Monica Cassel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/291226/images/8232_n.jpg",biography:'Degree in Biological Sciences at the Federal University of Mato Grosso with scholarship for Scientific Initiation by FAPEMAT (2008/1) and CNPq (2008/2-2009/2): Project \\"Histological evidence of reproductive activity in lizards of the Manso region, Chapada dos Guimarães, Mato Grosso, Brazil\\". Master\\\'s degree in Ecology and Biodiversity Conservation at Federal University of Mato Grosso with a scholarship by CAPES/REUNI program: Project \\"Reproductive biology of Melanorivulus punctatus\\". PhD\\\'s degree in Science (Cell and Tissue Biology Area) \n at University of Sao Paulo with scholarship granted by FAPESP; Project \\"Development of morphofunctional changes in ovary of Astyanax altiparanae Garutti & Britski, 2000 (Teleostei, Characidae)\\". She has experience in Reproduction of vertebrates and Morphology, with emphasis in Cellular Biology and Histology. She is currently a teacher in the medium / technical level courses at IFMT-Alta Floresta, as well as in the Bachelor\\\'s degree in Animal Science and in the Bachelor\\\'s degree in Business.',institutionString:null,institution:null},{id:"442807",title:"Dr.",name:"Busani",middleName:null,surname:"Moyo",slug:"busani-moyo",fullName:"Busani Moyo",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Gwanda State University",country:{name:"Zimbabwe"}}},{id:"439435",title:"Dr.",name:"Feda S.",middleName:null,surname:"Aljaser",slug:"feda-s.-aljaser",fullName:"Feda S. Aljaser",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"King Saud University",country:{name:"Saudi Arabia"}}},{id:"423023",title:"Dr.",name:"Yosra",middleName:null,surname:"Soltan",slug:"yosra-soltan",fullName:"Yosra Soltan",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Alexandria University",country:{name:"Egypt"}}},{id:"349788",title:"Dr.",name:"Florencia Nery",middleName:null,surname:"Sompie",slug:"florencia-nery-sompie",fullName:"Florencia Nery Sompie",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Sam Ratulangi University",country:{name:"Indonesia"}}},{id:"428600",title:"MSc.",name:"Adriana",middleName:null,surname:"García-Alarcón",slug:"adriana-garcia-alarcon",fullName:"Adriana García-Alarcón",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"National Autonomous University of Mexico",country:{name:"Mexico"}}},{id:"428599",title:"MSc.",name:"Gabino",middleName:null,surname:"De La Rosa-Cruz",slug:"gabino-de-la-rosa-cruz",fullName:"Gabino De La Rosa-Cruz",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"National Autonomous University of Mexico",country:{name:"Mexico"}}},{id:"428601",title:"MSc.",name:"Juan Carlos",middleName:null,surname:"Campuzano-Caballero",slug:"juan-carlos-campuzano-caballero",fullName:"Juan Carlos Campuzano-Caballero",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"National Autonomous University of Mexico",country:{name:"Mexico"}}}]}},subseries:{item:{id:"10",type:"subseries",title:"Animal Physiology",keywords:"Physiology, Comparative, Evolution, Biomolecules, Organ, Homeostasis, Anatomy, Pathology, Medical, Cell Division, Cell Signaling, Cell Growth, Cell Metabolism, Endocrine, Neuroscience, Cardiovascular, Development, Aging, Development",scope:"Physiology, the scientific study of functions and mechanisms of living systems, is an essential area of research in its own right, but also in relation to medicine and health sciences. The scope of this topic will range from molecular, biochemical, cellular, and physiological processes in all animal species. Work pertaining to the whole organism, organ systems, individual organs and tissues, cells, and biomolecules will be included. Medical, animal, cell, and comparative physiology and allied fields such as anatomy, histology, and pathology with physiology links will be covered in this topic. Physiology research may be linked to development, aging, environment, regular and pathological processes, adaptation and evolution, exercise, or several other factors affecting, or involved with, animal physiology.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/10.jpg",hasOnlineFirst:!1,hasPublishedBooks:!1,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. 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