Proof-of-principle gene-drive systems with and without antimalarial effectors in
\r\n\tThe development of the interpersonal model and the Kleinian school in the second half of the last century allowed the emergence of an original understanding of the unconscious mind. Within the intersubjective paradigm, the psychoanalytic situation is conceptualized as an interpersonal field to which both the analyst and the patient contribute substantially. We have shown elsewhere how the failure to give a full account of such an intersubjective dimension in both psychoanalytic theory and practice amounts to a core liability in contemporary psychoanalytic discourse.
\r\n\r\n\tThe present book will focus on a few areas where the insufficient development of our discipline is currently apparent: five wounds that mark the body of the psychoanalytic enterprise.
\r\n\r\n\tNew contributions are particularly needed in the following areas: Current conceptualization of the unconscious mind is mechanistic and not suited to incorporate the full network of interpersonal exchanges which unfolds in the analytic room; Furthermore, the development of interpersonal psychoanalysis and the theory of the object relations warrants a greater appreciation of the impact of extratranference relations (e.g., couple, family, peers) on the patient's inner life both within and without the psychoanalytic situation.
\r\n\r\n\tAn integration of theories and models from other psychological paradigms is clearly in order here; the book will also focus on Barangers’ theory of the bi-personal field that makes traditional unipersonal models of the psychoanalytic process untenable. Also, it will help in the understanding of the reciprocal interactions of the two partners in the psychoanalytic dyad in most psychoanalytic institutes the training format relies naively on models from the academic or the professional domains. This fosters rigidity, conformism, and a hierarchical organizational style in the institutional life; e) all over the long span of his creative life Freud showed consistent interest in the application of psychoanalysis to literature, the arts, religion, and politics. Contemporary psychoanalysis is getting more and shyer and is pressed at the margins of social and political debate. The psychoanalytic theory includes unique lore of knowledge about the conscious and unconscious mind. Without it, a comprehensive understanding of human reality will stay out of the reach of contemporary culture.
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Interventions to control anophelines have been ongoing since Sir Ronald Ross’s discovery of the complete malaria transmission cycle in the late nineteenth century. The first large-scale vector control interventions in the early twentieth century relied on management and control of anopheline breeding habitats via manipulation of the environment (Figure 1) [2]. However, the discovery and subsequent development of dichloro-diphenyl-trichloroethane (DDT) in the early 1940s led to a new era of vector control after successes with the insecticide by the U.S. Army in World War II and various field trials proved its powerful ability to control malaria [3]. The initial successes with DDT were so great that malaria eradication began to appear feasible to some malariologists, and in 1955, the World Health Assembly launched the Global Malaria Eradication Programme (GMEP) with a goal to assist nations in eradicating malaria by providing technical advice and consolidating the resources needed for large-scale eradication campaigns. The World Health Organization (WHO) Expert Committee on Malaria was responsible for designing the eradication campaign schedule, which consisted of four distinct phases: preparatory, attack, consolidation, and maintenance. Completion of the eradication schedule was estimated to require 8–10 years [4]. Despite previous observations of insecticide resistance to DDT in Greece in 1951, the attack phase relied almost exclusively on the use of indoor residual spraying (IRS) of this insecticide to reduce adult mosquito populations supplemented by chloroquine to treat infections [5]. Large reductions in malaria case incidence, morbidity and mortality were observed worldwide because of the GMEP campaign and malaria was eliminated in many countries with temperate climates (Figure 2) [6, 7, 8, 9, 10]. However, progress began to falter by the mid 1960s and some countries participating in the GMEP reverted from the consolidation phase back to the attack phase. Countries such as Sri Lanka, which was an exemplary model for GMEP successes, began to experience epidemic resurgences of malaria [11]. Additionally, resistance to DDT became widespread throughout the participating countries. By the late 1960s, political and financial support for the GMEP had waned and the aim for eradication within a finite timeline was replaced by the aim of controlling malaria within an indefinite timeline.
Timeline of vector-control approaches and outcomes. Important events and timepoints of malaria vector control efforts and progress in the perspective of obstacles and downturns. Although great progress was made through the history of malaria vector control, many natural and artificial challenges have hindered the goal of malaria eradication.
Global estimated number of malaria deaths. Estimated malaria mortality declined significantly from 1920s to 1970s due to many malaria control efforts countrywide and internationally but slowed from 1970s to 2020. Sources [
Control of malaria after the dissolution of the GMEP devolved to a country-by-country basis. Some nations that had benefited from participation in the GMEP continued to make progress in reducing the burden of malaria. However, most African nations were never included in the GMEP, and without dedicated resources, financial support or personnel trained in vector control techniques, the continent continued to suffer greatly as population growth paralleled an increase in malaria morbidity and mortality. In 1975 the WHO estimated that over one million infants and children were dying annually due to malaria in sub-Saharan Africa [12]. A systemic analysis of global malaria mortality from 1980 to 2010 estimated a peak of malaria deaths occurred in 2004 with over 1.8 million deaths occurring globally [13]. By the beginning of the second millennium, the rapid expansion of disease burden due to the absence of a global strategy and lack of unified political will became soberingly evident in the global malaria mortality rates.
The combination of skyrocketing malaria mortality and philanthropic interests of the world’s ultra-wealthy led to a renewed interest and consolidation of financial and political will for advances in malaria control and elimination at the beginning of the second millennium. The formation of the Roll Back Malaria Partnership (RBM) and creation of the United Nations Millennium Development Goals helped to solidify a new global strategy. After years of disparate global malaria control without clearly-defined metrics to track progress, the renewed enthusiasm ushered in a return to specific targets and strategies reminiscent of what was attempted in the 1950s with the GMEP. The new global malaria programme (GMP) had the benefit of additional vector control tools such as a wider variety of insecticide products for IRS and insecticide-treated nets (ITN). The new program also benefited from the historical perspectives of renown malariologists on the causes leading to the failures of the original eradication effort. The UN development goals included Target 6.C with a stated aim “to have halted by 2015 and begun to reverse the incidence of malaria and other major diseases” (UN Millennium goals [14]) and the RBM created a Global Malaria Action Plan, which outlined an overarching strategy and system of support needed to achieve malaria eradication [15]. The enhanced frameworks for combating malaria also were accompanied by increased funding in the formation of the Global Fund to Fight AIDS, Tuberculosis and Malaria and the US President’s Malaria Initiative [16]. The renewed efforts and consolidation of strategies and finances in the early 2000s proved successful, and Target 6.C of the development goals was achieved. There was a 30% reduction in global incidence and 47% decline in mortality due to malaria from 2001 to 2015 [1]. Continuing the momentum of the progress made in the early millennium, WHO member states created and adopted a new global technical strategy (GTS) in 2015 and set an ambitious new target for a 90% reduction in global malaria burden by 2030 [17].
The WHO and RBM developed a new framework of strategies and guidelines to meet the ambitious 2030 targets. The first pillar of the WHO’s post-2015 GTS called for expansions of access. Firstly, it called for expanded access to vector control using either IRS or long-lasting insecticide treated nets (LLINs) and secondly, it called for expanded access to chemoprevention and treatment, especially in vulnerable groups such as children and pregnant women. The new guidelines also highlighted the importance of generating entomological and epidemiological surveillance data to guide vector control and disease-treatment efforts and advised that accumulation of these data should be considered an intervention in itself. While supporting elements of the post-2015 GTS encouraged advancements in research and new technology, these were secondary to the ramp-up of coverage using existing vector control and treatment technologies. Unfortunately, despite the restructured objectives and continual commitment to malaria elimination by global parties in 2015, progress in reducing malaria morbidity and mortality has slowed or stalled in many mid- to high-transmission countries. The post-2015 GTS set an interim goal of achieving 40% reductions in malaria case incidence and mortality by 2020, however, the case incidence at that time had only decreased by 3% and mortality decreased by 22% compared to 2015 levels [17].
Many factors contribute to the decreased rate of reducing malaria incidence and mortality rates. Population growth in malaria-endemic countries has substantially increased the at-risk population. Initial modeling efforts completed during the creation of the post-2015 GTS predicted that with the existing vector control tools and treatment options available, coverage would have to exceed 80% of high-risk populations to reduce the malaria burden [17]. However, growing populations combined with continuing instabilities of governments, natural disasters, conflicts, and epidemics have hampered the ability to reach this needed intervention coverage. As a result, there has been inadequate access to available vector control interventions. It is estimated that only 46% of the population at risk for malaria is protected by an insecticide-treated net and the percent of at-risk population covered by IRS is only 2.4%, a 2.9% decrease when compared to 2010 coverage [1].
In addition to problems of access, the existing vector control interventions face problems of reduced efficacy due to the widespread emergence of insecticide resistance in the major anopheline vectors. Resistance in the form of either target-site insensitivity or metabolomic changes has been observed for all classes of insecticides currently being used to treat bed nets or in IRS campaigns [18]. Cuticular or penetration resistance has also been observed [19], which also reduces the impact of bed nets and IRS campaigns. As of 2020, only eight of the 82 malaria-endemic countries reported no resistance to all classes of insecticides. Resistance to pyrethroids, the only insecticide approved to treat bed nets, is widespread and resistance was reported in just under 70% of the locations that performed WHO approved standardized testing [1]. The varied resistance mechanisms and wide geographical spread of resistance imposes a major threat to the objectives of the GTS, yet no vector control products based on a new class of insecticide have been introduced to global markets since pyrethroids were introduced in the 1970s however, several have been re-purposed for their use in bed-nets and IRS and new formulations are under development with the World Health Organization Pesticide Evaluation Scheme [20, 21]. An additional challenge to current vector control tactics is behavioral resistance of the mosquito vectors. The long-term use of ITN and IRS creates a selective pressure that has been shown to result in behavioral and population compositional changes of malaria-vectoring species over time [22]. Changes in
An increase in access to vector control interventions to above 80% coverage of at-risk populations will likely lead to a reduction in case incidence and mortality but may not result in the desired 90% reduction of malaria burdens due to the challenges presented by resistance. With no new classes of insecticide approved for the control of malaria, widespread insecticide resistance and evidence of behavioral changes perpetuating residual transmission, the limitations of the current GTS vector control initiatives are obvious. New tools and technologies are needed urgently to meet the 2030 targets of the GTS. Ideally, novel vector control strategies should be cost-effective and sustainable as well as implementable and maintainable in a variety of regions irrespective of changes in government stability, conflicts or catastrophes. Population modification using genetic techniques to confer parasite refractoriness in mosquitoes is one such novel strategy that could greatly aid in achieving the ambitious goals of the GMP.
Population modification is the concept of incorporating genes or genetic elements in vector species that increase their refractoriness to the pathogens they transmit thereby inhibiting transfer of the pathogens to host species (Figure 3). Population modification was first described in the contemporary literature using the term ‘population replacement’ by Christopher Curtis in 1968 [26]. Due to misinterpretations of population replacement and negative connotations of the term ‘modification’ related to cultural perspectives on genetically-modified organisms (GMOs), a third term, ‘population alteration’, also was proposed [27]. The early conceptions of population modification were made prior to the discovery and refinement of current gene-drive technologies, however, the original concept as proposed by Curtis suggested the need for a mechanism to elicit fixation of the favorable genes in a population. The advancements and development of genetic-engineering techniques to inhibit
Outcomes anticipated from genetic control approaches. Vector control strategy utilizes genetic-engineering technology with gene drive via two different approaches, population modification/alteration (top) or population suppression (bottom). In both approaches, the transgenic mosquitoes qualified for releases should carry at least three components: the gene drive system, the marker and the effector or suppression component aiming at reducing the vector competence or the vector population, respectively. The anticipated outcome for the population modification/alteration approach is that the treated population become refractory to pathogen as the effector genes spread into the population; whereas with the population suppression approach the anticipated outcome would be the reduction or elimination of whole population. In both cases, the goal is to break the parasite cycle in the mosquito stages.
AsMCRkh2 | Reckh2 | AgNosCd-1 | AgTP13 | ||
---|---|---|---|---|---|
Species | |||||
Drive system | |||||
Target locus | |||||
Effector | Cp-1C3, Vg-2A10 | None | None | Cp-1C3, Vg-2A10 | |
Drive efficiency | Male | ~99% | ~99% | ~99% | ~99% |
Female | 65–90% | ~56% | ~95% | ~85–96% | |
Maternal effect | Significant | Significant | Mild | Mild | |
Fitness | Male contribution | Comparable with WT male | Comparable with WT male | mild reduction | Moderate reduction |
Fertility and fecundity | Post Blood meal lethality in homozygotes | Comparable with WT females | Comparable with WT females | Comparable with WT females | |
Small cage trials | Cage trial ratios, gene drive: wild-type males | 1:1, 1:3, 1:10 | 1:1, 1:3, 1:10 | 1:1, 1:3, 1:10 | 1:1, 1:3 |
Full introduction result | No | >95% introduction for all ratios | Yes | Yes for 1:1 ratio |
Proof-of-principle gene-drive systems with and without antimalarial effectors in
Cp, carboxypeptidase gene promoter; Vg, vitellogenin gene promoter; 1C3, 2A10: single-chain antibodies; WT: wild-type.
Population suppression is an alternative strategy to population modification that utilizes genetic-engineering technologies to reduce vector number and therefore reduce pathogen transmission (Figure 3). This can be achieved by diminishing the fitness or distorting sex ratios so that the vector populations reduce in number and eventually go extinct locally. Similar to population modification, proof-of-principle concepts also exist for population suppression in
Population modification and population suppression vary in their strengths and weaknesses so a complementary approach that involves the sequential application of both technologies can be proposed (Figure 4). This strategy maximizes the benefits of both approaches and lowers their respective hurdles to long-lasting success. The complementary approach includes an initial field release of a population suppression strain that will act to quickly reduce the local population of vectors and their associated population of parasites. When the population structure of native vectors has been sufficiently disrupted by the suppression strategy, the low level of individuals becomes more susceptible to events that may inhibit its ability to persist long term. For example, a re-introduction of wild-type individuals can occur, and these may overwhelm any low levels of remaining drive individuals, or individuals with drive-resistant alleles may build up over time inhibiting future suppression [43]. At this point, when a suppression system has driven the population to levels near extinction, a modification line can be introduced for maximal effect. Allowing a population replacement mosquito line to form the new population of mosquitoes prevents any negative ecological effects that may have occurred due to an empty ecological niche. It also allows the population modification drives to become established in an environment with a minimized risk for resistance to the transgene introduction. The effector genes will be less prone to having pathogen-based resistance develop as the natural pathogen population will have been greatly diminished by the suppression system, and lower pathogen reproduction numbers lower the likelihood of randomly-generated resistance conferring mutations in the pathogens. In the absence of threats from resistance, the only further threat faced by the population modification strain is long-term stability of the effector elements. However, new effector elements can be developed carefully as the needed window for protection resulting from the complementary approach is likely to be much longer than either approach alone.
Vector control with population modification and population suppression complementary approach. Proposed strategy combining sequential releases of mosquitoes with population modification and population suppression drives. The combined approach initiated with releasing population suppression gene-drive mosquitoes, which theoretically reduce the whole mosquito population in the treated area. Follow up with releasing of population modification gene-drive mosquitoes, this strategy ensures avoidance of an empty niche or re-introducing of wild mosquitoes that are susceptible to the malaria parasite. Black: wild-type mosquito; yellow: transgenics mosquitoes with suppression drive; Green: Transgenic mosquitoes with population modification drive.
The malaria parasites go through a multi-staged life cycle within their mosquito vectors (Figure 5). After the female
Malaria developmental pathway and compartments for blocking parasite development. Gametes are ingested with the blood meal. They differentiate, fertile and form a zygote. The zygote develops into a motile form, the ookinete, that then invades the mosquito midgut epithelium. There it develops into an oocyst in which many sporozoites are generated. These burst into the hemolymph and migrate to the salivary glands. From there the sporozoites can be transmitted to a new host during the next blood meal. The midgut compartment allows access to the gametes, zygotes, ookinetes and oocysts. The hemolymph and salivary gland compartments allow access to the sporozoites (image adapted from Isaacs et al. [
A synthetic approach was used in our laboratory to develop the anti-parasite effector genes and introduce these desired traits into the target genomes to generate the genetically-engineered mosquitoes (GEMs) [37]. This approach has several advantages, for example, the components of a synthetic construct can be relatively small, their functions are more fully known and the site in the mosquito genome where they will be located can be characterized or determined prior to genome integration. A synthetic cassette for population modification has two main components: (1) promoters and (2) antimalarial effector genes.
Promoters are regulatory DNA sequences that will drive the expression of a transgene (a marker or an antimalarial effector) in mosquitoes. During its development in the mosquito, the malaria parasite occupies three main compartments: midgut lumen, hemocoel and salivary gland lumen (Figure 5). Expression of the anti-parasite genes in these compartments is crucial to block their transmission and several tissue-specific promoters have been identified and used in mosquito transgenesis. These include control sequences for a gene encoding a carboxypeptidase, a digestive enzyme, and AgAper1, a peritrophic matrix protein, which are activated in response to a blood meal [44, 45, 46]. The vitellogenin-encoding gene promoters drive strong expression in the fat body and hemocoel [47, 48]. A hemocyte-specific hemolectin (hml) gene promoter and three salivary gland-specific promoters, (
The effector molecules can be classified into four groups depending on their mode of action.
Parasite blocking: exogenous molecules that eliminate the parasites such as antimicrobial peptides from the immune system of other insects (gambicin, defensin, cecropin) or other arthropods (scorpine). Natural and synthetic lytic peptides such as angiotensin II, magainins, Shiva-1, Shiva-3 and gomesin have been used to generate refractory
Interaction with parasites: single-chain monoclonal antibodies (scFvs) that bind to ookinete or sporozoite surface or secreted proteins, such as m2A10 that targets the
Interaction with mosquito tissues: molecules that bind putative mosquito receptors in the midgut or salivary glands blocking the ookinete and sporozoite invasion (for example, SM1) and molecules that can modify the properties of the midgut epithelia (mPLA2- phospholipase A2) [64, 65].
Mosquito immune system: manipulation of mosquito immune-related genes can lead to decreased mosquito vectorial competence. Expression of Akt, a key signaling component in the insulin signaling pathway or overexpression of IMD pathway-mediated transcription factor Rel2 can result in refractoriness to the parasite [66, 67].
The identification and characterization of efficient anti-
Mobile genetic elements called transposons can spread rapidly through populations despite severe costs to the host [69, 70, 71, 72]. Their ability to mobilize (excise and insert) led to their being developed as powerful systems for introducing exogenous DNA into several organisms. The adaptation of the P transposable element for transgenesis of the vinegar fly,
Other tools and systems for introducing genes into mosquito genomes include site-specific recombinases. These require the presence of an endogenous nucleotide sequence in the genome that is identical to the recombinase target cleavage site, or a mechanism for introducing such a site (called a docking site; [86]) into that genome. This has been achieved using the previously-described transposons. Two recombinases have been used successfully to generate transgenic mosquitoes, the bacteriophage φC31 integrase and Cre/lox recombinase derived from yeast. Their dependence on a precise site for integration of the desired transgene limits their usefulness as the basis of gene-drive systems for spreading transgenes into populations [82, 87, 88, 89, 90].
The application of zinc-finger nuclease (ZFNs) and the transcription activator-like effector nucleases (TALENs) for engineering target-site recognition in mosquitoes introduced a major advance for genetic modification in mosquitoes. However, the high cost and low success rate limited their use [91, 92, 93]. The application of homing endonucleases nucleases genes (HEGs) for spreading genes into mosquito populations was proposed in 2003 [94] as useful basis for gene drives and in 2011 a successful HEG-based gene drive in
A major breakthrough for mosquito transgenesis and gene-drive systems was achieved following the discovery and adaptation of the RNA-guided Cas9 nuclease from the bacterial Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR/Cas9) adaptive immune system [96]. This powerful tool simplified the highly-specific genome editing processes and made possible useful gene-drive systems. The Cas9 endonuclease is directed to its genomic target by a single 20 base-pair guide RNA (gRNA) complementary to its DNA target. This gRNA can be designed to target virtually any locus in a chromosome. CRISPR/Cas9 exploits the natural mechanism of cell repair to precisely insert a synthetic construct through homology-directed repair (HDR), a DNA repair system initiated by a double-strand break made at the site of a target location by the Cas9 nuclease [96]. CRISPR/Cas9 has been shown to be an excellent candidate technology for developing gene drive-based strategies to introduce beneficial genes into mosquito populations [28, 29, 30]. The properties of the system bias the inheritance of a desired trait, allowing them to quickly increase in frequency and spread through a mosquito population. CRISPR/Cas9 gene drives can efficiently convert pre-meiotic diploid germline cells in hemizygous mosquitoes (carrying one copy of the drive) into homozygotes carrying two copies [28, 29, 30]. Recently, the CRISPR/Cas9 technology has been adapted for the development of gene drives in anopheline mosquitoes and shows great promise for rapid introduction of anti-parasite genes into mosquito populations [28, 29, 30, 32].
The recent adaptation of CRISPR/Cas9-based biology to generate gene drives has been proposed to provide a powerful, inexpensive, and easily-implemented solution for malaria control due to the rapid introduction of the antimalarial genes into mosquito populations [37]. To produce the desired epidemiological outcomes of reduced malaria transmission, the drive system and associated effector components must be introduced quickly and efficiently into wild populations. Rapid introduction requires population modification lines to have high rates of drive allele conversion in the germline so that maximally-biased inheritance is achieved. This will result in a remarkable increase in frequency of the gene-drive system in the following generations.
The first CRISPR/Cas9 gene drive for mosquito population modification was described in 2015 for the Indo-Pakistani vector,
A next-generation gene drive system for
The fitness load in population modification CRISPR/Cas9 drive lines have been assessed on male and female mosquitoes. An ideal CRISPR/Cas9 drive candidate for population modification would have little-to-no fitness effects resulting from the drive system and its corresponding locus, as it is predicted that the effector components are likely to have some effect on overall fitness [98, 99].
One notable example of a fitness cost was observed in the
In contrast, AgNosCd-1 individuals do not have reduced fitness in most of the fitness parameters evaluated (fertility, fecundity, longevity, larval and pupal development), but a mild reduction in male mating competitiveness was observed [29]. AgNosCd-1 males are slightly less likely to contribute to the next generation than wild-type males, ~2% less likely for hemizygote males and ~8% for homozygote males. Despite these observed reductions in fitness, the power of the drive system was sufficient to negate the effects in subsequent generations and the AgNosCd-1 line achieved fixation in all multi-generation cage trial experiments at different release ratios of homozygous AgNosCd-1 to wild type males [29]. However, the AgTP13 homozygous males were ~22% less likely to contribute to the next generation than wild-type males in competition experiments and have a significantly reduced median lifespan than the hemizygous AgTP13 or the wild-type males. Despite the increased fitness burden in AgTP13 males, there was no increased fitness load on AgTP13 females [31]. Theoretical modeling supports the conclusion that given an appropriate drive mechanism, a gene-drive system could have a significant fitness cost and still be driven through the population [102, 103].
Ideally, GEMs should have no or minimal fitness costs to avoid reducing the effectiveness of the genetic drive mechanism that is used to introduce the synthetic construct into field mosquito populations and to maximize the likelihood of successfully introducing refractory genes into a wild population [98]. Several factors can impact the fitness, including the possible negative effect of the transgene products, insertional position effects (chromatin rearrangement and/or new regulatory element interactions/pressure), inbreeding, and to “leaky (low level constitutive) promoter expression”. GEMS can have different degrees of fitness cost and estimates of transgene fitness costs are essential for modeling and planning release strategies. However, it is clear that a robust drive system can compensate for reduced fitness.
The efficacy of population modification mosquito drive lines may be reduced by the presence of naturally-occurring cleavage-resistant allelic variants of the target site in wild populations or by such alleles generated through NHEJ during the Cas9/gRNA targeting and DNA repair processes. The latter may result from double-stranded DNA breaks necessary for drive that are occasionally repaired through NHEJ resulting in insertions or deletions at the target site, making them refractory to the drive system. Both the naturally-occurring and induced allelic variants have been called resistance alleles [104, 105, 106, 107]. The latter may arise in the germline and be passed on to subsequent generations or may be generated in somatic cells where they give rise to mosaic phenotypes [28, 29, 30]. Resistance alleles in the form of naturally-occurring mutations at the target site can be avoided by careful choice of the gene-drive target locus. Resistance alleles occurring because of NHEJ due to undesired Cas9 activity can be controlled by careful choice of the promoter used to induce Cas9 transcription.
Extensive analysis of suitable target loci must be performed prior to the creation of each proof-of-principle modification drive system. Loci must be chosen, in part, based on the minimization of naturally-present single nucleotide polymorphisms (SNPs) and overall conservation of the target site. Several SNPs in the AgNosCd-1
The pathways and frequency of resistance allele formation via undesired activity of the drive system was analyzed extensively for the AgNosCd-1 and AsMCRkh2 lines [29, 97]. Exceptional phenotype individuals (mosaics and LOF phenotypes) have been correlated to undesired Cas9 activity and possess indel mutations that would cause LOF in AgNosCd-1 and AsMCRkh2 lines. However, in contrast to the AgNosCd-1 drive system, the mosaic and LOF phenotypes made up the majority of the offspring (>99%) from AsMCRkh2 mothers [28]. The presence of mosaic and LOF phenotypes from female drive parents has been hypothesized to occur due to a maternal effect. The maternal effect is proposed to result from the accumulation of Cas9/gRNA complexes in the cytoplasm of embryos derived from mothers carrying the drive system, which perform cleavage on the paternally-donated allele during embryonic development. The differences in mosaic and LOF phenotypes observed in the progeny from AgNosCd-1 and AsMCRkh2 hemizygote females supports this hypothesis and this affect is higher in females with two copies (homozygous) of the drive system than those with one (hemizygous) [28, 29, 97]. In addition, the frequencies of such events are higher in the AsMCRkh2 line when compared to AgNosCd-1. These differences may result from the difference in the gene promoters used to express the Cas9 nuclease for each drive system,
As described previously, females homozygous for the drive system had a higher rate of resistance allele formation via maternal effect (~57% with mosaic phenotype and ~6% of progeny with LOF phenotype) than hemizygous females (~20% with mosaic phenotype and ~1% of progeny with LOF phenotype) but mosaic individuals were able to bias inheritance of the drive allele and had similar rates of drive efficiency when compared to AgNosCd-1 hemizygotes with wild-type eye phenotypes suggesting that the indels were primary somatic [29].
Suppression gene drive systems are much less flexible to drive-resistant alleles than population modification gene drive systems. Population modification mosquito lines can tolerate higher rates of drive-resistant alleles than population suppression mosquitoes, however, the former are still susceptible to instability and inability to achieve fixation in a population due to resistance alleles, especially if the drive system and respective cargo are associated with a significant fitness load [109]. Recent work suggests that suppression drive systems that incur a 100% fitness cost (death of females) would require a very low frequency of drive resistant alleles <5 × 10−7 in order to provide a 4–5-year window of protection, as opposed to population modification systems, which would provide a 4–5-year window of protection at a resistance allele frequency of 1%, given that fitness costs of the population modification strain are below 15% [109].
Multiplexed gene drives using additional gRNA target sites are expected to substantially decrease the likelihood of gene-drive resistant allele formation [110]. Practical ways to multiplex Cas9-based gene drives have been demonstrated using post-transcriptional processing of several gRNAs expressed from a single promoter, but these have not yet been applied to mosquitoes [110, 111, 112, 113].
The utility of CRISPR/Cas9 gene-drive systems may be affected by sequence similarity among gRNAs target and off-target sites in the mosquito genomes. Potential off-target sites can be predicted
The discovery, development, and deployment of CRISPR/Cas9 technologies is challenging due to the lack of an accepted pathway to move them from the laboratory to the field. The WHO released in 2014 the Guidance Framework for testing genetically modified (GM) mosquitoes (WHO Guidance Framework) describing a phased testing pathway and best practices to evaluate GEMs proposed as public health tools [120]. The Framework proposes a pathway to move from physically-confined studies in the laboratory/insectary (Phase 1) to a small-scale confined field-testing (Phase 2) that will lead to a staged open release trial (Phase 3). After successful completion of Phase 3, the national authorities in a malaria-endemic country will be responsible for determining if the tested GEMs can be included as part of their malaria control program and further deployment of the technology (Phase 4) [120]. However, pathways for moving gene-drive population modification mosquitoes to the field will be defined simultaneously with the laboratory work progress. As more CRISPR/Cas9 population modification gene-drive systems and strains are developed, new knowledge is being generated about the impact of introduced anti-parasite genes on the mosquitoes that carry them. Insight into genetic loads and their effects on fitness, generation of drive-resistant individuals as well as selection of resistant parasites and long-term stability of the system will emerge from these studies. The new empirical data generated is critical in the development of a phased pathway for further development and deployment. In 2018, James et al. published a series of recommendations that attempt to envision the development pathway for gene drive mosquitoes (from discovery to deployment) and to inform decision-making by regulators and policymakers [121]. They recognized that it is important to examine both the benefits and risks of this approach. Risk assessment will provide guidance on decision-making and information for the regulatory applications as well as for the development of mitigation plans, while cost-benefit analyses will compare the projected or estimated costs and benefits associated to the intervention. It also was recommended that these analyses be done by external third-party organizations or institutions with no interests in the success of the product and the outcomes of these analyses be made publicly available.
Any decision made to release gene-drive mosquitoes must be made on a case-by-case basis following a comprehensive environmental risk assessment [122], moreover, gene-drive population modification mosquitoes must meet the established Target Product Profile (TPP) criteria of safety and efficacy. A comprehensive draft TPP for gene-drive population modification mosquitoes was published providing the basis for evaluation of whether gene-drive mosquitoes should be made available for use [37]. Population modification TPPs will need to meet the efficacy and safety standards as well as the demands of different regulatory and social contexts. In addition, viable models for the inclusion of end-user and stakeholder involvement and control are absolutely needed before any such system can be brought to the field. We have favored the relationship-based model (RBM), which gives stakeholders and community key roles at the center of the decision-making processes [123]. It is important that open dialog and relationships with the scientists developing the technologies be established and that appropriate capacity-building take place to empower the communities affected by malaria to make informed decisions about the risk and use of the new technologies.
Population modification genetic control focuses on targeting the mosquito vector to interrupt the malaria transmission by introducing effector genes into the mosquito genome with the purpose of generating parasite-refractory mosquitoes.
Advances in gene-editing technologies using CRISPR/Cas9 gene drives have made available new possibilities for an efficient introduction of the desired genetic traits into mosquito populations. Gene drives represent a powerful tool to achieve genome editing in a species-specific targeted way with minimal infrastructure, are predicted to be self-sustaining and able to spread anti-parasite effectors to fixation.
Gene-drive systems for population modification of anopheline vector species to prevent transmission of parasites may play a future role in the malaria eradication agenda. Future steps will need to consider how to evaluate gene drives at large scale and evaluate their efficacy and robustness under more realistic ecological settings.
Challenges to such technologies are being addressed by scientists and regulators by development of pathways for their deployment and establishing acceptable efficacy and safety criteria. Importantly, the knowledge transfer process is being addressed in new models for public engagement that will further development, testing and eventual deployment of gene drives for malaria control.
Funding was provided by the University of California Irvine Malaria Initiative and ‘anonymous donor’. AAJ is a Donald Bren Professor at the University of California, Irvine.
The authors declare no conflict of interest.
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Two wind sensors will be included in the meteorological station MEDA because wind plays a very important role in Martian climate. High-quality wind data are required to build mathematical models of the Mars climate; therefore, powerful techniques are necessary to eliminate aerodynamic perturbations produced by the rover presence over wind measurements. This chapter is dedicated to the characterization of the aerodynamics around the Mars 2020 rover and its interaction with the rover Mars surface vehicle in order to get information to correct wind data coming from Mars.",book:{id:"8556",slug:"mars-exploration-a-step-forward",title:"Mars Exploration",fullTitle:"Mars Exploration - a Step Forward"},signatures:"Rafael Bardera, Suthyvann Sor and Adelaida García-Magariño",authors:[{id:"275076",title:"Dr.",name:"Suthyvann",middleName:null,surname:"Sor Mendi",slug:"suthyvann-sor-mendi",fullName:"Suthyvann Sor Mendi"},{id:"275078",title:"Dr.",name:"Rafael",middleName:null,surname:"Bardera",slug:"rafael-bardera",fullName:"Rafael Bardera"},{id:"313617",title:"Dr.",name:"Adelaida",middleName:null,surname:"García-Magariño",slug:"adelaida-garcia-magarino",fullName:"Adelaida García-Magariño"}]},{id:"67679",doi:"10.5772/intechopen.86728",title:"Oral Tissue Responses to Travel in Space",slug:"oral-tissue-responses-to-travel-in-space",totalDownloads:1071,totalCrossrefCites:1,totalDimensionsCites:1,abstract:"The oral cavity functions in taste, mastication, solubilization and digestion of nutrients, as well as in respiration and speech, and participates in innate and adaptive immunity. 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Second, the application of the autonomous navigation technology for the Mars exploration is presented. The corresponding issues in the Entry Descent and Landing (EDL) phase and the Mars surface roving phase are mainly discussed. Third, some challenges and development trends of the autonomous navigation technology are also addressed.",book:{id:"8556",slug:"mars-exploration-a-step-forward",title:"Mars Exploration",fullTitle:"Mars Exploration - a Step Forward"},signatures:"Haoting Liu",authors:[{id:"314772",title:"Associate Prof.",name:"Haoting",middleName:null,surname:"Liu",slug:"haoting-liu",fullName:"Haoting Liu"}]},{id:"70846",title:"Aerodynamics of Mars 2020 Rover Wind Sensors",slug:"aerodynamics-of-mars-2020-rover-wind-sensors",totalDownloads:720,totalCrossrefCites:1,totalDimensionsCites:1,abstract:"Environmental factors in Mars atmosphere are a part of the research issues of the future Mars 2020 mission. The new rover surface vehicle will transport different instruments to investigate the geology, biology, and meteorology of Mars. Amongst these instruments, the Mars Environmental Dynamics Analyzer (MEDA) will be dedicated to the measurement of environment parameters. Two wind sensors will be included in the meteorological station MEDA because wind plays a very important role in Martian climate. High-quality wind data are required to build mathematical models of the Mars climate; therefore, powerful techniques are necessary to eliminate aerodynamic perturbations produced by the rover presence over wind measurements. This chapter is dedicated to the characterization of the aerodynamics around the Mars 2020 rover and its interaction with the rover Mars surface vehicle in order to get information to correct wind data coming from Mars.",book:{id:"8556",slug:"mars-exploration-a-step-forward",title:"Mars Exploration",fullTitle:"Mars Exploration - a Step Forward"},signatures:"Rafael Bardera, Suthyvann Sor and Adelaida García-Magariño",authors:[{id:"275076",title:"Dr.",name:"Suthyvann",middleName:null,surname:"Sor Mendi",slug:"suthyvann-sor-mendi",fullName:"Suthyvann Sor Mendi"},{id:"275078",title:"Dr.",name:"Rafael",middleName:null,surname:"Bardera",slug:"rafael-bardera",fullName:"Rafael Bardera"},{id:"313617",title:"Dr.",name:"Adelaida",middleName:null,surname:"García-Magariño",slug:"adelaida-garcia-magarino",fullName:"Adelaida García-Magariño"}]},{id:"67679",title:"Oral Tissue Responses to Travel in Space",slug:"oral-tissue-responses-to-travel-in-space",totalDownloads:1071,totalCrossrefCites:1,totalDimensionsCites:1,abstract:"The oral cavity functions in taste, mastication, solubilization and digestion of nutrients, as well as in respiration and speech, and participates in innate and adaptive immunity. Saliva creates and regulates the environment of the oral cavity, and changes in its composition and rate of secretion have significant effects on oral tissues as well as on systemic health. The effects of microgravity on the salivary glands, mandible and teeth were studied in mice flown on US space shuttle STS-131 and STS-135 missions, and the Russian Bion-M1 biosatellite. Significant changes in morphology and secretory protein expression occurred in parotid glands; submandibular glands were affected only on the 30-day Bion-M1 mission, indicating tissue specificity of the effects due to changes in gravity which may be similar to those taking place in humans. Changes also occurred in mandibular bone and incisor teeth. 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Then we present a parametric analysis considering key design parameters such as interplanetary trajectory and vehicle design parameters (lift-to-drag ratio, ballistic coefficient, peak g-load, peak heat rate, and total heat load) for aerocapture, aerobraking, and entry. A new perspective on a rapid aerobraking concept will be provided. The analysis will include first-order estimates for thermal loading, thermal protection systems material selection, and vehicle design. 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He has more than 200 publications in reputed international journals, refereed conference proceedings, and 20 book chapters in books published by internationally renowned publishing houses, such as Springer, CRC press, IGI Global, etc. Currently, he is serving on the editorial board of the prestigious journal Frontiers in Communications and Networks and in the technical program committees of a number of high-ranked international conferences organized by the IEEE, USA, and the ACM, USA. 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Ms. Mehtab has published seven papers in international conferences and one of her papers has been accepted for publication in a reputable international journal. She has won the best paper awards in two prestigious international conferences – BAICONF 2019, and ICADCML 2021, organized in the Indian Institute of Management, Bangalore, India in December 2019, and SOA University, Bhubaneswar, India in January 2021. Besides, Ms. Mehtab has also published two book chapters in two books. Seven of her book chapters will be published in a volume shortly in 2021 by Cambridge Scholars’ Press, UK. Currently, she is working as the joint editor of two edited volumes on Time Series Analysis and Forecasting to be published in the first half of 2021 by an international house. Currently, she is working as a Data Scientist with an MNC in Delhi, India.",institutionString:"NSHM College of Management and Technology",institution:{name:"Association for Computing Machinery",country:{name:"United States of America"}}},{id:"226240",title:"Dr.",name:"Andri Irfan",middleName:null,surname:"Rifai",slug:"andri-irfan-rifai",fullName:"Andri Irfan Rifai",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/226240/images/7412_n.jpg",biography:"Andri IRFAN is a Senior Lecturer of Civil Engineering and Planning. He completed the PhD at the Universitas Indonesia & Universidade do Minho with Sandwich Program Scholarship from the Directorate General of Higher Education and LPDP scholarship. He has been teaching for more than 19 years and much active to applied his knowledge in the project construction in Indonesia. His research interest ranges from pavement management system to advanced data mining techniques for transportation engineering. He has published more than 50 papers in journals and 2 books.",institutionString:null,institution:{name:"Universitas Internasional Batam",country:{name:"Indonesia"}}},{id:"314576",title:"Dr.",name:"Ibai",middleName:null,surname:"Laña",slug:"ibai-lana",fullName:"Ibai Laña",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/314576/images/system/314576.jpg",biography:"Dr. Ibai Laña works at TECNALIA as a data analyst. He received his Ph.D. in Artificial Intelligence from the University of the Basque Country (UPV/EHU), Spain, in 2018. He is currently a senior researcher at TECNALIA. His research interests fall within the intersection of intelligent transportation systems, machine learning, traffic data analysis, and data science. He has dealt with urban traffic forecasting problems, applying machine learning models and evolutionary algorithms. He has experience in origin-destination matrix estimation or point of interest and trajectory detection. Working with large volumes of data has given him a good command of big data processing tools and NoSQL databases. He has also been a visiting scholar at the Knowledge Engineering and Discovery Research Institute, Auckland University of Technology.",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"314575",title:"Dr.",name:"Jesus",middleName:null,surname:"L. Lobo",slug:"jesus-l.-lobo",fullName:"Jesus L. Lobo",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/314575/images/system/314575.png",biography:"Dr. Jesús López is currently based in Bilbao (Spain) working at TECNALIA as Artificial Intelligence Research Scientist. In most cases, a project idea or a new research line needs to be investigated to see if it is good enough to take into production or to focus on it. That is exactly what he does, diving into Machine Learning algorithms and technologies to help TECNALIA to decide whether something is great in theory or will actually impact on the product or processes of its projects. So, he is expert at framing experiments, developing hypotheses, and proving whether they’re true or not, in order to investigate fundamental problems with a longer time horizon. He is also able to design and develop PoCs and system prototypes in simulation. He has participated in several national and internacional R&D projects.\n\nAs another relevant part of his everyday research work, he usually publishes his findings in reputed scientific refereed journals and international conferences, occasionally acting as reviewer and Programme Commitee member. Concretely, since 2018 he has published 9 JCR (8 Q1) journal papers, 9 conference papers (e.g. ECML PKDD 2021), and he has co-edited a book. He is also active in popular science writing data science stories for reputed blogs (KDNuggets, TowardsDataScience, Naukas). Besides, he has recently embarked on mentoring programmes as mentor, and has also worked as data science trainer.",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"103779",title:"Prof.",name:"Yalcin",middleName:null,surname:"Isler",slug:"yalcin-isler",fullName:"Yalcin Isler",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRyQ8QAK/Profile_Picture_1628834958734",biography:"Yalcin Isler (1971 - Burdur / Turkey) received the B.Sc. degree in the Department of Electrical and Electronics Engineering from Anadolu University, Eskisehir, Turkey, in 1993, the M.Sc. degree from the Department of Electronics and Communication Engineering, Suleyman Demirel University, Isparta, Turkey, in 1996, the Ph.D. degree from the Department of Electrical and Electronics Engineering, Dokuz Eylul University, Izmir, Turkey, in 2009, and the Competence of Associate Professorship from the Turkish Interuniversity Council in 2019.\n\nHe was Lecturer at Burdur Vocational School in Suleyman Demirel University (1993-2000, Burdur / Turkey), Software Engineer (2000-2002, Izmir / Turkey), Research Assistant in Bulent Ecevit University (2002-2003, Zonguldak / Turkey), Research Assistant in Dokuz Eylul University (2003-2010, Izmir / Turkey), Assistant Professor at the Department of Electrical and Electronics Engineering in Bulent Ecevit University (2010-2012, Zonguldak / Turkey), Assistant Professor at the Department of Biomedical Engineering in Izmir Katip Celebi University (2012-2019, Izmir / Turkey). He is an Associate Professor at the Department of Biomedical Engineering at Izmir Katip Celebi University, Izmir / Turkey, since 2019. In addition to academics, he has also founded Islerya Medical and Information Technologies Company, Izmir / Turkey, since 2017.\n\nHis main research interests cover biomedical signal processing, pattern recognition, medical device design, programming, and embedded systems. He has many scientific papers and participated in several projects in these study fields. He was an IEEE Student Member (2009-2011) and IEEE Member (2011-2014) and has been IEEE Senior Member since 2014.",institutionString:null,institution:{name:"Izmir Kâtip Çelebi University",country:{name:"Turkey"}}},{id:"339677",title:"Dr.",name:"Mrinmoy",middleName:null,surname:"Roy",slug:"mrinmoy-roy",fullName:"Mrinmoy Roy",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/339677/images/16768_n.jpg",biography:"An accomplished Sales & Marketing professional with 12 years of cross-functional experience in well-known organisations such as CIPLA, LUPIN, GLENMARK, ASTRAZENECA across different segment of Sales & Marketing, International Business, Institutional Business, Product Management, Strategic Marketing of HIV, Oncology, Derma, Respiratory, Anti-Diabetic, Nutraceutical & Stomatological Product Portfolio and Generic as well as Chronic Critical Care Portfolio. A First Class MBA in International Business & Strategic Marketing, B.Pharm, D.Pharm, Google Certified Digital Marketing Professional. Qualified PhD Candidate in Operations and Management with special focus on Artificial Intelligence and Machine Learning adoption, analysis and use in Healthcare, Hospital & Pharma Domain. Seasoned with diverse therapy area of Pharmaceutical Sales & Marketing ranging from generating revenue through generating prescriptions, launching new products, and making them big brands with continuous strategy execution at the Physician and Patients level. Moved from Sales to Marketing and Business Development for 3.5 years in South East Asian Market operating from Manila, Philippines. Came back to India and handled and developed Brands such as Gluconorm, Lupisulin, Supracal, Absolut Woman, Hemozink, Fabiflu (For COVID 19), and many more. In my previous assignment I used to develop and execute strategies on Sales & Marketing, Commercialization & Business Development for Institution and Corporate Hospital Business portfolio of Oncology Therapy Area for AstraZeneca Pharma India Ltd. Being a Research Scholar and Student of ‘Operations Research & Management: Artificial Intelligence’ I published several pioneer research papers and book chapters on the same in Internationally reputed journals and Books indexed in Scopus, Springer and Ei Compendex, Google Scholar etc. Currently, I am launching PGDM Pharmaceutical Management Program in IIHMR Bangalore and spearheading the course curriculum and structure of the same. I am interested in Collaboration for Healthcare Innovation, Pharma AI Innovation, Future trend in Marketing and Management with incubation on Healthcare, Healthcare IT startups, AI-ML Modelling and Healthcare Algorithm based training module development. I am also an affiliated member of the Institute of Management Consultant of India, looking forward to Healthcare, Healthcare IT and Innovation, Pharma and Hospital Management Consulting works.",institutionString:null,institution:{name:"Lovely Professional University",country:{name:"India"}}},{id:"310576",title:"Prof.",name:"Erick Giovani",middleName:null,surname:"Sperandio Nascimento",slug:"erick-giovani-sperandio-nascimento",fullName:"Erick Giovani Sperandio Nascimento",position:null,profilePictureURL:"https://intech-files.s3.amazonaws.com/0033Y00002pDKxDQAW/ProfilePicture%202022-06-20%2019%3A57%3A24.788",biography:"Prof. Erick Sperandio is the Lead Researcher and professor of Artificial Intelligence (AI) at SENAI CIMATEC, Bahia, Brazil, also working with Computational Modeling (CM) and HPC. He holds a PhD in Environmental Engineering in the area of Atmospheric Computational Modeling, a Master in Informatics in the field of Computational Intelligence and Graduated in Computer Science from UFES. He currently coordinates, leads and participates in R&D projects in the areas of AI, computational modeling and supercomputing applied to different areas such as Oil and Gas, Health, Advanced Manufacturing, Renewable Energies and Atmospheric Sciences, advising undergraduate, master's and doctoral students. He is the Lead Researcher at SENAI CIMATEC's Reference Center on Artificial Intelligence. In addition, he is a Certified Instructor and University Ambassador of the NVIDIA Deep Learning Institute (DLI) in the areas of Deep Learning, Computer Vision, Natural Language Processing and Recommender Systems, and Principal Investigator of the NVIDIA/CIMATEC AI Joint Lab, the first in Latin America within the NVIDIA AI Technology Center (NVAITC) worldwide program. He also works as a researcher at the Supercomputing Center for Industrial Innovation (CS2i) and at the SENAI Institute of Innovation for Automation (ISI Automação), both from SENAI CIMATEC. He is a member and vice-coordinator of the Basic Board of Scientific-Technological Advice and Evaluation, in the area of Innovation, of the Foundation for Research Support of the State of Bahia (FAPESB). He serves as Technology Transfer Coordinator and one of the Principal Investigators at the National Applied Research Center in Artificial Intelligence (CPA-IA) of SENAI CIMATEC, focusing on Industry, being one of the six CPA-IA in Brazil approved by MCTI / FAPESP / CGI.br. He also participates as one of the representatives of Brazil in the BRICS Innovation Collaboration Working Group on HPC, ICT and AI. He is the coordinator of the Work Group of the Axis 5 - Workforce and Training - of the Brazilian Strategy for Artificial Intelligence (EBIA), and member of the MCTI/EMBRAPII AI Innovation Network Training Committee. He is the coordinator, by SENAI CIMATEC, of the Artificial Intelligence Reference Network of the State of Bahia (REDE BAH.IA). He leads the working group of experts representing Brazil in the Global Partnership on Artificial Intelligence (GPAI), on the theme \"AI and the Pandemic Response\".",institutionString:"Manufacturing and Technology Integrated Campus – SENAI CIMATEC",institution:null},{id:"1063",title:"Prof.",name:"Constantin",middleName:null,surname:"Volosencu",slug:"constantin-volosencu",fullName:"Constantin Volosencu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/1063/images/system/1063.png",biography:"Prof. Dr. Constantin Voloşencu graduated as an engineer from\nPolitehnica University of Timișoara, Romania, where he also\nobtained a doctorate degree. He is currently a full professor in\nthe Department of Automation and Applied Informatics at the\nsame university. Dr. Voloşencu is the author of ten books, seven\nbook chapters, and more than 160 papers published in journals\nand conference proceedings. He has also edited twelve books and\nhas twenty-seven patents to his name. He is a manager of research grants, editor in\nchief and member of international journal editorial boards, a former plenary speaker, a member of scientific committees, and chair at international conferences. His\nresearch is in the fields of control systems, control of electric drives, fuzzy control\nsystems, neural network applications, fault detection and diagnosis, sensor network\napplications, monitoring of distributed parameter systems, and power ultrasound\napplications. He has developed automation equipment for machine tools, spooling\nmachines, high-power ultrasound processes, and more.",institutionString:'"Politechnica" University Timişoara',institution:null},{id:"221364",title:"Dr.",name:"Eneko",middleName:null,surname:"Osaba",slug:"eneko-osaba",fullName:"Eneko Osaba",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/221364/images/system/221364.jpg",biography:"Dr. Eneko Osaba works at TECNALIA as a senior researcher. He obtained his Ph.D. in Artificial Intelligence in 2015. He has participated in more than twenty-five local and European research projects, and in the publication of more than 130 papers. He has performed several stays at universities in the United Kingdom, Italy, and Malta. Dr. Osaba has served as a program committee member in more than forty international conferences and participated in organizing activities in more than ten international conferences. He is a member of the editorial board of the International Journal of Artificial Intelligence, Data in Brief, and Journal of Advanced Transportation. He is also a guest editor for the Journal of Computational Science, Neurocomputing, Swarm, and Evolutionary Computation and IEEE ITS Magazine.",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"275829",title:"Dr.",name:"Esther",middleName:null,surname:"Villar-Rodriguez",slug:"esther-villar-rodriguez",fullName:"Esther Villar-Rodriguez",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/275829/images/system/275829.jpg",biography:"Dr. Esther Villar obtained a Ph.D. in Information and Communication Technologies from the University of Alcalá, Spain, in 2015. She obtained a degree in Computer Science from the University of Deusto, Spain, in 2010, and an MSc in Computer Languages and Systems from the National University of Distance Education, Spain, in 2012. Her areas of interest and knowledge include natural language processing (NLP), detection of impersonation in social networks, semantic web, and machine learning. Dr. Esther Villar made several contributions at conferences and publishing in various journals in those fields. Currently, she is working within the OPTIMA (Optimization Modeling & Analytics) business of TECNALIA’s ICT Division as a data scientist in projects related to the prediction and optimization of management and industrial processes (resource planning, energy efficiency, etc).",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"49813",title:"Dr.",name:"Javier",middleName:null,surname:"Del Ser",slug:"javier-del-ser",fullName:"Javier Del Ser",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/49813/images/system/49813.png",biography:"Prof. Dr. Javier Del Ser received his first PhD in Telecommunication Engineering (Cum Laude) from the University of Navarra, Spain, in 2006, and a second PhD in Computational Intelligence (Summa Cum Laude) from the University of Alcala, Spain, in 2013. He is currently a principal researcher in data analytics and optimisation at TECNALIA (Spain), a visiting fellow at the Basque Center for Applied Mathematics (BCAM) and a part-time lecturer at the University of the Basque Country (UPV/EHU). His research interests gravitate on the use of descriptive, prescriptive and predictive algorithms for data mining and optimization in a diverse range of application fields such as Energy, Transport, Telecommunications, Health and Industry, among others. In these fields he has published more than 240 articles, co-supervised 8 Ph.D. theses, edited 6 books, coauthored 7 patents and participated/led more than 40 research projects. He is a Senior Member of the IEEE, and a recipient of the Biscay Talent prize for his academic career.",institutionString:"Tecnalia Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"278948",title:"Dr.",name:"Carlos Pedro",middleName:null,surname:"Gonçalves",slug:"carlos-pedro-goncalves",fullName:"Carlos Pedro Gonçalves",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRcmyQAC/Profile_Picture_1564224512145",biography:'Carlos Pedro Gonçalves (PhD) is an Associate Professor at Lusophone University of Humanities and Technologies and a researcher on Complexity Sciences, Quantum Technologies, Artificial Intelligence, Strategic Studies, Studies in Intelligence and Security, FinTech and Financial Risk Modeling. He is also a progammer with programming experience in:\n\nA) Quantum Computing using Qiskit Python module and IBM Quantum Experience Platform, with software developed on the simulation of Quantum Artificial Neural Networks and Quantum Cybersecurity;\n\nB) Artificial Intelligence and Machine learning programming in Python;\n\nC) Artificial Intelligence, Multiagent Systems Modeling and System Dynamics Modeling in Netlogo, with models developed in the areas of Chaos Theory, Econophysics, Artificial Intelligence, Classical and Quantum Complex Systems Science, with the Econophysics models having been cited worldwide and incorporated in PhD programs by different Universities.\n\nReceived an Arctic Code Vault Contributor status by GitHub, due to having developed open source software preserved in the \\"Arctic Code Vault\\" for future generations (https://archiveprogram.github.com/arctic-vault/), with the Strategy Analyzer A.I. module for decision making support (based on his PhD thesis, used in his Classes on Decision Making and in Strategic Intelligence Consulting Activities) and QNeural Python Quantum Neural Network simulator also preserved in the \\"Arctic Code Vault\\", for access to these software modules see: https://github.com/cpgoncalves. He is also a peer reviewer with outsanding review status from Elsevier journals, including Physica A, Neurocomputing and Engineering Applications of Artificial Intelligence. Science CV available at: https://www.cienciavitae.pt//pt/8E1C-A8B3-78C5 and ORCID: https://orcid.org/0000-0002-0298-3974',institutionString:"University of Lisbon",institution:{name:"Universidade Lusófona",country:{name:"Portugal"}}},{id:"241400",title:"Prof.",name:"Mohammed",middleName:null,surname:"Bsiss",slug:"mohammed-bsiss",fullName:"Mohammed Bsiss",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/241400/images/8062_n.jpg",biography:null,institutionString:null,institution:null},{id:"276128",title:"Dr.",name:"Hira",middleName:null,surname:"Fatima",slug:"hira-fatima",fullName:"Hira Fatima",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/276128/images/14420_n.jpg",biography:"Dr. Hira Fatima\nAssistant Professor\nDepartment of Mathematics\nInstitute of Applied Science\nMangalayatan University, Aligarh\nMobile: no : 8532041179\nhirafatima2014@gmal.com\n\nDr. Hira Fatima has received his Ph.D. degree in pure Mathematics from Aligarh Muslim University, Aligarh India. Currently working as an Assistant Professor in the Department of Mathematics, Institute of Applied Science, Mangalayatan University, Aligarh. She taught so many courses of Mathematics of UG and PG level. Her research Area of Expertise is Functional Analysis & Sequence Spaces. She has been working on Ideal Convergence of double sequence. She has published 17 research papers in National and International Journals including Cogent Mathematics, Filomat, Journal of Intelligent and Fuzzy Systems, Advances in Difference Equations, Journal of Mathematical Analysis, Journal of Mathematical & Computer Science etc. She has also reviewed few research papers for the and international journals. She is a member of Indian Mathematical Society.",institutionString:null,institution:null},{id:"414880",title:"Dr.",name:"Maryam",middleName:null,surname:"Vatankhah",slug:"maryam-vatankhah",fullName:"Maryam Vatankhah",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Borough of Manhattan Community College",country:{name:"United States of America"}}},{id:"414879",title:"Prof.",name:"Mohammad-Reza",middleName:null,surname:"Akbarzadeh-Totonchi",slug:"mohammad-reza-akbarzadeh-totonchi",fullName:"Mohammad-Reza Akbarzadeh-Totonchi",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Ferdowsi University of Mashhad",country:{name:"Iran"}}},{id:"414878",title:"Prof.",name:"Reza",middleName:null,surname:"Fazel-Rezai",slug:"reza-fazel-rezai",fullName:"Reza Fazel-Rezai",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"American Public University System",country:{name:"United States of America"}}},{id:"426586",title:"Dr.",name:"Oladunni A.",middleName:null,surname:"Daramola",slug:"oladunni-a.-daramola",fullName:"Oladunni A. Daramola",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Federal University of Technology",country:{name:"Nigeria"}}},{id:"357014",title:"Prof.",name:"Leon",middleName:null,surname:"Bobrowski",slug:"leon-bobrowski",fullName:"Leon Bobrowski",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Bialystok University of Technology",country:{name:"Poland"}}},{id:"302698",title:"Dr.",name:"Yao",middleName:null,surname:"Shan",slug:"yao-shan",fullName:"Yao Shan",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Dalian University of Technology",country:{name:"China"}}},{id:"354126",title:"Dr.",name:"Setiawan",middleName:null,surname:"Hadi",slug:"setiawan-hadi",fullName:"Setiawan Hadi",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Padjadjaran University",country:{name:"Indonesia"}}},{id:"125911",title:"Prof.",name:"Jia-Ching",middleName:null,surname:"Wang",slug:"jia-ching-wang",fullName:"Jia-Ching Wang",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"National Central University",country:{name:"Taiwan"}}},{id:"332603",title:"Prof.",name:"Kumar S.",middleName:null,surname:"Ray",slug:"kumar-s.-ray",fullName:"Kumar S. Ray",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Indian Statistical Institute",country:{name:"India"}}},{id:"415409",title:"Prof.",name:"Maghsoud",middleName:null,surname:"Amiri",slug:"maghsoud-amiri",fullName:"Maghsoud Amiri",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Allameh Tabataba'i University",country:{name:"Iran"}}},{id:"357085",title:"Mr.",name:"P. Mohan",middleName:null,surname:"Anand",slug:"p.-mohan-anand",fullName:"P. Mohan Anand",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Indian Institute of Technology Kanpur",country:{name:"India"}}},{id:"356696",title:"Ph.D. Student",name:"P.V.",middleName:null,surname:"Sai Charan",slug:"p.v.-sai-charan",fullName:"P.V. Sai Charan",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Indian Institute of Technology Kanpur",country:{name:"India"}}},{id:"357086",title:"Prof.",name:"Sandeep K.",middleName:null,surname:"Shukla",slug:"sandeep-k.-shukla",fullName:"Sandeep K. Shukla",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Indian Institute of Technology Kanpur",country:{name:"India"}}}]}},subseries:{item:{id:"87",type:"subseries",title:"Economics",keywords:"Globalization, Economic Integration, Growth and Development, International Trade, Environmental Development, Developed Countries, Developing Countries, Technical Innovation, Knowledge Management, Political Economy Analysis, Banking and Financial Markets",scope:"
\r\n\tThe topic on Economics is designed to disseminate knowledge around broad global economic issues. Original submissions will be accepted in English for applied and theoretical articles, case studies and reviews about the specific challenges and opportunities faced by the economies and markets around the world. The authors are encouraged to apply rigorous economic analysis with significant policy implications for developed and developing countries. Examples of subjects of interest will include, but are not limited to globalization, economic integration, growth and development, international trade, environmental development, country specific comparative analysis, technical innovation and knowledge management, political economy analysis, and banking and financial markets.
",coverUrl:"https://cdn.intechopen.com/series_topics/covers/87.jpg",hasOnlineFirst:!1,hasPublishedBooks:!1,annualVolume:11971,editor:{id:"327730",title:"Prof.",name:"Jaime",middleName:null,surname:"Ortiz",slug:"jaime-ortiz",fullName:"Jaime Ortiz",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00002zaOKZQA2/Profile_Picture_1642145584421",biography:"Dr. Jaime Ortiz holds degrees from Chile, the Netherlands, and the United States. He has held tenured faculty, distinguished professorship, and executive leadership appointments in several universities around the world. Dr. Ortiz has previously worked for international organizations and non-government entities in economic and business matters, and he has university-wide globalization engagement in more than thirty-six countries. 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Possible contributions can address (but are not limited to) the following research topics: Bioinspired design and control of exoskeletons, orthoses, and prostheses; Experimental evaluation of the effect of assistive devices (e.g., influence on gait, balance, and neuromuscular system); Bioinspired technologies for rehabilitation, including clinical studies reporting evaluations; Application of neuromuscular and biomechanical models to the development of bioinspired technology.',annualVolume:11404,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/8.jpg",editor:{id:"144937",title:"Prof.",name:"Adriano",middleName:"De Oliveira",surname:"Andrade",fullName:"Adriano Andrade",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRC8QQAW/Profile_Picture_1625219101815",institutionString:null,institution:{name:"Federal University of Uberlândia",institutionURL:null,country:{name:"Brazil"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"49517",title:"Prof.",name:"Hitoshi",middleName:null,surname:"Tsunashima",fullName:"Hitoshi Tsunashima",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYTP4QAO/Profile_Picture_1625819726528",institutionString:null,institution:{name:"Nihon University",institutionURL:null,country:{name:"Japan"}}},{id:"425354",title:"Dr.",name:"Marcus",middleName:"Fraga",surname:"Vieira",fullName:"Marcus Vieira",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00003BJSgIQAX/Profile_Picture_1627904687309",institutionString:null,institution:{name:"Universidade Federal de Goiás",institutionURL:null,country:{name:"Brazil"}}},{id:"196746",title:"Dr.",name:"Ramana",middleName:null,surname:"Vinjamuri",fullName:"Ramana Vinjamuri",profilePictureURL:"https://mts.intechopen.com/storage/users/196746/images/system/196746.jpeg",institutionString:"University of Maryland, Baltimore County",institution:{name:"University of Maryland, Baltimore County",institutionURL:null,country:{name:"United States of America"}}}]},{id:"9",title:"Biotechnology - Biosensors, Biomaterials and Tissue Engineering",keywords:"Biotechnology, Biosensors, Biomaterials, Tissue Engineering",scope:"The Biotechnology - Biosensors, Biomaterials and Tissue Engineering topic within the Biomedical Engineering Series aims to rapidly publish contributions on all aspects of biotechnology, biosensors, biomaterial and tissue engineering. We encourage the submission of manuscripts that provide novel and mechanistic insights that report significant advances in the fields. Topics can include but are not limited to: Biotechnology such as biotechnological products and process engineering; Biotechnologically relevant enzymes and proteins; Bioenergy and biofuels; Applied genetics and molecular biotechnology; Genomics, transcriptomics, proteomics; Applied microbial and cell physiology; Environmental biotechnology; Methods and protocols. Moreover, topics in biosensor technology, like sensors that incorporate enzymes, antibodies, nucleic acids, whole cells, tissues and organelles, and other biological or biologically inspired components will be considered, and topics exploring transducers, including those based on electrochemical and optical piezoelectric, thermal, magnetic, and micromechanical elements. Chapters exploring biomaterial approaches such as polymer synthesis and characterization, drug and gene vector design, biocompatibility, immunology and toxicology, and self-assembly at the nanoscale, are welcome. Finally, the tissue engineering subcategory will support topics such as the fundamentals of stem cells and progenitor cells and their proliferation, differentiation, bioreactors for three-dimensional culture and studies of phenotypic changes, stem and progenitor cells, both short and long term, ex vivo and in vivo implantation both in preclinical models and also in clinical trials.",annualVolume:11405,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/9.jpg",editor:{id:"126286",title:"Dr.",name:"Luis",middleName:"Jesús",surname:"Villarreal-Gómez",fullName:"Luis Villarreal-Gómez",profilePictureURL:"https://mts.intechopen.com/storage/users/126286/images/system/126286.jpg",institutionString:null,institution:{name:"Autonomous University of Baja California",institutionURL:null,country:{name:"Mexico"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"35539",title:"Dr.",name:"Cecilia",middleName:null,surname:"Cristea",fullName:"Cecilia Cristea",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYQ65QAG/Profile_Picture_1621007741527",institutionString:null,institution:{name:"Iuliu Hațieganu University of Medicine and Pharmacy",institutionURL:null,country:{name:"Romania"}}},{id:"40735",title:"Dr.",name:"Gil",middleName:"Alberto Batista",surname:"Gonçalves",fullName:"Gil Gonçalves",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYRLGQA4/Profile_Picture_1628492612759",institutionString:null,institution:{name:"University of Aveiro",institutionURL:null,country:{name:"Portugal"}}},{id:"211725",title:"Associate Prof.",name:"Johann F.",middleName:null,surname:"Osma",fullName:"Johann F. 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