Ligand information, CID number, and reference of 47 drugs with potential activity against the SARS-CoV-2 viral cycle.
\r\n\t
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Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3092",title:"Anopheles mosquitoes",subtitle:"New insights into malaria vectors",isOpenForSubmission:!1,hash:"c9e622485316d5e296288bf24d2b0d64",slug:"anopheles-mosquitoes-new-insights-into-malaria-vectors",bookSignature:"Sylvie Manguin",coverURL:"https://cdn.intechopen.com/books/images_new/3092.jpg",editedByType:"Edited by",editors:[{id:"50017",title:"Prof.",name:"Sylvie",surname:"Manguin",slug:"sylvie-manguin",fullName:"Sylvie Manguin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"72",title:"Ionic Liquids",subtitle:"Theory, Properties, New Approaches",isOpenForSubmission:!1,hash:"d94ffa3cfa10505e3b1d676d46fcd3f5",slug:"ionic-liquids-theory-properties-new-approaches",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/72.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"2270",title:"Fourier Transform",subtitle:"Materials Analysis",isOpenForSubmission:!1,hash:"5e094b066da527193e878e160b4772af",slug:"fourier-transform-materials-analysis",bookSignature:"Salih Mohammed Salih",coverURL:"https://cdn.intechopen.com/books/images_new/2270.jpg",editedByType:"Edited by",editors:[{id:"111691",title:"Dr.Ing.",name:"Salih",surname:"Salih",slug:"salih-salih",fullName:"Salih Salih"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"59742",title:"Advanced Technologies in Manufacturing 3D-Layered Structures for Defense and Aerospace",doi:"10.5772/intechopen.74331",slug:"advanced-technologies-in-manufacturing-3d-layered-structures-for-defense-and-aerospace",body:'It was back in the late 1960s, when the creation of solid objects using photopolymerized resins was attempted, by employing a laser. The attempt took place at the Battelle Memorial Institute in Columbus, Ohio, USA [1]. During this pioneering experiment, two laser beams with non-similar wavelengths were pointed to intersect in the middle of a transparent container filled with of resin. Inside the vat of resin (usual term nowadays), the polymer crosslinked and solidified at the point where the laser beams intersected. DuPont had already made available the photopolymerization of resins as a technology in the 1950s. Quite similar to this approach, Swainson filed a patent titled “
According to many sources, Hideo Kodama, working at the Nagoya Municipal Industrial Research Institute (Nagoya, Japan), was one of the first to invent the single-beam laser curing approach, In mid-1980, he filed a patent in Japan, which unfortunately expired without proceeding to the examination stage, this being a requirement of the Japanese patent application procedure. Kodama apparently had obstacles in securing funds for additional research and development. In 1981, he published a paper titled “
The real market-available additive manufacturing, however, first saw light in 1987 with stereolithography (SL) from 3D Systems. Their process involved solidification of thin layers of light-sensitive liquid resin polymer using a UV-laser beam. They marketed their SLA-1, being the first commercially available AM machine worldwide. This system was the precursor of the SLA 250 machine, which became a commercial success (SLA acronym means Stereo-Lithography-Apparatus). SLA 250 was replaced by Viper SLA, and nowadays replaced by the ProJet series of SLA Printers.
A year later, in 1988, 3D Systems and Ciba-Geigy formed a partnership aiming at the development of stereolithography materials and marketed their first-generation acrylate resins. DuPont developed its stereolithography system named Somos along with proper resins in the same year. Loctite had also attempted to enter the SL resins market in the late 1980s, but closed the corresponding department in 1993.
Japan’s NTT Data CMET and Sony/D-MEC commercialized versions of stereolithography in 1988 and 1989, as an answer to 3D Systems SL in the U.S. NTT Data CMET (now a part of Teijin Seiki, a subsidiary of Nabtesco) called its machine Solid Object Ultraviolet Plotter (SOUP) and Sony/D-MEC (now D-MEC) called its device Solid Creation System (SCS). Sony closed its production for SL systems for D-MEC in 2007. In 1988, Asahi Denka Kogyo introduced the first epoxy resin for the CMET SL machine. In 1989, Japan Synthetic Rubber (now JSR Corp.) and DSM Desotech started to supply polymers for the Sony/D-MEC stereolithography machines.
In 1990, Electro Optical Systems (EOS) based in Germany sold its first Stereos stereolithography system. The same year, Quadrax introduced the Mark 1000 SL system, which employed visible light resin. The following year, Imperial Chemical Industries introduced a visible light resin product for the Mark 1000. ICI stopped selling its resin about 1 year later when Quadrax dissolved due legal issues with 3D Systems.
Back in 1991, three AM technologies were made available to the market, e.g., fused deposition modeling (FDM) as coined by Stratasys, solid ground curing (SGC) marketed by Cubital, and as mentioned above, laminated object manufacturing (LOM) by Helisys. FDM utilizes molten thermoplastic polymers in the form of a filament to structure an object in a layer-by-layer fashion. In SGC, a UV-sensitive liquid polymer is used, and each complete layer solidifies in each laser scan by ample UV light which passes through masks created using an electrostatic toner on a glass plate. LOM cut sheet material using a digitally guided laser and bonds the stacked layers together into a 3D object. Cubital and Helisys are not in the market anymore. Selective laser sintering (SLS) from DTM (now a part of 3D Systems) and the Soliform stereolithography system from Teijin Seiki became available in 1992. Using laser as an extreme heat source, SLS sinters powder materials by local fusion. DuPont had developed the Soliform technology originally, under the name Somos and licensed it to Teijin Seiki. The latter company had the exclusive distribution rights in parts of East Asia. Also, in the same year, a company called Allied Signal marketed vinylether Exactomer resin polymers for SL applications. In the next year, Soligen of Germany presented a device under the name direct shell production casting (DSPC). DSPC employed an inkjet printer mechanism, which deposited liquid binder onto ceramic powder. In this way, shells were formed for later use in the investment-casting procedure. The patent Soligen used was filed by the Massachusetts Institute of Technology (MIT). In January 2006, Solingen stopped its production of DSPC systems. That year, Denken marketed an SL system that featured a solid-state laser. It should be mentioned here that Denken’s SL system was presumably, compact enough, to sit on a bench top. Moreover, it was also given away at a relatively low price, compared to other SL systems available in the market. In 1993, 3D Systems and Ciba made their first epoxy resin product for SLA, commercially available. In the same period, the QuickCast structuring scheme was presented. QuickCast, still used to-date, is a process in which hollow investment-casting molds are produced. After casting, the polymer mold would burn out, without damaging the fragile ceramic shell. In 1994, many new additive manufacturing systems found their way into the markets. ModelMaker from Solidscape (then called Sanders Prototype) was delivered, as many new systems from Japanese and European firms did. By making use of an inkjet print head, ModelMaker had the ability to deposit waxy materials layer, by layer. Aiming at a new market sector, namely jewelry makers, Meiko in Japan produced a novel small stereolithography device. Meiko is no more in the SL sector since 2006. Also, in Japan, KiraCorp. marketed its first non-stereolithographic device. The device called Solid Center was actually a complete LOM system featuring a typical laserprinter engine, toner, an x-y plotter, and knife; it was able to produce wood-like models by paper lamination. Kira referred to Solid Center as the first plain-paper 3D printer. In the same year 1994, Fockele & Schwarze (F&S) in Germany introduced a stereolithography machine, but on a limited basis, and a German company named EOS commercialized a printer called EOSINT based on laser-sintering technology. Ushio from Japan (Unirapid Inc. nowadays) sold its first stereolithography machine in 1995.
In 1996, Stratasys introduced the Genisys machine. This type of printer utilized an extrusion process similar to FDM, however, based on technology developed at IBM’s Watson Research Center. Being a decade almost in the market of stereolithography systems, 3D Systems offered to the market its first 3D printer (Actua 2100) in 1996, using a technology that deposits waxy materials in a layer after layer fashion, utilizing an inkjet-printing mechanism. In the same year, a company called Z Corp. marketed its Z402 modeling 3D printer, aiming at conceptual use. The Z402 machine profited from MIT’s inkjet-printing (3DP) technology, and models were manufactured using starch- or plaster-based powders and a water-soluble liquid binder. Also in 1996, Schroff Development started to offer to the market its semi-automated paper lamination system below the threshold of $10,000. BPM Technology begun to sell its Personal Modeler 2100 model in 1996 too. By employing a process named ballistic particle manufacturing (BPM), the machine could deposit waxy material layers by use of an inkjet-printing head. The company ceased operations in October 1997. Kinergy based in Singapore started selling its Zippy paper lamination systems, which worked much alike as the LOM process. AeroMet founded in 1997 was a subsidiary of MTS Systems Corp. This company developed a procedure called laser additive manufacturing (LAM) that employed a high-power laser and titanium alloys in the form of powder. Until it stopped operations in December 2005, AeroMet was a 3D printed parts subcontractor for the aerospace industry. That year, Ciba acquired the Exactomer resins business from Allied Signal. In 1998, Yinhua Laser Rapid Prototypes Making & Mould Technology Co., Ltd. based in Beijing-China, intensively pursued the marketing of its products. Not by chance, Tsinghua University in Beijing, being the original developer of these systems, has developed processes much alike to FDM and other additive manufacturing technologies, since 1996. Autostrade started to market a stereolithography system called E-DARTS to firms in Japan at prices no higher than $25,000, in the same year. Also in 1998, Optomec made available to the industry its laser-engineered net shaping (LENS) metal powder system. The machine was based on the technology developed at Sandia National Labs. From that point, the markets begin to open even more and also the international demand for such systems. In March 1999, 3D Systems introduced a machine called ThermoJet, a much faster and less costly version of Actua 2100. At that time, 3D Systems was selling its SLA 7000 system for $800,000, which was the most expensive AM system for plastic materials, available worldwide. In April 1999, on demand by Motorola, a company under the name Extrude Hone AM business (nowadays named Ex One) installed its first ProMetal RTS-300 system, for building metal parts. The machine was utilizing MIT’s 3DP inkjet-printing technology. In 1999, Fockele & Schwarze based in Germany, revealed its selective laser-melting system for steel-based powders. This system was developed in cooperation with the Fraunhofer Institute for Laser Technology, in Aachen. The same Institute provided know-how for Röders, who developed and sold its controlled metal buildup (CMB) machine. Also, in 1999, DSM acquired the Somos branch from DuPont. In January 2000, Helisys announced that Toyoda Machine Works of Japan would manufacture and sell LOM systems in Japan. In June 2000, Toyoda exhibited its proprietary machine based on LOM technology, at a technology fair in Tokyo. Sanders Design International proclaimed the development of a system named Rapid Tool Maker (RTM) in January 2000, and they also announced that it had licensed the RTM technology to a German company called Buss Modeling Technology (BMT). BMT, which was formerly Buss Müller Technology, had the strategic plan to manufacture RTM systems and provide it to the European markets. At that time, BMT announced manufacturing and marketing a color 3D printer based on powder and binder technology, developed by Aad van der Geest of the Netherlands. The process was quite similar to the 3DP process from Z Corp.
Since the beginning of the first decade of the new century, many systems are available in the market for producing layered structures, now under the name 3D printed structures utilizing the prevailing technologies as described above in summary and in the following chapters in detail. Nowadays, many affordable systems are available in the open market, even as DIY kits, for applications in almost all industrial sectors as well as for hobby and recreation as it will be shown.
Up to year 2009, layering technology of 3D printing was largely employed for industrial applications, as reported above; however, exactly then, the patent protecting fused deposition modeling (FDM)—one of the most simple and commonly used 3D printing technologies nowadays—expired. Thanks to the RepRap people’s project’s mission and vision, to build a self-replicating 3D printer, the first desktop 3D printer was born. This caused an avalanche effect and many manufacturers followed, and the cost which was initially $200,000 back in early 2000, suddenly sunk below $2000, and the consumer 3D printing market took off in 2009. Nowadays, a simple DIY system costs about $150 for hobbyists.
The sales and market of 3D printing have been skyrocketing ever since. Of course, important patents on additive manufacturing expired and technology is made available to more bright minds, hence more innovations are foreseen in the near future as well as enormous revenues in the main and niece markets. There are, nowadays, almost 300,000 enterprise users and more than 1,000,000 private owners of 3D printers in the world. These numbers are doubling every other year. 3D printing industry is still in its childhood phase and its growing bigger and bigger. The number of companies that manufacture 3D printers has doubled in the last 2 years. According to Wohler’s Report for 2017, 97 manufacturers produced and sold additive manufacturing machines and devices in 2016. A year later, they were 62. The industry achieved worldwide revenues of $6.063 billion in 2016 about three times the maximum forecasted value as seen in Figure 1.
Estimated 3D printer sales per year from 2013 to 2018 [
It is of paramount significance to understand that 3D printing is a rapidly developing technology, rather immature, which comes with its family of inherent benefits, but also lags behind traditional manufacturing processes in many aspects. Examples from all aspects will enable the reader, get a grasp of these factors and foresee where the technology is headed in the near future.
3D printing allows designers and engineers create complex shapes and parts—many of which cannot be produced by traditional manufacturing techniques. Of course, evidently, manufacturing through additive methods implies that complexity comes at a price; elaborate product designs with complicated design features now cost just as much to produce as simple product designs that follow all the traditional rules of conventional manufacturing.
Utilizing traditional production methods, at a high volume or numbers of products, it is simply cheaper to make and sell products at reasonable prices to the consumer. Alternatively, 3D printing allows easy customization; one only needs to change the design digitally in CAD software to make changes with no additional tooling or other expensive or high efficiency manufacturing processes required to produce the final product. This results in an item that can be customized to meet a user’s specific needs without additional manufacturing costs, only the design labor remaining.
In metal casting or injection molding, each specific part of each product requires a mold—a factor that can skyrocket manufacturing costs rapidly. To counteract these permanent manufacturing costs, most companies anticipate thousands of the same items being sold. On the other hand, 3D printing is
Strategically thinking, once its manifested that there is no expensive tooling required to produce objects through 3D printing technologies, designers or entrepreneurs, might consider it, and they usually do so, as a cost effective method to produce items for a market test run or small production series. Possibly best, exploit the internet, through crowdfunding sites like Kickstarter, in order to launch their products. At the early stages of product development, it appears both also practical and wise to make design changes, in the product, without compromising their name in more formal—and expensive—manufacturing orders. Concluding, 3D printing technology opens a much less dire route to the market for those who want to materialize a novel product or an idea.
Most conventional manufacturing processes are subtractive especially the second grade ones: you start with a block of material (or a cast item), and usually through cutting, milling, drilling or similar, it is being processed at the intended final design. For many products—such as a bracket for an airplane—90% of the raw material is lost during processing.
On the other hand, 3D printing belongs to the additive processes; object is created from the raw material layer-by-layer. According to the laws of Mother Nature (she creates things exactly this way we found), when an object is manufactured this way, it only uses as much material—and energy—that is needed to create that particular object and no more. Additionally, most of these materials can be recycled and repurposed into more 3D-printed objects.
Alas, having all of the benefits of manufacturing through additive techniques, 3D printing is not yet competitive with conventional manufacturing processes, when it comes to large production volumes. The critical turning point lies between 1000 and 10,000 units, the numbers being a function on the material and the design. Of course, as the prices of printers and raw materials continue to decrease, the range of efficient production is expected to increase above the reported numbers in the following years.
Nowadays, there are more than 600 3D printing raw materials marketed, most of which are plastics and metals, but the choices are still limited compared to conventional product materials, available colors and finishes. The pseudo-lack of materials, however, is increasing, the number of new materials added to the 3D printing palette is growing rapidly now including wood, metals, alloys, composites, ceramics, and even chocolates.
A key aspect, of course, is the mechanical properties. In most 3D printing technologies, the part strength is neither uniform nor high, due to the layer-by-layer fabrication process. Practically, parts that have been 3D printed are usually weaker than their traditionally manufactured counterparts. Repeatability is also an open question; parts made on different 3D printers might have varying properties. However, as technical improvements are rapidly achieved and as novel continuous 3D printing processes like Carbon3D are made available, these disadvantages are prone to extinct in coming years.
Despite, the fact that we are not still able to manufacture 3D-printed objects with submicron tolerances like an iPhone, 3D printing technology is considered as a very straightforward and practical procedure of layering objects. These parts feature precision within the scale 20–100 microns, which correspond to a natural scale from the diameter of a human hair to the height of a single sheet of paper. 3D printing enables designers and engineers, who are creating objects with few tolerances and design details, to make products and bright ideas real. As known, many high-tech objects demand fine working parts and even finer details—such as the silent switch on the iPhone—it is still difficult to compete with the high precision capabilities of certain manufacturing processes, but time will prove this technology in every case. In every case, 3D printing is changing business model innovation in a very rapid manner (Figure 2) [7].
Available technologies and materials for 3D printing and lamination techniques. Source:
This part refers to the main 3D printing technologies which enable us in printing layered structures in some detail. Only the principal ones in use nowadays are reported, and some innovative ones are shown in the applications chapter.
The FDM printing process begins with a string of solid material called the filament. This line of filament is pulled from a reel attached to the 3D printer to a heated nozzle inside of the 3D printer that heats the material above its melting point. Once in a melted state, the material pushed out of a nozzle is extruded on a specific and predetermined path guided by the software on the computer usually instructed in G-code language. As the material is extruded, as a layer of the object on this path, it instantly cools down and solidifies—providing the base for the next layer of material until the entire object is manufactured.
Considered nowadays as the cheapest 3D printing technology commercially available, FDM also offers a wide variety of plastic-matrix materials in a rainbow of colors including ABS, PLA, nylon, and blends with more exotic materials, including carbon, bronze, or wood (Figure 3).
FDM technique sketch. Source: Caliskan and Durgun [
FDM is a considered to be the most practical choice for quick and low-cost prototyping. It can be used for a wide range of applications and objects with a typically wide palette of polymers as filaments in pure or reinforced form. Recently, FDM 3D printing has become very famous among hobbyists for enabling them to design and produce functional products, with embedded electronics and mechanical parts such as drones. FDM 3D printing is hampered by design and material limitations, although improvements appear almost continuously nowadays. The technology generally is not considered suitable for more intricate designs or where high strength is required [8]. Usually, the parts manufactured with this technique can exhibit some internal anisotropy due to layering procedure [9].
These techniques are reported together, due to the fact that both technologies produce 3D-printed parts using a photo polymerizing polymer resin, featuring a UV light source to cross-link the liquid material [10].
Analytically, the procedure is as follows: a building platform submerges into a translucent tank (vat) filled with the liquid photo polymerizing resin. After submerging the tank, the UV light source located inside the machine, focuses through the bottom of the tank, scans each layer of the object, effectively solidifies-crosslinks, or polymerizes the material in other words. Consequently, the platform is lifted upward by a few microns, thus allowing a fresh layer of resin to flow beneath the object. The UV light source shall map and solidify the new layer onto the previous one. Micron-by-micron step, the process is repeated in a layer-by-layer fashion, top to bottom until the whole part is finished. The methods are differentiating only by the light source used: In SLA, a UV-laser is used; whereas in DLP, a UV-projector lamp is employed.
The progress made in the past decades delivered enabled 3D printing processes to be applied in desktop 3D printers. Needless to mention here, materials selection is limited to UV-crosslinked polymers. The materials selection, however, broadens each year, new resins with enhanced strength or flexibility are available on the market.
One of the most favorable advantages of SLA & DLP 3D printers is the high accuracy in the produced objects characterized by very smooth surface finishes. This makes them especially famous among artists, for manufacturing sculptures, jewelry molds, and other prototypes. On the other hand, the SLA-DLP technologies are not suitable for printing relatively large or high strength objects. The technology has been accessed as a useful tool in biomedical engineering too [11] (Figure 4).
(A) Stereolithography (SLA) vs. (B) digital light processing (DLP) techniques.
In the process called selective laser sintering (SLS), a high-power laser is required. The laser is employed in order to melt and solidify layers of powder and produce, again layer-by-layer, 3D objects. The SLS printers are commonly equipped with two plates called pistons. First, a first layer of powder is laid onto the fabrication piston. The high-power laser maps/scans the first layer in the powder, thus selectively melting and sintering—the powder material [12]. In this way, the first layer is fabricated. After solidification of the first layer, the fabrication piston is slightly lowered, and the powder delivery bed, in which the power is contained, is raised by some microns. Then, a roller forces another layer of powder on top of the previous solidified layer. The aforementioned procedure is repeated, allowing the laser to melt and solidify all successive layers one by one, until the designed part has been finished bottom to top (Figure 5).
Selective laser sintering (SLS) method. © Materialgeeza—own work, CC BY-SA 3.0,
SLS is a highly efficient method, though rather expensive, but has established itself into the industrial 3D printing applications. Desktop SLS printers are widely available on the open market, and prices are already quite affordable. In 2017, a small SLS system could be acquired for as much as $15,000. The usual materials available nowadays as powders for SLS include most thermoplastics such as polyamides (nylon), polystyrene, thermoplastic elastomers, etc.
Due to its high accuracy and production fidelity, SLS machines are widely used for manufacturing end products as well as functional prototypes. Complete design freedom is its most important advantage. There is no need for support of structure. The surrounding unmolten powder acts as a support for the structure as it is layered, which allows for complex, sophisticated, and delicate shapes to be manufactured. Finished objects, as a side effect, take a bit more time to cool, and thus longer lead times are expected. Excess and attached object powder is removed by blowing air or using high pressure water or liquids, and is recycled after filtering; hence, economy of raw materials is
Selective laser melting and electron beam melting (SLM and EBM) are two of the most common metal 3D printing technologies. They are considered as offspring of the SLS technique described above. Just like SLS, these processes create objects from thin layers material. Raw material is the form of powder and it is selectively melted using an intense heat source. As metals and also ceramics, are characterized by higher melting points, consequently much more power is required; this is provided by a high-power laser for SLM or even an electron beam in the EBM technology.
The printing process begins by distribution of a thin layer of metal powder onto a build plate. The powder is selectively melted by a laser (SLM) [13] or an electron beam (EBM) [14] which maps the object layer. The platform or build plate is afterwards lowered by some microns and rapidly coated with new layer of metal powder on top of the solidified layer. The process is repeated until all layers have been solidified resulting in the finished part. Contrary to SLS, the SLM and EBM techniques require support structures, in order to stabilize the object to the build platform and enable manufacturing of overhanging parts. As a side effect, these enable heat transfer away from the solidified powder. Moreover, SLM is performed in a low-oxygen environment and EBM in vacuum. These conditions enable thermal stresses reduction and warping prevention, and they also allow reactive metals and alloys to be used as raw material.
Due to their high accuracy and costs, SLM and EBM are mainly applied in industrial 3D printing. Materials include various metals and alloys including steel, titanium, aluminum, cobalt-chrome, and nickel.
Metal printing is considered to be as the “holy grail” of additive manufacturing and 3D printing; it has found its path in the aerospace, aircraft, automotive, and healthcare industries for a range of high-tech, low-volume part production, from prototyping to final production. 3D printed metal parts allow for monolithic structuring (reducing the quantity of components), miniaturization, and mass reduction combined with design optimization, as shown in Figure 6. SLM and EBM have evolved to a stage where these prints are directly comparable to traditionally manufactured parts in terms of chemical composition, mechanical properties (static and fatigue), as well as microstructure. In the year 2017, for the first time, direct metal laser sintering (DMLS) devices, as the latest generation of SLM printers are referred to, were presented in the market at a cost lower than $100,000. Prices for such systems in the previous years were over half and near 1 M$.
A stainless-steel bracket optimized for weight reduction (front) and the traditional cast bracket in the back. Source: European Space Agency events via Flickr.
3D printing is becoming more and more a familiar technology to the automotive industry, enabling manufacturing of not only prototypes but also finished parts as well. In February 2017, BMW iVentures, the automaker’s venture capital arm, announced an investment in Desktop Metal, a startup devoted to 3D printing metal objects. BMW wants to help accelerate the rollout of this technology in both its design and manufacturing departments. Ιn Formula 1, quite a few racing teams have been testing and ultimately creating custom car parts, using 3D printing for prototyping that are used in high speed races. In the same spirit, Swedish car manufacturer Koenigsegg employed 3D printing to manufacture the variable turbocharger for their One:1 model—a car that has an astonishing 1:1 HP-to-Kg curb weight ratio. Although the 100% metal part is not only very lightweight, more importantly, it can also endure the high forces of supercar combustion and demanding racetrack conditions. Other high-tech examples include Ai Design company’s bespoke interior items for high-end cars with popular items including housings for radar detectors, iPhones, and aftermarket SatNav units that blend in with the car’s interior. The company often services customers with Lamborghinis, Ferraris, and classic Bentleys, so the fit and finish on the OEM-grade thermoplastics has to be perfect. Ai’s experienced engineering was reluctant to abandon the highly efficient CNC manufacturing behind. It took a lot of expert consulting from Stratasys to make Ai Design’s people to comprehend the potential in manufacturing its models with a 3D printer and fused deposition modeling.
BMW, as mentioned above, went for 3D printing technologies quite early. The company has its own Rapid Manufacturing Facility at the HQ in Munich. BMW is considered to be of the founding fathers of stereolithography having recently revealed plans and approach for a fully 3D printed car. One can understand how deeply 3D printing has become incorporated into the company culture by the fact that even a thumb cast for assembly line workers was produced in that way. Evidently, the workers have to push by thumb, a huge number of rubber plugs into chassis holes on the assembly line. This repetitive work causes a repetitive strain type injury in many of them. Confronting the issue, BMW engineers came up with a bright idea: a cast of the thumb and hand that relieved all the strain out the process. Quite simple, very brilliant, and it just proves just how deep 3D Printing has gone into the corporate culture at BMW. It also shows that 3D printing goes beyond the actual manufacturing process itself into biomechanics and ergonomic concepts (Figure 7) [15, 16].
BMW has turned to 3D printing to augment its workers and stop strain on limbs frequently found on manufacturing lines. Photograph: BMW (republished from the Guardian).
Being always at the cutting edge of technology, biomedical and prosthetics fields has largely benefited from the introduction of 3D printing in these sectors. Custom-shaped personalized-hearing aids no longer require manual labor to manufacture; with 3D printing, they can be made with the click of a button in a very short time. This of course implies substantially lower costs and shorter production times. Even orthopedic implants manufacturing at custom dimensions from CT or MRI scans from the patients is nowadays feasible.
Prosthetics and other assistive medical devices, braces, and retainers are tailored specifically for the needs of the patient. This has totally reversed an inherent problem that of time and energy required to manually produce each product. As a natural consequence, introduction of 3D printing in the dental and orthodontics fields was an inevitable event. With today’s technology, a dental surgeon or orthodontist can use an intraoral 3D camera to scan a client’s oral cavity and teeth, use afterward a specialized software and digitally design dental prosthetics, braces, crowns, bridges, etc. Then, he can send the files to a dental technician to 3D print the required molds or directly print the prosthetic itself. As if it was meant to be invented for them the dental industry fully adopted 3D printing technologies. Nowadays, there are dedicated 3D printer models produced specifically for manufacturing dental aids and molds. Alone 3D printer company Stratasys offers two wax 3D printers available to the dental industry. The Stratasys CrownWorx and FrameWorx 3D Printers are supposed to provide the highest precision in wax 3D printing, allowing dental laboratories to produce wax-ups for crowns, bridges, and denture frameworks. Imagine economy in time and costly silicon imprinting materials and gypsum molding. 3D Printers for dental applications such as Stratasys CrownWorx and FrameWorx use wax deposition modeling (WDM) technology. Mainly based on jetting technology and waxy polymers, they allow production of wax-ups characterized by smooth surface finishes and minimal post-processing effort and time requirements. Stratasys claims that the waxy materials burn out leaving no residue, no material shrinkage, neither invoking cracking, nor expansion (Figure 8).
An example of a dental frame built using wax deposition modeling. Source:
Nowadays, many types of 3D printers are used also in other areas of biomedical applications, such as manufacturing scaffolds for tissue engineering [17, 18] and many other areas of biomaterials engineering [19].
SpaceX designed and built its famous SuperDraco hypergolic propellant liquid rocket engine. It is a member of SpaceX’s Draco rocket engines family. Dragon V2 passenger-carrying space capsule shall be powered by a redundant array of eight SuperDraco engines. These provide fault-tolerant propulsion in the launch escape system and propulsive-landing thrust (Figure 9).
SPACEX, Superdraco engine [
The combustion chamber of the SuperDraco space engine is created with direct metal laser sintering (DMLS), using Inconel powder. This super-strong nickel-chromium-based “superalloy” is quite difficult to machine in the traditional way with CNC’s. The use of 3D printing DMLS technology “
On the other hand, in early 2016, rocket and missile propulsion manufacturer Aerojet Rocketdyne, a renowned aerospace and defense leader, was the recipient of a $6 million contract from the US Air Force to define 3D-printed rocket engine component standards. The standards will be used to qualify the 3D printed components used in liquid-fueled rocket engine applications, in order to follow through with a mandate set down by US Congress: that the Department of Defense will stop using Russian-made RD-180 engines to launch US satellites and national security payloads into space and begin using domestically produced options instead. Shortly after, Aerojet signed its own contract with Sigma Labs, to non-exclusively license its PrintRite 3D software system to evaluate and redefine the 3D-printed components used in Air Force manufacturing (Figure 10).
The Aerojet Rocketdyne AR1 booster engine can be configured as a single engine or a twin booster.
Aerojet, being certainly the right company for the Air Force contract, had already successfully completed hot-fire testing of the 3D printed rocket engine injectors for its liquid-fueled AR1 booster rocket engine in 2015; selective laser melting was used to manufacture the components. It has been known that Aerojet has also successfully completed its Critical Design Review (CDR) for the 500,000 foot-pound thrust-class AR1 engine. This achievement will keep the AR1 on track for flight certification in 2019, as a replacement for the Russian RD-180 engine. Twenty-two incremental CDRs came before the recent system-level CDR, along with full-scale testing of critical subsystem components, like the staged combustion system.
In the aviation sector, GE Aviation and Safran companies have successfully launched a method for 3D printing of jet engine fuel nozzles. The remarkable technology allows engineers to replace complex assemblies with a single part. The 3D-printed nozzles are lighter than previous designs, and boost a jet engine’s fuel efficiency by up to 15%. LEAP engines of GE equipped with 3D-printed fuel nozzles which will power new generation narrow-body planes, e.g., Boeing 737MAX and Airbus A320neo. Especially, the A320neo Airbus passenger airplane is powered by twin LEAP jet engines with 3D-printed parts based on new advanced materials. LEAP (“Leading Edge Aviation Propulsion”) is a high-bypass turbofan engine which, due to its advanced space age materials operates at higher pressures than the previous CFM56 machine. The LEAP is the first engine equipped with actually 19 (!) 3D-printed fuel nozzles and parts from space age, super-strong ceramics that make it 15% more fuel efficient than the previous CFM56 airplane jet engines built by CFM International. CFM is the 50/50 joint-venture between GE Aviation and France’s Safran (Snecma) who designed the engine. Airbus picked the LEAP for the A320neo in 2010. Since then, CFM has received more than 2500 orders and commitments for the LEAP-1A engine, representing 55% of A320neo orders to-date (Figures 11 and 12).
An Airbus A320neo powered by a pair of LEAP-1A engines took a maiden flight on May 19 in Toulouse, France. The two engines used for the four-and-a-half-hour flight were the LEAP-1A, developed specifically for the Airbus jet [
The LEAP engine (to left) has 19 3D-printed fuel nozzles (top right) and static turbine shrouds made from ceramic matrix composites (CMCs) (above left). Image credit: CFM.
In August 2016, the LEAP engine was installed on the Airbus A320neo with Pegasus Airlines and CFM delivered 77 machines. Following the introduction of Boeing 737 MAX, CFM delivered 257 LEAPS in the first 9 months of 2017, including 110 in the last three: 49 to Airbus and 61 to Boeing, and targets 450 in the year. The predictions for production at CFM are 1200 engines in 2018, 1900 in 2019, and 2100 in 2020, respectively. This is compared to the 1700 CFM56 produced in 2016. FAA has recently certified the first 3D-printed part for a GE jet engine—a casing that houses the compressor inlet temperature sensor inside the GE90 jet engine.
In the totally innovative additive manufacturing process technology invented by Sciaky [22, 23], it is possible to build the two hemispherical halves of fuel tanks. Layer-by-layer, spools of titanium wire is spun, providing the material which melts and deposits, forming thus the tank walls. Lockheed Martin Space Systems, after carefully reviewing and applying the process, stated that they plan to re-think the way they produce satellite propellant tanks. Moreover, eventually the construction of those tanks will be shifted in-house, and thus results in significant capital savings. Up to this point, Lockheed Martin bought those critical titanium tanks from Orbital ATK. The three Mars orbiters use the Orbital ATK tanks as will NASA’s OSIRIS-Rex asteroid-probing space vehicle upon its completion and launch. Lockheed Martin official Ambrose stated that it has become critical to reduce the lead times for building satellites, and he said that 3D printing holds the keys to reaching that goal (Figure 13).
The manufacturing procedure of one half of a satellite fuel tank according to the Sciaky method (top left) and finished half-product (top right). Source: Sciaky Inc. Video capture.
Sciaky Inc. had already begun developing the wire-feed electron beam process back in the mid-1960s [24]. The process was further developed in the 1990s allowing for production of jet engine knife edge seals [25]. The EBAM process was more advanced early in the 2000s, allowing manufacturers’ significant savings in time and money on the production of large, high-value metal parts. Sciaky formally launched the EBAM process, in 2009, which was then marketed as Electron Beam Direct Manufacturing, as a service option. Lockheed Martin Aeronautics selected Sciaky for the Department of Defense (DOD) Mentor-Protégé Program in 2011. The special focus of this agreement was the application of additive manufacturing for titanium structural components for Lockheed Martin’s F-35 Lightning II fighter project. Further on, in 2012, Sciaky signed a partnership with Penn State University, via DARPA (Defense Advanced Research Projects Agency) funding. Their goal was to advance Direct Digital Manufacturing (DDM) technologies for highly engineered and critical metallic systems and components in applications for the Department of Defense (DOD) and US industry.
Finally, in 2014, Sciaky started delivering fully operational commercially available EBAM systems. Needless to mention, Lockheed Martin Space Systems was one of the first customers to acquire an EBAM system for developing and producing “3D-printed” titanium propellant tanks. The EBAM system which Lockheed bought last year from Sciaky Inc. costs $4 million and is capable of “printing” out fuel tanks of nearly 150 cm in diameter. There is even better news: the method cuts down the cost of manufacturing propellant tanks by as much as 50%. The process is also much faster than casting those tanks in molds. With around 20 months being the lead time of the casting technique, and the time spent procuring the bulk, forged titanium billets also considered, EBAM additive manufacturing is considerably quicker. Material costs are also reduced with respect to structural titanium parts that are machined from a billet or forged. The EBAM spare also all the required involved machining time by as much as 80%. Dennis Little, Lockheed’s vice president of production for space systems, stated that, those manufacturing advantages involved in the 3D EBAM-printed titanium tanks, will be in use on spacecraft before the decade is out, provided that internal evaluation of the process meets certification requirements from the US Air Force and NASA.
Drone fashion hobby, also used in serious applications, has dramatically increased in the past several years. Global unit sales grew 60% (to 2.2 million) and revenue increased 36% (to $4.5 billion) in 2016 [26]. American consumers in the United States alone, bought 2.4 million hobbyist drones, compared to 1.1 million in the previous year. In 2017, revenue is anticipated to reach $6 billion, while units should rise up to 3 million. The latter figures substantiate a revenue growth of 39% and unit growth 34% within 2 years time, according to a study conducted by the research firm Gartner Inc. [27].
Impressively, engineers, designers, and other individual end-users become more and more involved in current research and development efforts to manufacture 3D-printed drones are now eligible for R&D federal and state tax credits.
Military sectors are intensively exploring novel paths to make cheaper, lighter, and more energy-efficient drones. A Marine Corp named Rhet McNeal created Scout, a drone composed of 3D-printed components. Scout only costs $600 to build. In comparison, a similar military-grade drone costs hundreds of thousands of dollars to build from advanced materials with conventional methods. Another benefit which arises from the technology, being a 3D-printed drone, should it receive any damage, any part or parts can be directly printed out and installed within hours. On the other side of the fence, a standard-issue drone would require weeks, sometimes months, to get a replacement through the Marine Corps’ supply chain. Scout has been delivered to Mitre Corp., a USMC drone supplier, for certification testing. Prior to Scout, Mitre Corp. experimented with a 3D-printed drone called Nibbler. In the following period of time, the USMC is planning to test Nibbler into a real combat zone in order to supply troops with required resources. At the same time, they are investing resources in R&D on how to manufacture 3D-printed drones for surveillance purposes.
The University of Virginia, in its term, designed and created a 3D-printed UAV drone for the Department of Defense. The Drone can be printed in less than 24 h at an end-user price of $2500, electronics development included. The fuselage of the drone costs only $800. Resembling to one long wing, it was nicknamed the Razor. The Razor can fly at maximum speed of 40 mph for up to 45 min, having a gross weight at 6 pounds with all the equipment installed.
None of its features and capabilities is compromised by the fact that it is 3D-printed; in fact, it features all the same functions and operational capabilities as a typical military-grade drone, including GPS waypoints for navigation and mile-distance control. Even camera hoisting and phone linking capabilities that extend the distance it can be controlled are present. Being 3D printed, it has even greater advantage that it can be modified and reprinted by desire and need. It is fully customizable, as it can be made smaller or bigger, geared to carry a sensor instead of a camera, or fly slower or faster as each different operation requires.
Solid Concepts uses additive manufacturing to produce fixed-wing UAS airframes (such as the PTERA shown in Figure 14) that are used to test high-risk circulation control systems, conformal fuel tank concepts, and other advanced aerospace concepts with SLS 3D-printed parts.
3D-printed military drone-PTERA of solid concepts.
Additive manufacturing—or 3D printing—is almost 30 years old. Today, it is not only just found in industry but also in households, as the price of high accuracy 3D printers has fallen below US$1000. Understanding of this new power enabling us to design and print almost anything in three dimensions, not just scribes and symbols on paper, opens up unlimited opportunities for everyday people to manufacture from toys and household appliances, to jewels and tools, in our homes and work places.
Well, guess again, there is even more that can be done with 3D-printed materials. We can make them more flexible and more useful. Smart structures can be also printed, featuring embedded sensors and actuators. These objects, also 3D-printed, can transform in a pre-programmed way in response to an external stimulus. Such a technology enabling objects, parts, or even complete systems to be manufactured was baptized by the popular science name of “4D printing.” Perhaps, it leads us to a better or easier way to think about that the object transforms or reacts over time.
Of course, such a behavior of structural deformations is not at all quite new. Researchers have been for decades researching and demonstrating “memory” and “smart material” effects and properties. In their recent Nature article, Raviv et al. propose a new design of complex self-evolving structures that vary over time due to environmental interactions [28]. Logically, in conventional 3D printing systems, materials are expected to exhibit a stable response rather than an active one and fabricated objects are designed and printed as static items or functional parts at the most. In this paper, a novel approach is introduced for simulating and fabricating self-evolving structures. These “smart” structures transform into a predetermined shape, by changing properties and functions after fabrication has been completed. The new locally coordinated bending primitives combine into a single system, allowing for a global deformation which can stretch, fold, and bend in the given environmental stimulus. The physics of 4D printing often requires multiple materials to be embedded into a single 3D structure. Much work is anticipated to be invested on such 4D printers and structures over the next decades.
In our days, it is apparent that we experience a very large revolution as far as novel production techniques is concerned, in manufacturing structures by advanced layering techniques, processes widely known under the simplistic name of 3D printing, for the wide public. The truth is that this new kind of industrial revolution regarding manufacturing has not been completed yet. Although techniques for glass and ceramics similar to 3D printing are developed as these lines are written, no mature methods have been proposed yet. Moreover, upon completion of this revolution, which owes a lot to electronics, software (CAD), and computer technology, we will be able to manufacture almost all our products utilizing 3D printing or even 4D printing technologies for smart structures.
It is of course common sense that this will influence our way of thinking and designing items and parts or even whole devices at once, since results of simulation and design optimization are nowadays directly printable. Mankind will benefit, as already does, from applications ranging from medical equipment and implants, biomaterials, or biomedical devices, to possible automated orbital factories fully equipped with 3D printers for space exploration equipment. The limits for this new technology for manufacturing are far from being set as yet. Transport and automotive sectors are also supposed to profit from the impact of 3D printing technologies.
Since these techniques are saving energy and CO2 emissions, and their products or by-products are recyclable too; it is also a revolution of green manufacturing. Furthermore, as scientists are moving into MEMS and NEMS device manufacturing techniques, it is certainly implied that in some future era, mankind will possess technology to perform atom by atom structuring. This has already been shown. From atom scale to nano-, micro-, and macroscale, we are almost able to manipulate matter totally.
The coronavirus disease-2019 (COVID-19) is the third documented viral outbreak caused by a member of the
The initial stage of the infection cycle starts with the recognition and anchoring of the SARS-CoV-2 spike protein complex into the host angiotensin-converting enzyme 2 (ACE2) through the receptor-binding domain (RBD) located at each one of the 3S proteins [13]. Then, the activation of the spike occurs at the surface or endosome level by transmembrane serine protease 2 (TMPRSS2) or cathepsin B/L proteases, respectively, to allow viral entry [14]. Once the virus membrane merges with the cell membrane, the genomic material enters the cell. The cell’s ribosomes then translate the viral RNA into pp1a/ab polyproteins, which will be later processed by cleavage through the enzymatic activity of the main protease (Mpro) and the papain-like protease (PLpro) [15]. This process will release 16 non-structural proteins (NSPs), including the RNA-dependent RNA polymerase (NSP12) and co-factors NSP7, and NSP8 of the RNA-replication machinery (Rdrp). After replication, expression of the structural proteins occurs, the genomic material is packaged, and the virion is assembled on a lipid membrane and matured for subsequent exocytosis. In addition, evidence suggests that the SARS-CoV-2 proteases and some of their cleavage products, besides their critical function for the proper infection process, interplay with the host’s innate immune response through different mechanisms [16]. In particular, PLpro-ISG15 interaction allows the virus to evade the innate immune response through deubiquitination and deISGylation activities of the protease [17, 18]. Interestingly, the process occurs at the same binding cavity as the PLpro known inhibitor, GRL0617 [19].
The code for the cavity-detection guided blind docking (CB-Dock) [20] stand-alone version is freely available at Yang Cao’s Lab webpage [http://clab.labshare.cn/cb-dock/php/manual.php#download].
The customized high-throughput virtual screening pipeline we developed can be accessed at GitHub [https://github.com/tripplab/HTVS].
We conducted an extensive scientific literature search for drugs reported as potentially able to prevent SARS-CoV-2 infection. The search included
We performed the molecular
ID | Drug | CIDa | References |
---|---|---|---|
RPA01 | Losartan | 3961 | [30, 31] |
RPA02 | Telmisartan | 65,999 | [30, 32] |
RPA03 | Arbidol | 131,411 | [33, 34] |
RPA04 | Camostat mesylate | 5,284,360 | [33, 35] |
RPA05 | Rimantadine | 5071 | [36] |
RPA06 | Chloroquine | 2719 | [33, 37] |
RPA07 | Hydroxychloroquine | 3652 | [33, 37] |
RPA08 | Baricitinib | 44,205,240 | [38, 39] |
RPA09 | Colchicine | 6167 | [40, 41] |
RPA10 | Disulfiram | 3117 | [42, 43] |
RPA11 | Ebselen | 3194 | [42, 43, 44] |
RPA12 | Hesperidin | 10,621 | [45, 46] |
RPA13 | Qingdainone | 3,035,728 | [47] |
RPA14 | Nafamostat | 4413 | [48, 49] |
RPA15 | Dipeptidyl nitrile-derivative | Compound 10 | [50] |
RPB01 | Lopinavir | 92,727 | [33, 51] |
RPB02 | Ritonavir | 392,622 | [33, 51] |
RPB03 | Darunavir | 213,039 | [36, 52] |
RPB04 | Cobicistat | 25,151,504 | [52] |
RPB05 | Isatin-derivative | Compound 26 | [53] |
RPB06 | Rupinatrivir | 6,440,352 | [54, 55] |
RPB07 | E-64 | 123,985 | [56] |
RPB08 | N3 inhibitor | 405,067,310 | [57] |
RPC01 | Ribavirin | 37,542 | [58, 59] |
RPC02 | Sofosbuvir | 45,375,808 | [58, 59] |
RPC03 | Molnupiravir | 145,996,610 | [58, 59] |
RPC04 | Nilotinib | 644,241 | [60, 61, 62] |
RPC05 | Saquinavir | 441,243 | [36, 58, 59, 62] |
RPC06 | Tipranavir | 54,682,461 | [58, 59, 62] |
RPC07 | Lonafarnib | 148,195 | [62] |
RPC08 | Tegobuvir | 23,649,154 | [58, 59, 62] |
RPC09 | Simeprevir | 24,873,435 | [58, 59] |
RPC10 | Filibuvir | 54,708,673 | [58, 59, 62] |
RPC11 | Cepharanthine | 10,206 | [62] |
RPC12 | Redemsivir | 121,304,016 | [33, 58, 59] |
RPC13 | Favipiravir | 492,405 | [33, 58, 59] |
RPD01 | rac5c | 76,853,649 | [18] |
EXT01 | Ascorbic Acid | 54,670,067 | [63] |
EXT02 | Ergocalciferol | 5,280,793 | [64, 65] |
EXT03 | Cholecalciferol | 5,280,795 | [64, 65] |
EXT04 | Ivermectin | 6,321,424 | [66] |
EXT05 | Azithromycin | 447,043 | [67] |
EXT06 | Heparin | 772 | [68] |
EXT07 | Methylprednisolone | 6741 | [69] |
EXT08 | Carvacrol | 10,364 | [70] |
EXT09 | Ursolic acid | 45,358,157 | [71] |
EXT10 | Oleanolic acid | 485,707 | [71] |
Ligand information, CID number, and reference of 47 drugs with potential activity against the SARS-CoV-2 viral cycle.
In the absence of the CID, the reference to the original investigation and the compound number are provided.
We included viral and cellular targets involved in the SARS-CoV-2 infection cycle, covering the entry, polyprotein processing, and replication. The targets’ three-dimensional structures were obtained from the Research Collaboratory for Structural Bioinformatics Protein Data Bank (RCSB) in PDB format [23]. The complete structure of the spike homotrimer complex (PDB: 6VXX-1-1-1) was retrieved from the CHARMM-GUI Archive-COVID-19 proteins library [24]. We took special consideration to the spike complex given its large size and quaternary structure. We focused on four independent spike-based structures to extend the cavity sampling: the full-length spike’s homotrimer complex, the homotrimer head (S1), 1 S protein monomer, and one isolated receptor-binding domain (RBD).
Water, ions, glycosylations, and co-crystallized ligands were removed from all targets. Charges and hydrogens were fixed at neutral pH using chimera 1.15, their structure optimized, and the final configuration saved in PDB format [21]. In total, 16 structures of 10 targets were curated, as summarized in Table 2.
ID | Target | PDB IDa | SARS-CoV-2 infection step | References |
---|---|---|---|---|
H00 | ACE2 | 1R4L_A | Viral recognition | [72] |
H01 | ACE2 (B0AT1 closed complex) | 6M18_B | Viral recognition | [73] |
H02 | ACE2 (B0AT1 open complex) | 6M1D_B | Viral recognition | [73] |
H03 | TMPRSS2 | 7MEQ_A | Viral priming | [74] |
H04 | Cathepsin B | 3AI8_B | Viral priming | [75] |
H05 | Cathepsin L | 2NQD_B | Viral priming | [76] |
V01 | Spike homotrimer | 6VXX1-1-1 | Viral recognition | [77, 78] |
V01H | Spike homotrimer head | 6VXX1-1-1 | Viral recognition | [77, 78] |
V02 | S protein | 6VXX1-1-1 | Viral recognition | [77, 78] |
V02R | S protein’s RBD | 6VXX1-1-1 | Viral recognition | [77, 78] |
V03 | Mpro | 6LU7_A | Polyprotein processing | [79] |
V08 | PLpro | 7JRN_A | Polyprotein processing | [19] |
V04 | NSP12 | 7AAP_A | RNA replication | [80] |
V05 | NSP7 | 6M71_C | RNA replication | [81] |
V06 | NSP8 | 6NUR_B | RNA replication | [82] |
V07 | Rdrp-complex (NSP12-NSP7-NSP8) | 6M71_ABC | RNA replication | [81] |
Structural information and PDB entries of viral (V) and host (H) targets included.
Underscore denotes the chain selected from PDB coordinates files.
Molecular docking is a computational method that allows to sample the conformational space and rank the ligand poses through an energy scoring function. It attempts to generate an optimized target-ligand complex conformation with the lowest binding free-energy change estimate, predicting the interaction of the two molecules in the energy minimum. This task is a cyclic process performed by systematic or stochastic search methods. However, the latter is the choice of preference since it increases the probability of finding an energetic global minimum conformation because the search initiates from different random points [27]. For this reason, the results of two or more molecular docking cycles are not necessarily the same due to the random nature of the conformational search method. Therefore, performing as many cycles as necessary to get as close as possible to the energetic global minimum conformation is essential.
Easy customization of this parameter in the developed high-throughput virtual screening code offers the user the possibility of an exhaustive sampling of the conformational space that maximizes the accuracy of target-ligand complex prediction.
We have developed in-house bash scripts that integrate the CB-Dock’s cavity-guided blind molecular docking method, which automatically identifies binding sites by calculating putative cavities through a curvature-based detection approach. Molecular docking analysis is conducted in these putative cavities to sample and rank ligand poses and estimate the best target-ligand complex binding energy scores per cycle.
The pipeline has three phases comprised of nested loops, schematized in Figure 1 as a flowchart. First, each target
Flowchart of the customized high-throughput virtual screening pipeline implemented in this work. Four phases are involved, i) target and ligand molecular modeling (blue), ii) target cavity detection (green), iii) docking box optimization (orange), and iv) target-ligand docking (red).
In our study, we found that the optimal number of independent rounds is
The method we used for automatizing the virtual high-throughput screening process is blind; that is, it does not require any information on the binding site. Hence, we validated its predictions by reproducing the enzymatic targets’ experimental binding complexes. We gathered a set of ligands with available complex co-crystallized data. Eight known enzymatic inhibitors were modeled, optimized, and evaluated under the same methodology conditions as the rest of the ligands included in this study. The ligands in the control set are listed in Table 3.
Target ID | Target name | Ligand | PDB ID | Reference |
---|---|---|---|---|
1. Co-crystallized reproducibility | ||||
INH01 | ACE2 | MLN-4760 | 1R4L | [72] |
INH02 | TMPRSS2 | 4-Guanidinobenzoic acid | 7MEQ | [74] |
INH03 | Cathepsin B | Nitroxoline | 3AI8 | [75] |
INH04 | Cathepsin L | 4-Bipheylacetyl-cys-(D)-ARG-TYR -N-(2-Phenylethyl) Amide | 2NQD | [76] |
INV01 | Mpro | Narlaprevir | 7JYC | [19] |
INV02 | NSP12 | Remdesivir | 7BV2 | [84] |
INV03 | NSP12 | Favipiravir | 7AAP | [80] |
INV04 | PLpro | GRL0617 | 7JRN | [19] |
2. Negative controla | ||||
INV05 | Spike | Amantadine | NA | [83] |
Modeled ligands to validate that the method is capable of reproducing the co-crystallized complex conformations and previous
Does not prevent ACE2-Spike interaction despite inhibiting
Furthermore, at this time, a small drug-like co-crystallized molecule in complex with the spike homotrimer does not yet exist. We included amantadine (INV05) in our set as a negative control since it inhibits the SARS-CoV-2 infection but does not prevent spike-ACE2 interaction [83].
We inspected the top 10 size-ranked putative cavity sites screened for each target. We selected those that either had the active site (targets ACE2, TMPRSS2, cathepsin B/L, Mpro, and NSP12), or were inside a quaternary interface (targets spike, PLpro, and Rdrp). We selected the
We found that the
Target-ligand complex superimposition of native co-crystallized inhibitors (yellow) and the best-predicted ligand conformation after
After doing all the blind docking calculations with an extended conformation sampling, we analyzed the most negative energy scores. We performed a Z-score transformation of the data for each independent column in the matrix (targets
Target (columns) and ligand (rows) complex docking results. Heatmap of binding free-energy change estimates, using a color-based code according to the Z-score value through column analysis. Targets are grouped as host proteins (blue) and virus proteins (pink). Ligands are grouped by control set (green), potential repurposing drugs (orange), and others (brown). IDs correspond to those defined in
Since each column gathers the results for a different target, it is thus possible to identify which ligands had the best scores for each target (in green). It is worth noting that cathepsin L (H05) and PLpro (V08) co-crystallized inhibitors give a good binding free-energy estimate. Most of the co-crystallized inhibitors remained near the mean (in black, with respect to the experimental drug set), except for amantadine (INV05), which presents a positive Z-score value for the spike’s RBD (in red). The latter is concomitant to previous works, where amantadine fails to prevent the spike-ACE2 quaternary interaction [83].
Out of the 47 drugs screened, nine showed potential inhibition against viral or host targets of the SARS-CoV-2 infection cycle. Saquinavir, simeprevir, nilotinib, an isatin-derivative, telmisartan, tegobuvir, qingdainone, rac5c, and nafamostat achieved the selection criteria. Interestingly, all but rac5c and nafamostat showed the best scores against more than one target. The schematic representation of these results is summarized in Table 4.
ID | Drug | Target | VINA score | Z-scorea |
---|---|---|---|---|
RPC05 | Saquinavir | ACE2 (H00) | −12.9 | −1.70 |
RPB05 | Isatin-derivative | ACE2 (H01) | −10.7 | −2.06 |
RPC04 | Nilotinib | −10.2 | −1.72 | |
RPD01 | rac5c | −9.9 | −1.51 | |
RPC04 | Nilotinib | ACE2 (H02) | −10.7 | −1.85 |
RPC09 | Simeprevir | −10.4 | −1.62 | |
RPC04 | Nilotinib | TMPRSS2 (H03) | −8.9 | −1.58 |
RPC05 | Saquinavir | −8.8 | −1.49 | |
RPC04 | Nilotinib | Cathepsin B (H04) | −9.6 | −1.64 |
RPC09 | Simeprevir | −10.3 | −2.20 | |
RPA02 | Telmisartan | Spike (V02) | −9.4 | −1.63 |
RPB05 | Isatin-derivative | Spike (V01H) | −10.9 | −1.67 |
RPA13 | Qingdainone | Mpro (V03) | −9.4 | −1.56 |
RPC04 | Nilotinib | −9.7 | −1.80 | |
RPC09 | Simeprevir | NSP12 (V04) | −9.1 | −1.60 |
RPA13 | Qingdainone | NSP7 (V05) | −7.4 | −1.69 |
RPC08 | Tegobuvir | −7.3 | −1.59 | |
RPC09 | Simeprevir | −7.6 | −1.89 | |
RPA02 | Telmisartan | NSP8 (V06) | −8.8 | −1.65 |
RPC04 | Nilotinib | −8.9 | −1.73 | |
RPC05 | Saquinavir | −9 | −1.80 | |
RPC09 | Simeprevir | Rdrp (V07) | −10 | −1.96 |
RPA13 | Qingdainone | PLpro (V08) | −9.9 | −1.72 |
RPA14 | Nafamostat | −10.1 | −1.88 | |
RPC04 | Nilotinib | −9.8 | −1.65 | |
RPC08 | Tegobuvir | −9.8 | −1.65 |
Potential drugs for repurposing with the most negative free-energy change score found and their corresponding Z-score value grouped by the target.
Z-scores were calculated by the target.
Also, we inspected the results by ligand, performing a Z-score analysis by row (ligands). Since the rows gather data from the
Target (columns) and ligand (rows) complex docking results. Heatmap of binding free-energy change estimates, using a color-based code according to the Z-score value through row analysis. Targets are grouped as host proteins (blue) and virus proteins (pink). Ligands are grouped by control set (green), potential repurposing drugs (orange), and others (brown). IDs correspond to those defined in
The ligands such as arbidol, colchicine, qingdainone, nafamostat, and carvacrol exhibit a binding preference to PLpro (V08). It is important to highlight the essential function of the protease PLpro for processing the viral proteome and evading the host’s innate immune system. In the latter case, PLpro cleaves off post-translational modifications, such as ubiquitin and ubiquitin-like proteins from cell proteins, disrupting the inflammatory signaling pathway necessary for an appropriate immune response [17, 100]. Noteworthy, the potential PLpro inhibitors we have identified in the present work as repurposed drugs form a
Saquinavir is a peptide-mimetic HIV inhibitor. However, some reports suggest potential inhibitory activity against SARS-CoV-2 proteases [85, 86, 87] and other targets involved in the viral infection, such as the Rdrp replication complex [62, 88] and the spike-ACE2 PPI [89]. In our study, saquinavir showed the best energy scores against TMPRSS2, ACE2, and the NSP8-NSP12 interface of the Rdrp complex, as shown in Figure 5. The transmembrane serine protease 2 (TMPRRS2) is essential in several viral infections. Previous reports have shown that the inhibition of this target significantly reduces SARS-CoV-2 entry in lung cells at nM concentrations and therefore the viral infection [90]. Saquinavir also presented the best energy scores against the ACE2 active site, a critical host target needed to initiate entry through the formation of the spike-ACE2 quaternary complex. In this scenario, conformational changes upon ligand binding into the catalytic cavity may shift the relative positions of the receptor’s interface residues that bind to the spike protein and prevent the anchoring of the spike on host cells [91]. However, because saquinavir targets the catalytic site of ACE2, the main activity of this enzyme in the renin-angiotensin system requires further investigation of its biological effect as a competitive inhibitor [92]. In addition, our results show that this drug targets the Rdrp replication complex, which is consistent with the previous results reported in the literature [62, 93]. Interestingly, saquinavir appears to target two essential steps, compromising the entry and viral replication of the SARS-CoV-2.
Target-ligand complex conformations of potential drugs for repurposing. Molecular docking against viral and host targets relevant in the SARS-CoV-2 infection cycle. A. Superposition of ACE2 target (H00, H01, and H02) docked with saquinavir (cyan), isatin-derivative (red), nilotinib (pink), rac5c (brown), and simeprevir (yellow). B. TMPRSS2 docked with saquinavir (cyan) and nilotinib (pink). C. Spike docked with telmisartan (purple) and isatin-derivative (red). D. Cathepsin B docked with nilotinib and simeprevir (yellow). E. Mpro docked with nilotinib (pink) and qingdainone (orange). F. PLpro docked with nafamostat (green), nilotinib (pink), qingdainone (orange), and tegobuvir (dark orange). G. Superposition of NSP12 and NSP7 and NSP8 cofactors docked with simeprevir (yellow), tegobuvir (dark orange), nilotinib (pink), telmisartan (purple), qingdainone (orange), and saquinavir (cyan), created with the visual molecular dynamics (VMD) [
On the other hand, simeprevir also showed the best energy scores on targets relevant to viral entry and replication, including the active cavities of ACE2, cathepsin B, NSP12, and the Rdrp complex interface. We show a molecular visualization of these results in panels A, C, and G of Figure 5. This drug is a protease inhibitor that has presented potent
Nilotinib is used to treat chronic myelogenous leukemia as a Bcr-Abl tyrosine kinase antagonist. Our results suggest the potential inhibition of six targets involved in the SARS-CoV-2 infection process, including the catalytic cavities of enzyme targets ACE2, TMPRSS2, cathepsin B, Mpro, and the PLpro-ISG15 and Rdrp’s NSP8-NSP12 interfaces. We show a molecular visualization of these results in Figure 5. Reports suggest that nilotinib can inhibit the SARS-CoV and SARS-CoV-2 infection processes, but not MERS-CoV. Interestingly, the latter does not use ACE2 as a cell receptor [97, 98]. This observation is particularly interesting since other reports suggest that nilotinib can destabilize the SARS-CoV-2 spike-ACE2 complex [63]. According to our results, nilotinib might prevent the spike priming and activation since it showed the best energy scores against TMPRSS2 and cathepsin B at the active site cavities. These findings represent a potential inhibition of two independent priming pathways. Moreover, nilotinib potentially inhibits the Mpro and Rdrp complex and is consistent with previous
Interestingly, nilotinib also had the best energy scores against PLpro. In addition to PLpro’s essential protease activity in the processing of pp1a polyprotein, it is also implicated in host immune innate response evasion mechanisms as described in Section 4.4. The inhibition of PLpro decreases the exacerbated immune response, as described by other members of the Bcr-Abl inhibitors family, for example, ponatinib, which protects against cytokine storm in mouse models [101, 102].
Isatin-derivatives have shown potential antiviral properties, some of them with promising results against HCV, SARS-CoV [103, 104], and SARS-CoV-2 [53]. In particular, the compound 1-(naphthalen-2-ylmethyl)-2,3-dioxoindoline-5-carboxamide inhibits Mpro from SARS-CoV-2. Therefore, we decided to evaluate it against our whole set of targets. It presented the best score against the ACE2 active site, which might disrupt the spike-ACE2 interaction as discussed previously (see Section 5.1). Moreover, it also showed the best energy scores against the spike protein, precisely in the quaternary interface region of the homotrimer complex, and thus a plausible termination of the viral cycle at an early stage in the replication process.
Telmisartan is an anti-antihypertensive. There is evidence of a morbidity and mortality reduction in hospitalized patients infected with SARS-CoV-2 treated with this drug [105]. Telmisartan showed the best energy scores against a spike’s cavity in the homotrimer quaternary interface. Therefore, the isatin-derivative could inhibit two targets involved in the viral entry (spike and ACE2), while telmisartan might prevent the spike homotrimer formation and the Rdrp complex. We show the molecular visualization of these results in panels A, C, and G of Figure 5.
Tegobuvir is a non-nucleoside inhibitor of the NS5B polymerase of HCV. Our results suggest that this drug may prevent the formation of the Rdrp quaternary complex. Previously,
In addition, qingdainone also showed the potential inhibitory activity on Mpro active site, suggesting that this drug might completely disrupt the polyprotein processing stage by targeting both proteases, Mpro and PLpro. We show a molecular visualization of these results in Figure 5.
We included nafamostat and rac5c in our ligand sets due to evidence suggesting their inhibitory capacity against TMPRSS2 [108] and PLpro [18], respectively. Neither ligand achieved the selection criteria for their expected targets despite being on the borderline with scores of −8.3 and − 9.3 kcal/mol, which indicates the selection criteria’s exhaustiveness. However, nafamostat does achieve the best scores against PLpro’s USP domain, while rac5c presented the best score on the ACE2 active site. We show these results in panels A and F of Figure 5.
We have theoretically identified nine drugs or compounds for potential drug repurposing against SARS-CoV-2 through a cavity-based blind molecular docking protocol (Figure 6). Interestingly, seven of them present potential inhibitory activity on multiple targets at different stages of the viral infection cycle, including innate immune evasion. We have implemented an in-house high-throughput virtual screening pipeline that successfully reproduces experimental data and findings from previous works. After the target’s cavity detection and ranking by surface area, we used the pipeline to perform the numerous independent blind molecular docking rounds to achieve a sufficiently extensive conformational target-ligand complex search.
Repurposing drugs (left) with corresponding potential inhibitory activity on multiple viral or host targets (right).
Experimental design is a critical step in every scientific study, for example, method validation by including a control group. Nonetheless, one has to be wary of the limitations of the methodology employed. In this case, molecular docking can be a good estimator for the most energetically favorable
We analyzed the molecular binding predictions through rigorous visualization and Z-score-based statistical algorithms to identify the potential drugs for repurposing. In this context, our findings suggest that:
Saquinavir and simeprevir could target viral entry and Rdrp complex quaternary formation,
Nilotinib could target viral entry, polyprotein processing, and Rdrp quaternary complex formation,
An isatin-derivative and telmisartan could target SARS-CoV-2 entry into the host,
Tegobuvir, qingdainone, and nafamostat could target quaternary interface Rdrp regions, and
Nafamostat and rac5c could be potential inhibitors of PLpro and ACE2.
These results are relevant in understanding the SARS-CoV-2 drug’s molecular mechanisms and further clinical treatment development, either at a single or multi-target activity.
The authors acknowledge funding from the Consejo Nacional de Ciencia y Tecnología México [grant number 132376] and Fondo Sectorial de Investigación para la Educación [grant number A1-S-17041] to MCT. All computations and analyses reported here were performed at the bmdhpc computing resources of the Biomolecular Diversity Lab (tripplab.com) at CINVESTAV Unidad Monterrey, México.
The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.
Li-Ta | H00 | H01 | H02 | H03 | H04 | H05 | V01 | V01H | V02 | V02R | V03 | V04 | V05 | V06 | V07 | V08 |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
INH01 | −9.5 | −7.3 | −7.7 | |||||||||||||
INH02 | −6 | |||||||||||||||
INH03 | −6.2 | |||||||||||||||
INH04 | −9 | |||||||||||||||
INV01 | −7.2 | |||||||||||||||
INV02 | −7.5 | −5.5 | −6.7 | −7.8 | ||||||||||||
INV03 | −7.6 | −5.7 | −6.6 | −8.6 | ||||||||||||
INV04 | −9.8 | |||||||||||||||
INV05 | −6 | −6 | −4.1 | −3.4 |
VINA scores of the conformation with the lowest scores after 30 independent cycles of each target–ligand pair for the enzymatic known inhibitors included.
Li-Ta | H00 | H01 | H02 | H03 | H04 | H05 | V01 | V01H | V02 | V02R | V03 | V04 | V05 | V06 | V07 | V08 |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
RPA01 | −9.8 | −8.5 | −7.9 | −6.8 | −8 | −6.6 | −9.7 | −9.6 | −8.9 | −6.8 | −7.7 | −7.5 | −5.6 | −6.5 | −7.1 | −8.8 |
RPA02 | −11.4 | −8.8 | −10.3 | −8.2 | −8.1 | −7.5 | −9.3 | −10 | −9.4 | −7.7 | −8.7 | −8.2 | −6.9 | −8.8 | −9.2 | −9.2 |
RPA03 | −8.6 | −6.5 | −6.9 | −5.9 | −6.3 | −5.9 | −7.6 | −7.3 | −5.9 | −5.7 | −6.6 | −5.9 | −4.7 | −5.9 | −5.9 | −7.5 |
RPA04 | −9.8 | −8.7 | −8.7 | −7.6 | −7.6 | −7.8 | −9.5 | −9.4 | −7.8 | −6.6 | −7.4 | −7.3 | −6 | −7 | −7.6 | −8.4 |
RPA05 | −6.1 | −5 | −6.6 | −4.8 | −5.3 | −4.9 | −6.8 | −6.7 | −4.6 | −4.2 | −4.6 | −4.2 | −4.3 | −4.5 | −4.3 | −6 |
RPA06 | −7.3 | −7 | −7.6 | −5.7 | −5.8 | −5.9 | −7.8 | −7.8 | −6.4 | −5.2 | −6.1 | −5 | −4.5 | −5.8 | −5.3 | −7.3 |
RPA07 | −7.3 | −6.4 | −7.7 | −5.9 | −6 | −5.9 | −7.9 | −7.9 | −6.4 | −5.3 | −6.3 | −5.6 | −4.7 | −5.9 | −5.7 | −7.2 |
RPA08 | −9.5 | −8 | −7.9 | −7.3 | −7.9 | −6.7 | −8.9 | −8.9 | −8.3 | −5.9 | −8.2 | −6.9 | −5.3 | −6.2 | −6.9 | −8.1 |
RPA09 | −8.9 | −6.3 | −7.1 | −5.9 | −7 | −6.8 | −7.4 | −7.2 | −6.3 | −5.7 | −7 | −6.2 | −5.7 | −5.9 | −6.9 | −7.7 |
RPA10 | −4.7 | −5 | −5.1 | −3.9 | −4.3 | −4 | −5.2 | −5.2 | −4.1 | −3.4 | −4.5 | −3.6 | −3 | −3.6 | −3.7 | −4.7 |
RPA11 | −7.8 | −6.6 | −7.5 | −5.6 | −6.7 | −6 | −7.8 | −7.8 | −6.2 | −5.3 | −6.6 | −5.1 | −5.1 | −5.4 | −5.6 | −7.3 |
RPA12 | −11.6 | −9.1 | −8.9 | −8.7 | −8.8 | −8 | −9.2 | −9 | −7.8 | −7.5 | −8.9 | −8.9 | −6.5 | −7.1 | −8.8 | −8.3 |
RPA13 | −12 | −7.7 | −9.5 | −8 | −8.5 | −7.7 | −8.8 | −9.1 | −7.9 | −7 | −9.4 | −8 | −7.4 | −7.3 | −8.6 | −9.9 |
RPA14 | −10.5 | −9.2 | −9.5 | −8.3 | −8.3 | −7.8 | −9.8 | −9.9 | −8.2 | −7 | −8.5 | −8.4 | −6.8 | −7.7 | −8.9 | −10.1 |
RPA15 | −10.9 | −9.4 | −9.3 | −7.8 | −7.8 | −8.2 | −10.1 | −9.9 | −8.7 | −7.2 | −8.7 | −8 | −6 | −8 | −7.9 | −9 |
RPB01 | −11.1 | −8.7 | −9.3 | −7.6 | −8.3 | −7.7 | −9.1 | −9.8 | −8.8 | −7.5 | −8.9 | −7.3 | −5.8 | −7.8 | −8.3 | −8 |
RPB02 | −11.3 | −7.8 | −8.8 | −7.5 | −7.7 | −7.1 | −8.4 | −9.3 | −8.2 | −6.8 | −7.7 | −7.4 | −5.7 | −7.4 | −7.9 | −7.5 |
RPB03 | −10.6 | −7.8 | −8.5 | −7.5 | −8.6 | −7.6 | −9.7 | −9.6 | −8.6 | −6.9 | −8 | −7.3 | −5.9 | −6.8 | −7.6 | −7.8 |
RPB04 | −11.8 | −8 | −9 | −7.6 | −8.1 | −7.6 | −8 | −8.6 | −8.2 | −7.5 | −7.9 | −7.2 | −6.2 | −7.4 | −8.2 | −8 |
RPB05 | −10.4 | −10.7 | −9 | −8.2 | −8.9 | −8.4 | −11 | −10.9 | −8 | −6.9 | −8.3 | −7.6 | −6.2 | −8.1 | −7.6 | −9.7 |
RPB06 | −10.7 | −7.7 | −9.4 | −7.5 | −8.8 | −7.4 | −9.1 | −9.7 | −7.9 | −6.7 | −7.8 | −7.3 | −6.1 | −7.6 | −8.2 | −8 |
RPB07 | −8 | −6.3 | −7.3 | −6.3 | −7.6 | −6.4 | −8.3 | −8.1 | −6.8 | −5.8 | −7 | −6.6 | −5 | −5.5 | −6.8 | −7.6 |
RPB08 | −11.6 | −8.6 | −9 | −7.6 | −8.2 | −7.6 | −8.6 | −8.5 | −8.4 | −7.4 | −7.6 | −7.2 | −6.1 | −7.1 | −7.9 | −8.2 |
RPC01 | −7.6 | −6.1 | −7.2 | −7 | −6.7 | −5.9 | −7.7 | −7.7 | −6.5 | −5.4 | −6.6 | −5.9 | −4.5 | −5.1 | −6.4 | −6.4 |
RPC02 | −10.3 | −7.7 | −8.3 | −7.7 | −8.2 | −7.3 | −9.9 | −9.8 | −7.4 | −7.2 | −8.1 | −7.2 | −6.1 | −7 | −7.3 | −8 |
RPC03 | −8.1 | −6.7 | −7.8 | −7 | −7.2 | −5.9 | −8.6 | −8.6 | −7.1 | −5.8 | −7.4 | −6.8 | −5.1 | −5.8 | −6.6 | −6.9 |
RPC04 | −12.3 | −10.2 | −10.7 | −8.9 | −9.6 | −8.3 | −10 | −10.7 | −8.8 | −7.9 | −9.7 | −8.6 | −7.2 | −8.9 | −9.1 | −9.8 |
RPC05 | −12.9 | −8.7 | −9.3 | −8.8 | −8.2 | −8.4 | −10 | −10.4 | −8.6 | −7.7 | −9.1 | −8 | −6.5 | −9 | −8.6 | −8.4 |
RPC06 | −11 | −9.8 | −9.8 | −7.7 | −8.6 | −7.6 | −9.9 | −9.6 | −7.6 | −7.7 | −8.1 | −7.6 | −6.2 | −8 | −8.1 | −8.1 |
RPC07 | −12.5 | −8.9 | −9.8 | −8.6 | −9 | −7.8 | −8.9 | −9.5 | −8.4 | −7.2 | −9.1 | −8.7 | −6.9 | −8.1 | −8.8 | −8.9 |
RPC08 | −11.5 | −9.5 | −10.2 | −7.9 | −9 | −8.1 | −9.7 | −9.7 | −8.6 | −8.1 | −8.6 | −8.8 | −7.3 | −8.1 | −8.7 | −9.8 |
RPC09 | −10.9 | −9.3 | −10.4 | −8.6 | −10.3 | −8.6 | −4.9 | −8.7 | −9.1 | −8.1 | −8.4 | −9.1 | −7.6 | −8.3 | −10 | −9.3 |
RPC10 | −11.2 | −8.7 | −9 | −7.7 | −8.4 | −7.9 | −9.2 | −9.2 | −8.6 | −7.7 | −8.6 | −7.8 | −6.4 | −7.9 | −8.1 | −8.7 |
RPC11 | −8.5 | −7.4 | −9.1 | −7.7 | −8.8 | −7.4 | −8 | −7.9 | −8.7 | −6.5 | −7.7 | −8.8 | −6.8 | −6.6 | −8.9 | −7.2 |
RPC12 | −10.3 | −8.3 | −8.9 | −7.7 | −8.1 | −7.3 | −8.9 | −8.7 | −8.1 | −6.7 | −8.2 | −7.4 | −5.8 | −7.6 | −7.5 | −7.6 |
RPC13 | −6.3 | −5.5 | −5.9 | −6.2 | −5.7 | −5.4 | −6.2 | −6.2 | −6.5 | −4.4 | −5.3 | −4.7 | −4.1 | −4.5 | −5.5 | −5.5 |
RPC14 | −6.4 | −5.5 | −6 | −6.3 | −5.8 | −5.4 | −6.2 | −6.1 | −6.6 | −4.3 | −5.1 | −4.6 | −3.9 | −4.4 | −5.4 | −5.7 |
RPD01 | −11 | −9.9 | −9 | −8.1 | −7.9 | −8.3 | −8.8 | −8.6 | −8.1 | −7 | −7.7 | −7.4 | −6.4 | −7.8 | −7.7 | −9.1 |
EXT01 | −6.3 | −5.1 | −5.5 | −5.9 | −5.8 | −5.3 | −6.2 | −6.2 | −6.2 | −4.4 | −5.1 | −4.9 | −3.9 | −4.3 | −5.3 | −5.6 |
EXT02 | −10 | −8.4 | −8.5 | −6.5 | −7.1 | −7.2 | −9.8 | −9.6 | −7.6 | −6.3 | −7.3 | −6.6 | −6 | −7 | −7.1 | −7.2 |
EXT03 | −9 | −7.8 | −8.3 | −6.5 | −6.9 | −6.8 | −10.1 | −10 | −7.1 | −5.7 | −6.8 | −6.1 | −5.7 | −6.4 | −6.8 | −6.9 |
EXT04 | −8 | −9 | −9.6 | −8.4 | −8.2 | −7.9 | 0.9 | −3.1 | −8.2 | −7.5 | −8.2 | −8.7 | −7.2 | −7.2 | −9.3 | −8.2 |
EXT05 | −6.2 | −6.1 | −7.2 | −6.5 | −6.9 | −5.6 | −6.9 | −6.7 | −6.1 | −5.4 | −7.4 | −7 | −5.3 | −5.7 | −7.4 | −5.2 |
EXT06 | −9.6 | −6.9 | −7.4 | −6.9 | −7.6 | −7.5 | −5.1 | −5.5 | −6.5 | −6 | −7.7 | −7.6 | −5.4 | −6 | −8 | −6.9 |
EXT07 | −9.9 | −7.3 | −8.1 | −6.7 | −7.5 | −6.3 | −7.2 | −7.8 | −6.7 | −6.3 | −7.2 | −6.6 | −5.9 | −6.5 | −6.5 | −7.1 |
EXT08 | −6 | −6.8 | −6.1 | −4.9 | −5 | −5 | −6 | −6 | −5.3 | −4.4 | −4.8 | −4 | −4.4 | −5 | −4.5 | −6.5 |
EXT09 | −11.2 | −7 | −9.2 | −6.7 | −8.6 | −6.6 | −7.8 | −7.8 | −7.6 | −6.4 | −7 | −7.4 | −6.4 | −7.2 | −7 | −6.1 |
EXT10 | −9.7 | −7.7 | −9 | −7.3 | −8.3 | −6.1 | −7.1 | −7.8 | −6.8 | −6.7 | −7.7 | −7.4 | −6.3 | −6.9 | −7.6 | −6 |
VINA scores of the conformation with the lowest scores after 30 independent cycles of each target–ligand pair for the set of ligands evaluated.
ACE2 | |
COVID-19 | Coronavirus disease 19 |
HCV | |
HTVS | |
ISG15 | |
MERS-CoV | Middle East respiratory syndrome coronavirus |
Mpro | |
PLpro | |
PPI | |
RBD | |
Rdrp complex | RNA-dependent RNA polymerase complex |
SARS-CoV | Severe acute respiratory syndrome coronavirus |
SARS-CoV-2 | Severe acute respiratory syndrome coronavirus 2 |
ssRNA | |
TMPRSS2 | Transmembrane serine protease 2 |
Our journals are currently in their launching issue. They will be applied to all relevant indexes as soon as they are eligible. These include (but are not limited to): Web of Science, Scopus, PubMed, MEDLINE, Database of Open Access Journals (DOAJ), Google Scholar and Inspec.
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This chapter will focus on usage of virtual reality in occupational therapy, history and recent developments, types of virtual reality technologic equipment, pros and cons, usage for pediatric, adult and geriatric people and recent research and articles.",book:{id:"5711",slug:"occupational-therapy-occupation-focused-holistic-practice-in-rehabilitation",title:"Occupational Therapy",fullTitle:"Occupational Therapy - Occupation Focused Holistic Practice in Rehabilitation"},signatures:"Orkun Tahir Aran, Sedef Şahin, Berkan Torpil, Tarık Demirok and\nHülya Kayıhan",authors:[{id:"172938",title:"Prof.",name:"Hulya",middleName:null,surname:"Kayihan",slug:"hulya-kayihan",fullName:"Hulya Kayihan"},{id:"183079",title:"Ph.D.",name:"Sedef",middleName:null,surname:"Şahin",slug:"sedef-sahin",fullName:"Sedef Şahin"},{id:"196848",title:"M.Sc.",name:"Orkun Tahir",middleName:null,surname:"Aran",slug:"orkun-tahir-aran",fullName:"Orkun Tahir Aran"},{id:"197159",title:"Mr.",name:"Tarık",middleName:null,surname:"Demirok",slug:"tarik-demirok",fullName:"Tarık Demirok"},{id:"197312",title:"M.Sc.",name:"Berkan",middleName:null,surname:"Torpil",slug:"berkan-torpil",fullName:"Berkan Torpil"}]},{id:"61806",doi:"10.5772/intechopen.78312",title:"Executive Functions and Neurology in Children and Adolescents",slug:"executive-functions-and-neurology-in-children-and-adolescents",totalDownloads:1759,totalCrossrefCites:3,totalDimensionsCites:5,abstract:"This chapter discusses the theoretical and methodological issues of creating a developmental perspective on executive function (EF) in childhood and adolescence. Focusing on school periods, this section outlines the development of the basic components of EF—inhibition, working memory, and attention. Cognitive and neurophysiological evaluations show that despite the emergence of EF in the first few years of life, it continues to grow significantly in childhood and adolescence. The components vary slightly according to their developmental sequence. The chapter links findings to long-standing developmental issues (i.e. developmental sequences and processes) and suggests the necessary research to establish a developmental framework covering early childhood throughout adolescence.",book:{id:"6772",slug:"occupational-therapy-therapeutic-and-creative-use-of-activity",title:"Occupational Therapy",fullTitle:"Occupational Therapy - Therapeutic and Creative Use of Activity"},signatures:"Gokcen Akyurek",authors:[{id:"197265",title:"Dr.",name:"Gokcen",middleName:null,surname:"Akyurek",slug:"gokcen-akyurek",fullName:"Gokcen Akyurek"}]},{id:"55024",doi:"10.5772/intechopen.68463",title:"Occupational Therapy in Oncology and Palliative Care",slug:"occupational-therapy-in-oncology-and-palliative-care",totalDownloads:2699,totalCrossrefCites:1,totalDimensionsCites:4,abstract:"Cancer is a chronic disease that may occur in both children and adults. Occupational therapy focuses on the activity limitations and participation problems in their life. Oncology rehabilitation involves in helping an individual with cancer to regain maximum physical, psychological, cognitive, social, and vocational functioning with the limits up to disease and its treatments in an interdisciplinary team concept. These treatment options are associated with the risk of some side effects, including fatigue, pain, cognitive problems, decrease in bone density and muscle endurance, weight loss, and stress- or anxiety-related psychosocial problems. Occupational therapy approaches are a holistic view in a client center and use training in activities of daily living, assistive technology, education of energy conservation techniques, and management of treatment-related problems, such as pain, fatigue, and nausea. In palliative and hospice care, occupational therapists support clients with cancer by minimizing the secondary symptoms related to cancer and its treatments. At the end of life, occupational therapy offers to identify the roles and activities that are meaningful and purposeful to the client with cancer and try to determine the barriers that limit their performance. Clients with cancer who have childhood cancer or adult cancer can face problems about body structure and functions, activity, and participation, which may limit their participation to their daily life.",book:{id:"5711",slug:"occupational-therapy-occupation-focused-holistic-practice-in-rehabilitation",title:"Occupational Therapy",fullTitle:"Occupational Therapy - Occupation Focused Holistic Practice in Rehabilitation"},signatures:"Sedef Şahin, Semin Akel and Meral Zarif",authors:[{id:"183079",title:"Ph.D.",name:"Sedef",middleName:null,surname:"Şahin",slug:"sedef-sahin",fullName:"Sedef Şahin"},{id:"183078",title:"Dr.",name:"Burcu Semin",middleName:null,surname:"Akel",slug:"burcu-semin-akel",fullName:"Burcu Semin Akel"},{id:"198859",title:"Dr.",name:"Meral",middleName:null,surname:"Zarif",slug:"meral-zarif",fullName:"Meral Zarif"}]},{id:"56049",doi:"10.5772/intechopen.69101",title:"Measurement of Participation: The Role Checklist Version 3: Satisfaction and Performance",slug:"measurement-of-participation-the-role-checklist-version-3-satisfaction-and-performance",totalDownloads:2823,totalCrossrefCites:3,totalDimensionsCites:4,abstract:"Participation in society is an area of interest to both clinicians and population researchers. Measurement of participation is therefore important, yet differences in definition, in terms of both content and scope, have made general agreement on one instrument tool elusive. What is recognized is the need for a theoretically based tool that captures both the insider and the outsider perspective. The outsider perspective, inclusive of the generally held views of a society, supports the utility for aggregating population data, whereas the insider perspective provides the internally held views of an individual needed for client-centered treatment planning. The Role Checklist Version 3 modifies one of the most commonly used assessment tools in occupational therapy practice, has good preliminary psychometric properties, and is theoretically consistent with both the ICF and the Model of Human Occupation. The Model of Human Occupation is the most widely used theoretical model in occupational therapy. This chapter provides an overview of the theoretical development, empirical testing, and implications for use of this participation measure by occupational therapists along with implications for population researchers.",book:{id:"5711",slug:"occupational-therapy-occupation-focused-holistic-practice-in-rehabilitation",title:"Occupational Therapy",fullTitle:"Occupational Therapy - Occupation Focused Holistic Practice in Rehabilitation"},signatures:"Patricia J. Scott, Kelsey McKinney, Jeff Perron, Emily Ruff and Jessica\nSmiley",authors:[{id:"195495",title:"Dr.",name:"Patricia J",middleName:null,surname:"Scott",slug:"patricia-j-scott",fullName:"Patricia J Scott"},{id:"208801",title:"Dr.",name:"Kelsey G.",middleName:null,surname:"McKinney",slug:"kelsey-g.-mckinney",fullName:"Kelsey G. McKinney"},{id:"208802",title:"Mr.",name:"Jeffrey M.",middleName:null,surname:"Perron",slug:"jeffrey-m.-perron",fullName:"Jeffrey M. Perron"},{id:"208803",title:"Dr.",name:"Emily G.",middleName:null,surname:"Ruff",slug:"emily-g.-ruff",fullName:"Emily G. Ruff"},{id:"208804",title:"Dr.",name:"Jessica L.",middleName:null,surname:"Smiley",slug:"jessica-l.-smiley",fullName:"Jessica L. Smiley"}]},{id:"55018",doi:"10.5772/intechopen.68315",title:"Psychomotor Therapy for Patients with Severe Mental Health Disorders",slug:"psychomotor-therapy-for-patients-with-severe-mental-health-disorders",totalDownloads:2274,totalCrossrefCites:3,totalDimensionsCites:3,abstract:"Psychomotor therapy is defined as a method of treatment based on a holistic view of the human being that is derived from the unity of body and mind. Assessments (observation and/or evaluation) are essential to achieving concrete psychosocial objectives methodically. Psychomotor therapy uses movement, body awareness and a wide range of movement activities to optimize movement behaviour as well as the cognitive, affective and relational aspects of psychomotor functioning (i.e. the relationships between physical movements and cognitive and social-affective aspects). Consequently, the approach to this type of therapy integrates the physical, cognitive and emotional aspects of functioning in relation to the capacity of being and acting in a psychosocial context in order to achieve clearly defined goals in consultation with the patients. Psychomotor therapy framework consists of three different approaches: a health-related approach, a psychosocial approach and a psychotherapeutic approach, which can be embedded in several psychotherapeutic approaches. Through the implementation of both systematically planned evaluations and individually targeted interventions in group, the psychomotor therapist strives to broaden the general action competences and specific skills and to stimulate a positive self-image and personal well-being in balanced social relationships. Today, there is sufficient evidence that psychomotor therapy has a major contribution to both well-being and mental health of patients with severe psychiatric problems. In Flemish psychiatric hospitals, psychomotor therapy is imbedded in different treatment programmes. In this chapter, the theory behind this approach and some practical examples will be provided.",book:{id:"5711",slug:"occupational-therapy-occupation-focused-holistic-practice-in-rehabilitation",title:"Occupational Therapy",fullTitle:"Occupational Therapy - Occupation Focused Holistic Practice in Rehabilitation"},signatures:"Michel Probst",authors:[{id:"196227",title:"Prof.",name:"Michel",middleName:null,surname:"Probst",slug:"michel-probst",fullName:"Michel Probst"}]}],mostDownloadedChaptersLast30Days:[{id:"55080",title:"Life Skills in Occupational Therapy",slug:"life-skills-in-occupational-therapy",totalDownloads:6079,totalCrossrefCites:4,totalDimensionsCites:1,abstract:"Occupational therapy is a health profession that uses the purposeful activities to achieve multiple and complex rehabilitation aims. The main goals of the occupational therapy are to support the reintegration of individuals in daily living skills as well as to increase their independence and autonomy. Interventions of occupational therapists have primarily focused on self-care, productivity, and leisure time activities. Since the life skills includes a wide range of abilities that enable a person to perform personal care and more complicated tasks such as traveling, shopping, community participation etc., occupational therapists provide life skills training programs to meet the needs of the clients. This chapter aims to contribute to the current understanding and practices of life skills from an occupational therapy perspective. The chapter starts with a brief discussion of the importance of life skills in occupational therapy. After this introduction, the first part takes a look at the definition of life skills and identifies core components of life skills. The second part describes assessment and interventions of life skills. The third one gives an overview about school life skills programs for children and adolescents. Finally, the last part explains some life skills programs in people with disadvantages.",book:{id:"5711",slug:"occupational-therapy-occupation-focused-holistic-practice-in-rehabilitation",title:"Occupational Therapy",fullTitle:"Occupational Therapy - Occupation Focused Holistic Practice in Rehabilitation"},signatures:"Hatice Abaoğlu, Özge Buket Cesim, Sinem Kars and Zeynep Çelik",authors:[{id:"197551",title:"Dr.",name:"Hatice",middleName:null,surname:"Abaoğlu",slug:"hatice-abaoglu",fullName:"Hatice Abaoğlu"},{id:"205199",title:"Dr.",name:"Sinem",middleName:null,surname:"Kars",slug:"sinem-kars",fullName:"Sinem Kars"},{id:"205200",title:"Dr.",name:"Zeynep",middleName:null,surname:"Celik",slug:"zeynep-celik",fullName:"Zeynep Celik"},{id:"205203",title:"Ms.",name:"Özge Buket",middleName:null,surname:"Cesim",slug:"ozge-buket-cesim",fullName:"Özge Buket Cesim"}]},{id:"62493",title:"Occupational Therapy in Forensic Settings",slug:"occupational-therapy-in-forensic-settings",totalDownloads:2547,totalCrossrefCites:2,totalDimensionsCites:2,abstract:"It is necessary for a person to comply with the expectations of society and the rules of law to which these expectations are secured. Offenders turn back to the community after the penalty was executed by isolating from society and some occupations. An occupational imbalance is seen in the individuals, during this penalty period and afterward, because of limited occupational participation. As an occupational being, this affects their physical, mental and psychological well-being. Imprisonment is an important practice in criminal law to punish criminals. This may be necessary for the protection of society from criminals, but successful integration into a community after exiting the prison is the most important factor in preventing recidivism. Occupational therapy focuses on health and well-being by using meaningful and purposeful occupations. Occupation involves any activity that people perform or participate in, such as giving care to themselves or others, working, learning, playing games, and interacting with others. From this perspective, the role of occupational therapists in forensic settings is to determine the abilities of these individuals to congregate their deprived freedoms and use them to train them for an independent and autonomous life; to provide a professional orientation, career counseling, and self-esteem; to gain some habits for physical, spiritual and moral life and to reinforce.",book:{id:"6772",slug:"occupational-therapy-therapeutic-and-creative-use-of-activity",title:"Occupational Therapy",fullTitle:"Occupational Therapy - Therapeutic and Creative Use of Activity"},signatures:"Esma Ozkan, Sümeyye Belhan, Mahmut Yaran and Meral Zarif",authors:null},{id:"70122",title:"Parkinson’s Disease Rehabilitation: Effectiveness Approaches and New Perspectives",slug:"parkinson-s-disease-rehabilitation-effectiveness-approaches-and-new-perspectives",totalDownloads:2085,totalCrossrefCites:2,totalDimensionsCites:3,abstract:"Parkinson’s disease has been considered one of the most important and common neurodegenerative diseases in the world. Its motor and nonmotor signs determine a huge functional loss, leading the individuals to lose their independence. Although the treatment requires a pharmacological approach, physical therapy has confirmed its importance in this process. Today, neurorehabilitation is indispensable to increase many of the cardinal signs of the disease. Using traditional or technological approaches, physical therapy has reached good results in improving motor and nonmotor functions, as well as the quality of life of Parkinsonians. However, it is important to develop and to fortify the physical therapy approach so that we can provide stronger evidence about our practice.",book:{id:"7543",slug:"physical-therapy-effectiveness",title:"Physical Therapy Effectiveness",fullTitle:"Physical Therapy Effectiveness"},signatures:"Luciana Auxiliadora de Paula Vasconcelos",authors:[{id:"98546",title:"Dr.",name:"Luciana Auxiliadora",middleName:null,surname:"De Paula Vasconcelos",slug:"luciana-auxiliadora-de-paula-vasconcelos",fullName:"Luciana Auxiliadora De Paula Vasconcelos"}]},{id:"62210",title:"Occupational Therapy’s Role in the Treatment of Children with Autism Spectrum Disorders",slug:"occupational-therapy-s-role-in-the-treatment-of-children-with-autism-spectrum-disorders",totalDownloads:2761,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"Occupational therapists (OT) offer a wide range of therapies for individuals with ASD on the basis of specific deficits and difficulties. This chapter explores the role that OT plays, and the expertise, in relation to the interdisciplinary team. In addition, it discusses and presents empirical support for several therapeutic approaches commonly used by OTs working with individuals with ASD.",book:{id:"6772",slug:"occupational-therapy-therapeutic-and-creative-use-of-activity",title:"Occupational Therapy",fullTitle:"Occupational Therapy - Therapeutic and Creative Use of Activity"},signatures:"Bryan M. Gee, Amy Nwora and Theodore W. Peterson",authors:null},{id:"55049",title:"Community Participation in People with Disabilities",slug:"community-participation-in-people-with-disabilities",totalDownloads:2440,totalCrossrefCites:2,totalDimensionsCites:2,abstract:"Despite the fact that participation is an important building and a valuable target, the conceptualization, identification and measurement methods vary widely. This chapter tried to gain an insider’s perspective from the obstacles that summarize what meaning participation means, how to characterize it, and what prevents and supports participation. Participation is seen as a right and a responsibility attributed to and attributed to both the person and the community. Participation does not take place in a vacuum; the environment dynamically influences participation. The effects of this conceptual framework are discussed for change at the level of evaluation, research and systems to support the participation of the people with disability.",book:{id:"5711",slug:"occupational-therapy-occupation-focused-holistic-practice-in-rehabilitation",title:"Occupational Therapy",fullTitle:"Occupational Therapy - Occupation Focused Holistic Practice in Rehabilitation"},signatures:"Gokcen Akyurek and Gonca Bumin",authors:[{id:"32431",title:"Prof.",name:"Gonca",middleName:null,surname:"Bumin",slug:"gonca-bumin",fullName:"Gonca Bumin"},{id:"197265",title:"Dr.",name:"Gokcen",middleName:null,surname:"Akyurek",slug:"gokcen-akyurek",fullName:"Gokcen Akyurek"}]}],onlineFirstChaptersFilter:{topicId:"198",limit:6,offset:0},onlineFirstChaptersCollection:[],onlineFirstChaptersTotal:0},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:8,limit:8,total:0},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:11,numberOfPublishedChapters:91,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:108,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:33,numberOfPublishedChapters:333,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:14,numberOfPublishedChapters:145,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:11,numberOfPublishedChapters:144,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!0},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:126,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:11,numberOfPublishedChapters:113,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2632-0517",doi:"10.5772/intechopen.73681",isOpenForSubmission:!0}],sshSeriesList:[{id:"22",title:"Business, Management and Economics",numberOfPublishedBooks:1,numberOfPublishedChapters:23,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2753-894X",doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:13,numberOfOpenTopics:1,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!0},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:5,numberOfUpcomingTopics:0,issn:"2753-6580",doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{id:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. The whole process of submitting an article and editing of the submitted article goes extremely smooth and fast, the number of reads and downloads of chapters is high, and the contributions are also frequently cited.",author:{id:"55578",name:"Antonio",surname:"Jurado-Navas",institutionString:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRisIQAS/Profile_Picture_1626166543950",slug:"antonio-jurado-navas",institution:{id:"720",name:"University of Malaga",country:{id:null,name:"Spain"}}}},{id:"6",text:"It is great to work with the IntechOpen to produce a worthwhile collection of research that also becomes a great educational resource and guide for future research endeavors.",author:{id:"259298",name:"Edward",surname:"Narayan",institutionString:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259298/images/system/259298.jpeg",slug:"edward-narayan",institution:{id:"3",name:"University of Queensland",country:{id:null,name:"Australia"}}}}]},series:{item:{id:"14",title:"Artificial Intelligence",doi:"10.5772/intechopen.79920",issn:"2633-1403",scope:"Artificial Intelligence (AI) is a rapidly developing multidisciplinary research area that aims to solve increasingly complex problems. In today's highly integrated world, AI promises to become a robust and powerful means for obtaining solutions to previously unsolvable problems. This Series is intended for researchers and students alike interested in this fascinating field and its many applications.",coverUrl:"https://cdn.intechopen.com/series/covers/14.jpg",latestPublicationDate:"August 17th, 2022",hasOnlineFirst:!0,numberOfPublishedBooks:11,editor:{id:"218714",title:"Prof.",name:"Andries",middleName:null,surname:"Engelbrecht",slug:"andries-engelbrecht",fullName:"Andries Engelbrecht",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRNR8QAO/Profile_Picture_1622640468300",biography:"Andries Engelbrecht received the Masters and PhD degrees in Computer Science from the University of Stellenbosch, South Africa, in 1994 and 1999 respectively. He is currently appointed as the Voigt Chair in Data Science in the Department of Industrial Engineering, with a joint appointment as Professor in the Computer Science Division, Stellenbosch University. Prior to his appointment at Stellenbosch University, he has been at the University of Pretoria, Department of Computer Science (1998-2018), where he was appointed as South Africa Research Chair in Artifical Intelligence (2007-2018), the head of the Department of Computer Science (2008-2017), and Director of the Institute for Big Data and Data Science (2017-2018). In addition to a number of research articles, he has written two books, Computational Intelligence: An Introduction and Fundamentals of Computational Swarm Intelligence.",institutionString:null,institution:{name:"Stellenbosch University",institutionURL:null,country:{name:"South Africa"}}},editorTwo:null,editorThree:null},subseries:{paginationCount:6,paginationItems:[{id:"22",title:"Applied Intelligence",coverUrl:"https://cdn.intechopen.com/series_topics/covers/22.jpg",isOpenForSubmission:!0,editor:{id:"27170",title:"Prof.",name:"Carlos",middleName:"M.",surname:"Travieso-Gonzalez",slug:"carlos-travieso-gonzalez",fullName:"Carlos Travieso-Gonzalez",profilePictureURL:"https://mts.intechopen.com/storage/users/27170/images/system/27170.jpeg",biography:"Carlos M. Travieso-González received his MSc degree in Telecommunication Engineering at Polytechnic University of Catalonia (UPC), Spain in 1997, and his Ph.D. degree in 2002 at the University of Las Palmas de Gran Canaria (ULPGC-Spain). He is a full professor of signal processing and pattern recognition and is head of the Signals and Communications Department at ULPGC, teaching from 2001 on subjects on signal processing and learning theory. His research lines are biometrics, biomedical signals and images, data mining, classification system, signal and image processing, machine learning, and environmental intelligence. He has researched in 52 international and Spanish research projects, some of them as head researcher. He is co-author of 4 books, co-editor of 27 proceedings books, guest editor for 8 JCR-ISI international journals, and up to 24 book chapters. He has over 450 papers published in international journals and conferences (81 of them indexed on JCR – ISI - Web of Science). He has published seven patents in the Spanish Patent and Trademark Office. He has been a supervisor on 8 Ph.D. theses (11 more are under supervision), and 130 master theses. He is the founder of The IEEE IWOBI conference series and the president of its Steering Committee, as well as the founder of both the InnoEducaTIC and APPIS conference series. He is an evaluator of project proposals for the European Union (H2020), Medical Research Council (MRC, UK), Spanish Government (ANECA, Spain), Research National Agency (ANR, France), DAAD (Germany), Argentinian Government, and the Colombian Institutions. He has been a reviewer in different indexed international journals (<70) and conferences (<250) since 2001. He has been a member of the IASTED Technical Committee on Image Processing from 2007 and a member of the IASTED Technical Committee on Artificial Intelligence and Expert Systems from 2011. \n\nHe has held the general chair position for the following: ACM-APPIS (2020, 2021), IEEE-IWOBI (2019, 2020 and 2020), A PPIS (2018, 2019), IEEE-IWOBI (2014, 2015, 2017, 2018), InnoEducaTIC (2014, 2017), IEEE-INES (2013), NoLISP (2011), JRBP (2012), and IEEE-ICCST (2005)\n\nHe is an associate editor of the Computational Intelligence and Neuroscience Journal (Hindawi – Q2 JCR-ISI). He was vice dean from 2004 to 2010 in the Higher Technical School of Telecommunication Engineers at ULPGC and the vice dean of Graduate and Postgraduate Studies from March 2013 to November 2017. He won the “Catedra Telefonica” Awards in Modality of Knowledge Transfer, 2017, 2018, and 2019 editions, and awards in Modality of COVID Research in 2020.\n\nPublic References:\nResearcher ID http://www.researcherid.com/rid/N-5967-2014\nORCID https://orcid.org/0000-0002-4621-2768 \nScopus Author ID https://www.scopus.com/authid/detail.uri?authorId=6602376272\nScholar Google https://scholar.google.es/citations?user=G1ks9nIAAAAJ&hl=en \nResearchGate https://www.researchgate.net/profile/Carlos_Travieso",institutionString:null,institution:{name:"University of Las Palmas de Gran Canaria",institutionURL:null,country:{name:"Spain"}}},editorTwo:null,editorThree:null},{id:"23",title:"Computational Neuroscience",coverUrl:"https://cdn.intechopen.com/series_topics/covers/23.jpg",isOpenForSubmission:!0,editor:{id:"14004",title:"Dr.",name:"Magnus",middleName:null,surname:"Johnsson",slug:"magnus-johnsson",fullName:"Magnus Johnsson",profilePictureURL:"https://mts.intechopen.com/storage/users/14004/images/system/14004.png",biography:"Dr Magnus Johnsson is a cross-disciplinary scientist, lecturer, scientific editor and AI/machine learning consultant from Sweden. \n\nHe is currently at Malmö University in Sweden, but also held positions at Lund University in Sweden and at Moscow Engineering Physics Institute. \nHe holds editorial positions at several international scientific journals and has served as a scientific editor for books and special journal issues. \nHis research interests are wide and include, but are not limited to, autonomous systems, computer modeling, artificial neural networks, artificial intelligence, cognitive neuroscience, cognitive robotics, cognitive architectures, cognitive aids and the philosophy of mind. \n\nDr. Johnsson has experience from working in the industry and he has a keen interest in the application of neural networks and artificial intelligence to fields like industry, finance, and medicine. \n\nWeb page: www.magnusjohnsson.se",institutionString:null,institution:{name:"Malmö University",institutionURL:null,country:{name:"Sweden"}}},editorTwo:null,editorThree:null},{id:"24",title:"Computer Vision",coverUrl:"https://cdn.intechopen.com/series_topics/covers/24.jpg",isOpenForSubmission:!0,editor:{id:"294154",title:"Prof.",name:"George",middleName:null,surname:"Papakostas",slug:"george-papakostas",fullName:"George Papakostas",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002hYaGbQAK/Profile_Picture_1624519712088",biography:"George A. Papakostas has received a diploma in Electrical and Computer Engineering in 1999 and the M.Sc. and Ph.D. degrees in Electrical and Computer Engineering in 2002 and 2007, respectively, from the Democritus University of Thrace (DUTH), Greece. Dr. Papakostas serves as a Tenured Full Professor at the Department of Computer Science, International Hellenic University, Greece. Dr. Papakostas has 10 years of experience in large-scale systems design as a senior software engineer and technical manager, and 20 years of research experience in the field of Artificial Intelligence. Currently, he is the Head of the “Visual Computing” division of HUman-MAchines INteraction Laboratory (HUMAIN-Lab) and the Director of the MPhil program “Advanced Technologies in Informatics and Computers” hosted by the Department of Computer Science, International Hellenic University. He has (co)authored more than 150 publications in indexed journals, international conferences and book chapters, 1 book (in Greek), 3 edited books, and 5 journal special issues. His publications have more than 2100 citations with h-index 27 (GoogleScholar). His research interests include computer/machine vision, machine learning, pattern recognition, computational intelligence. \nDr. Papakostas served as a reviewer in numerous journals, as a program\ncommittee member in international conferences and he is a member of the IAENG, MIR Labs, EUCogIII, INSTICC and the Technical Chamber of Greece (TEE).",institutionString:null,institution:{name:"International Hellenic University",institutionURL:null,country:{name:"Greece"}}},editorTwo:null,editorThree:null},{id:"25",title:"Evolutionary Computation",coverUrl:"https://cdn.intechopen.com/series_topics/covers/25.jpg",isOpenForSubmission:!0,editor:{id:"136112",title:"Dr.",name:"Sebastian",middleName:null,surname:"Ventura Soto",slug:"sebastian-ventura-soto",fullName:"Sebastian Ventura Soto",profilePictureURL:"https://mts.intechopen.com/storage/users/136112/images/system/136112.png",biography:"Sebastian Ventura is a Spanish researcher, a full professor with the Department of Computer Science and Numerical Analysis, University of Córdoba. Dr Ventura also holds the positions of Affiliated Professor at Virginia Commonwealth University (Richmond, USA) and Distinguished Adjunct Professor at King Abdulaziz University (Jeddah, Saudi Arabia). Additionally, he is deputy director of the Andalusian Research Institute in Data Science and Computational Intelligence (DaSCI) and heads the Knowledge Discovery and Intelligent Systems Research Laboratory. He has published more than ten books and over 300 articles in journals and scientific conferences. Currently, his work has received over 18,000 citations according to Google Scholar, including more than 2200 citations in 2020. In the last five years, he has published more than 60 papers in international journals indexed in the JCR (around 70% of them belonging to first quartile journals) and he has edited some Springer books “Supervised Descriptive Pattern Mining” (2018), “Multiple Instance Learning - Foundations and Algorithms” (2016), and “Pattern Mining with Evolutionary Algorithms” (2016). He has also been involved in more than 20 research projects supported by the Spanish and Andalusian governments and the European Union. He currently belongs to the editorial board of PeerJ Computer Science, Information Fusion and Engineering Applications of Artificial Intelligence journals, being also associate editor of Applied Computational Intelligence and Soft Computing and IEEE Transactions on Cybernetics. Finally, he is editor-in-chief of Progress in Artificial Intelligence. He is a Senior Member of the IEEE Computer, the IEEE Computational Intelligence, and the IEEE Systems, Man, and Cybernetics Societies, and the Association of Computing Machinery (ACM). Finally, his main research interests include data science, computational intelligence, and their applications.",institutionString:null,institution:{name:"University of Córdoba",institutionURL:null,country:{name:"Spain"}}},editorTwo:null,editorThree:null},{id:"26",title:"Machine Learning and Data Mining",coverUrl:"https://cdn.intechopen.com/series_topics/covers/26.jpg",isOpenForSubmission:!0,editor:{id:"24555",title:"Dr.",name:"Marco Antonio",middleName:null,surname:"Aceves Fernandez",slug:"marco-antonio-aceves-fernandez",fullName:"Marco Antonio Aceves Fernandez",profilePictureURL:"https://mts.intechopen.com/storage/users/24555/images/system/24555.jpg",biography:"Dr. Marco Antonio Aceves Fernandez obtained his B.Sc. (Eng.) in Telematics from the Universidad de Colima, Mexico. 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He is currently a principal researcher in data analytics and optimisation at TECNALIA (Spain), a visiting fellow at the Basque Center for Applied Mathematics (BCAM) and a part-time lecturer at the University of the Basque Country (UPV/EHU). His research interests gravitate on the use of descriptive, prescriptive and predictive algorithms for data mining and optimization in a diverse range of application fields such as Energy, Transport, Telecommunications, Health and Industry, among others. In these fields he has published more than 240 articles, co-supervised 8 Ph.D. theses, edited 6 books, coauthored 7 patents and participated/led more than 40 research projects. 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He is currently a full professor in\nthe Department of Automation and Applied Informatics at the\nsame university. Dr. Voloşencu is the author of ten books, seven\nbook chapters, and more than 160 papers published in journals\nand conference proceedings. He has also edited twelve books and\nhas twenty-seven patents to his name. He is a manager of research grants, editor in\nchief and member of international journal editorial boards, a former plenary speaker, a member of scientific committees, and chair at international conferences. His\nresearch is in the fields of control systems, control of electric drives, fuzzy control\nsystems, neural network applications, fault detection and diagnosis, sensor network\napplications, monitoring of distributed parameter systems, and power ultrasound\napplications. 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He worked as a post-doctoral fellow at the Public Health Research Institute (PHRI), Newark, NJ for four years before accepting a three-year faculty position at Brigham Young University-Hawaii. Dr. Engohang-Ndong is a tenured faculty member with the academic rank of Full Professor at Kent State University, Ohio, where he teaches a wide range of biological science courses and pursues his research in medical and environmental microbiology. Recently, he expanded his research interest to epidemiology and biostatistics of chronic diseases in Gabon.",institutionString:"Kent State University",institution:{name:"Kent State University",country:{name:"United States of America"}}},{id:"188773",title:"Prof.",name:"Emmanuel",middleName:null,surname:"Drouet",slug:"emmanuel-drouet",fullName:"Emmanuel Drouet",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/188773/images/system/188773.png",biography:"Emmanuel Drouet, PharmD, is a Professor of Virology at the Faculty of Pharmacy, the University Grenoble-Alpes, France. As a head scientist at the Institute of Structural Biology in Grenoble, Dr. Drouet’s research investigates persisting viruses in humans (RNA and DNA viruses) and the balance with our host immune system. He focuses on these viruses’ effects on humans (both their impact on pathology and their symbiotic relationships in humans). He has an excellent track record in the herpesvirus field, and his group is engaged in clinical research in the field of Epstein-Barr virus diseases. He is the editor of the online Encyclopedia of Environment and he coordinates the Universal Health Coverage education program for the BioHealth Computing Schools of the European Institute of Science.",institutionString:null,institution:{name:"Grenoble Alpes University",country:{name:"France"}}},{id:"131400",title:"Prof.",name:"Alfonso J.",middleName:null,surname:"Rodriguez-Morales",slug:"alfonso-j.-rodriguez-morales",fullName:"Alfonso J. Rodriguez-Morales",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/131400/images/system/131400.png",biography:"Dr. Rodriguez-Morales is an expert in tropical and emerging diseases, particularly zoonotic and vector-borne diseases (especially arboviral diseases). He is the president of the Travel Medicine Committee of the Pan-American Infectious Diseases Association (API), as well as the president of the Colombian Association of Infectious Diseases (ACIN). He is a member of the Committee on Tropical Medicine, Zoonoses, and Travel Medicine of ACIN. He is a vice-president of the Latin American Society for Travel Medicine (SLAMVI) and a Member of the Council of the International Society for Infectious Diseases (ISID). Since 2014, he has been recognized as a Senior Researcher, at the Ministry of Science of Colombia. He is a professor at the Faculty of Medicine of the Fundacion Universitaria Autonoma de las Americas, in Pereira, Risaralda, Colombia. He is an External Professor, Master in Research on Tropical Medicine and International Health, Universitat de Barcelona, Spain. He is also a professor at the Master in Clinical Epidemiology and Biostatistics, Universidad Científica del Sur, Lima, Peru. In 2021 he has been awarded the “Raul Isturiz Award” Medal of the API. Also, in 2021, he was awarded with the “Jose Felix Patiño” Asclepius Staff Medal of the Colombian Medical College, due to his scientific contributions to COVID-19 during the pandemic. He is currently the Editor in Chief of the journal Travel Medicine and Infectious Diseases. His Scopus H index is 47 (Google Scholar H index, 68).",institutionString:"Institución Universitaria Visión de las Américas, Colombia",institution:null},{id:"332819",title:"Dr.",name:"Chukwudi Michael",middleName:"Michael",surname:"Egbuche",slug:"chukwudi-michael-egbuche",fullName:"Chukwudi Michael Egbuche",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/332819/images/14624_n.jpg",biography:"I an Dr. Chukwudi Michael Egbuche. I am a Senior Lecturer in the Department of Parasitology and Entomology, Nnamdi Azikiwe University, Awka.",institutionString:null,institution:{name:"Nnamdi Azikiwe University",country:{name:"Nigeria"}}},{id:"284232",title:"Mr.",name:"Nikunj",middleName:"U",surname:"Tandel",slug:"nikunj-tandel",fullName:"Nikunj Tandel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/284232/images/8275_n.jpg",biography:'Mr. Nikunj Tandel has completed his Master\'s degree in Biotechnology from VIT University, India in the year of 2012. He is having 8 years of research experience especially in the field of malaria epidemiology, immunology, and nanoparticle-based drug delivery system against the infectious diseases, autoimmune disorders and cancer. He has worked for the NIH funded-International Center of Excellence in Malaria Research project "Center for the study of complex malaria in India (CSCMi)" in collaboration with New York University. The preliminary objectives of the study are to understand and develop the evidence-based tools and interventions for the control and prevention of malaria in different sites of the INDIA. Alongside, with the help of next-generation genomics study, the team has studied the antimalarial drug resistance in India. Further, he has extended his research in the development of Humanized mice for the study of liver-stage malaria and identification of molecular marker(s) for the Artemisinin resistance. At present, his research focuses on understanding the role of B cells in the activation of CD8+ T cells in malaria. Received the CSIR-SRF (Senior Research Fellow) award-2018, FIMSA (Federation of Immunological Societies of Asia-Oceania) Travel Bursary award to attend the IUIS-IIS-FIMSA Immunology course-2019',institutionString:"Nirma University",institution:{name:"Nirma University",country:{name:"India"}}},{id:"334383",title:"Ph.D.",name:"Simone",middleName:"Ulrich",surname:"Ulrich Picoli",slug:"simone-ulrich-picoli",fullName:"Simone Ulrich Picoli",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/334383/images/15919_n.jpg",biography:"Graduated in Pharmacy from Universidade Luterana do Brasil (1999), Master in Agricultural and Environmental Microbiology from Federal University of Rio Grande do Sul (2002), Specialization in Clinical Microbiology from Universidade de São Paulo, USP (2007) and PhD in Sciences in Gastroenterology and Hepatology (2012). She is currently an Adjunct Professor at Feevale University in Medicine and Biomedicine courses and a permanent professor of the Academic Master\\'s Degree in Virology. She has experience in the field of Microbiology, with an emphasis on Bacteriology, working mainly on the following topics: bacteriophages, bacterial resistance, clinical microbiology and food microbiology.",institutionString:null,institution:{name:"Universidade Feevale",country:{name:"Brazil"}}},{id:"229220",title:"Dr.",name:"Amjad",middleName:"Islam",surname:"Aqib",slug:"amjad-aqib",fullName:"Amjad Aqib",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/229220/images/system/229220.png",biography:"Dr. Amjad Islam Aqib obtained a DVM and MSc (Hons) from University of Agriculture Faisalabad (UAF), Pakistan, and a PhD from the University of Veterinary and Animal Sciences Lahore, Pakistan. 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Professor Derbel has published many articles in journals and collaborates intensively with IntechOpen Access Publisher as an editor.",institutionString:"Clinique les Oliviers",institution:null},{id:"300144",title:"Dr.",name:"Meriem",middleName:null,surname:"Braiki",slug:"meriem-braiki",fullName:"Meriem Braiki",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/300144/images/system/300144.jpg",biography:"Dr. Meriem Braiki is a specialist in pediatric surgeon from Tunisia. She was born in 1985. She received her medical degree from the University of Medicine at Sousse, Tunisia. She achieved her surgical residency training periods in Pediatric Surgery departments at University Hospitals in Monastir, Tunis and France.\r\nShe is currently working at the Pediatric surgery department, Sidi Bouzid Hospital, Tunisia. Her hospital activities are mostly concerned with laparoscopic, parietal, urological and digestive surgery. 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I am currently working as a Professor at the Department of Medical Parasitology at Dokuz Eylul University, Izmir, Turkey.\n\nI have given many lectures, presentations in different academic meetings. I have more than 60 articles in peer-reviewed journals, 18 book chapters, 1 book editorship.\n\nMy research interests are Echinococcus granulosus, Echinococcus multilocularis (diagnosis, life cycle, in vitro and in vivo cultivation), and Trichomonas vaginalis (diagnosis, PCR, and in vitro cultivation).",institutionString:"Dokuz Eylül University",institution:{name:"Dokuz Eylül University",country:{name:"Turkey"}}},{id:"71812",title:"Prof.",name:"Hanem Fathy",middleName:"Fathy",surname:"Khater",slug:"hanem-fathy-khater",fullName:"Hanem Fathy Khater",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/71812/images/1167_n.jpg",biography:"Prof. Khater is a Professor of Parasitology at Benha University, Egypt. 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Her research is focused on searching of pesticides against mosquitoes, house flies, lice, green bottle fly, camel nasal botfly, soft and hard ticks, mites, and the diamondback moth as well as control of several parasites using safe and natural materials to avoid drug resistances and environmental contamination.",institutionString:null,institution:{name:"Banha University",country:{name:"Egypt"}}},{id:"99780",title:"Prof.",name:"Omolade",middleName:"Olayinka",surname:"Okwa",slug:"omolade-okwa",fullName:"Omolade Okwa",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/99780/images/system/99780.jpg",biography:"Omolade Olayinka Okwa is presently a Professor of Parasitology at Lagos State University, Nigeria. She has a PhD in Parasitology (1997), an MSc in Cellular Parasitology (1992), and a BSc (Hons) Zoology (1990) all from the University of Ibadan, Nigeria. She teaches parasitology at the undergraduate and postgraduate levels. She was a recipient of a Commonwealth fellowship supported by British Council tenable at the Centre for Entomology and Parasitology (CAEP), Keele University, United Kingdom between 2004 and 2005. She was awarded an Honorary Visiting Research Fellow at the same university from 2005 to 2007. \nShe has been an external examiner to the Department of Veterinary Microbiology and Parasitology, University of Ibadan, MSc programme between 2010 and 2012. She is a member of the Nigerian Society of Experimental Biology (NISEB), Parasitology and Public Health Society of Nigeria (PPSN), Science Association of Nigeria (SAN), Zoological Society of Nigeria (ZSN), and is Vice Chairperson of the Organisation of Women in Science (OWSG), LASU chapter. She served as Head of Department of Zoology and Environmental Biology, Lagos State University from 2007 to 2010 and 2014 to 2016. She is a reviewer for several local and international journals such as Unilag Journal of Science, Libyan Journal of Medicine, Journal of Medicine and Medical Sciences, and Annual Research and Review in Science. \nShe has authored 45 scientific research publications in local and international journals, 8 scientific reviews, 4 books, and 3 book chapters, which includes the books “Malaria Parasites” and “Malaria” which are IntechOpen access publications.",institutionString:"Lagos State University",institution:{name:"Lagos State University",country:{name:"Nigeria"}}},{id:"273100",title:"Dr.",name:"Vijay",middleName:null,surname:"Gayam",slug:"vijay-gayam",fullName:"Vijay Gayam",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/273100/images/system/273100.jpeg",biography:"Dr. Vijay Bhaskar Reddy Gayam is currently practicing as an internist at Interfaith Medical Center in Brooklyn, New York, USA. 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He serves as an editor, editorial board member and reviewer for multiple international journals. His research on Hepatitis C has been very successful and has led to multiple research awards, including the 'Equity in Prevention and Treatment Award” from the New York Department of Health Viral Hepatitis Symposium (2018) and the 'Presidential Poster Award” awarded to him by the American College of Gastroenterology (2018). He was also awarded 'Outstanding Clinician in General Medicine” by Venus International Foundation for his extensive research expertise and services, perform over and above the standard expected in the advancement of healthcare, patient safety and quality of care.",institutionString:"Interfaith Medical Center",institution:{name:"Interfaith Medical Center",country:{name:"United States of America"}}},{id:"93517",title:"Dr.",name:"Clement",middleName:"Adebajo",surname:"Meseko",slug:"clement-meseko",fullName:"Clement Meseko",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/93517/images/system/93517.jpg",biography:"Dr. Clement Meseko obtained DVM and PhD degree in Veterinary Medicine and Virology respectively. He has worked for over 20 years in both private and public sectors including the academia, contributing to knowledge and control of infectious disease. Through the application of epidemiological skill, classical and molecular virological skills, he investigates viruses of economic and public health importance for the mitigation of the negative impact on people, animal and the environment in the context of Onehealth. \r\nDr. Meseko’s field experience on animal and zoonotic diseases and pathogen dynamics at the human-animal interface over the years shaped his carrier in research and scientific inquiries. He has been part of the investigation of Highly Pathogenic Avian Influenza incursions in sub Saharan Africa and monitors swine Influenza (Pandemic influenza Virus) agro-ecology and potential for interspecies transmission. 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His research work has been published in various high-impact factor journals (Science, PNAS, Nature Medicine) with a high number of citations. He has received many awards and honors in India and abroad including various Young Scientist Awards, BBSRC India Partnering Award, and Dr. JC Bose National Award of Department of Biotechnology, Min. of Science and Technology, Govt. of India. Dr. Saxena is a fellow of various international societies/academies including the Royal College of Pathologists, United Kingdom; Royal Society of Medicine, London; Royal Society of Biology, United Kingdom; Royal Society of Chemistry, London; and Academy of Translational Medicine Professionals, Austria. He was named a Global Leader in Science by The Scientist. He is also an international opinion leader/expert in vaccination for Japanese encephalitis by IPIC (UK).",institutionString:"King George's Medical University",institution:{name:"King George's Medical University",country:{name:"India"}}},{id:"94928",title:"Dr.",name:"Takuo",middleName:null,surname:"Mizukami",slug:"takuo-mizukami",fullName:"Takuo Mizukami",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/94928/images/6402_n.jpg",biography:null,institutionString:null,institution:{name:"National Institute of Infectious Diseases",country:{name:"Japan"}}},{id:"233433",title:"Dr.",name:"Yulia",middleName:null,surname:"Desheva",slug:"yulia-desheva",fullName:"Yulia Desheva",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/233433/images/system/233433.png",biography:"Dr. Yulia Desheva is a leading researcher at the Institute of Experimental Medicine, St. Petersburg, Russia. She is a professor in the Stomatology Faculty, St. Petersburg State University. She has expertise in the development and evaluation of a wide range of live mucosal vaccines against influenza and bacterial complications. Her research interests include immunity against influenza and COVID-19 and the development of immunization schemes for high-risk individuals.",institutionString:'Federal State Budgetary Scientific Institution "Institute of Experimental Medicine"',institution:null},{id:"238958",title:"Mr.",name:"Atamjit",middleName:null,surname:"Singh",slug:"atamjit-singh",fullName:"Atamjit Singh",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/238958/images/6575_n.jpg",biography:null,institutionString:null,institution:null},{id:"252058",title:"M.Sc.",name:"Juan",middleName:null,surname:"Sulca",slug:"juan-sulca",fullName:"Juan Sulca",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/252058/images/12834_n.jpg",biography:null,institutionString:null,institution:null},{id:"191392",title:"Dr.",name:"Marimuthu",middleName:null,surname:"Govindarajan",slug:"marimuthu-govindarajan",fullName:"Marimuthu Govindarajan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/191392/images/5828_n.jpg",biography:"Dr. M. 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