The automotive lightweighting trends, being driven by sustainability, cost, and performance, that create the enormous demand for lightweight materials and design concepts, are assessed as a part of the circular economy solutions in modern mobility and transportation. The current strategies that aim beyond the basic weight reduction and cover also the structural efficiency as well as the economic and environmental impact are explained with an essence of guidelines for materials selection with an eco-friendly approach, substitution rules, and a paradigm of the multi-material design. Particular attention is paid to the metallic alloys sector and progress in global R&D activities that cover the “lightweight steel”, conventional aluminum, and magnesium alloys, together with well-established technologies of components manufacturing and future-oriented solutions, and with both adjusting to a transition from internal combustion engines to electric vehicles. Moreover, opportunities and challenges that the lightweighting creates are discussed with strategies of achieving its goals through structural engineering, including the metal-matrix composites, laminates, sandwich structures, and bionic-inspired archetypes. The profound role of the aerospace and car-racing industries is emphasized as the key drivers of lightweighting in mainstream automotive vehicles. Lightweighting is becoming the major trend, reaching many industrial sectors associated not only with all forms of transportation but more broadly with civil infrastructure, manufacturing, and clean energy technologies . In contThe core lightweighting objectives can be achieved through a number of individual strategies or their combinations that balance the design and material factors. The aim of lightweight design is to build structures with a minimal use of materials and an optimized utilization of the material strength, with numerical methods being developed to model the complex geometries of lightweight structures, e.g., in a parametric isogeometric environment . The matThe ultimate lightweighting goal can be accomplished, however, through an application of lightweight materials and by combining their unique features with other strategies . An incrlinear economy, with its predisposition towards wasting valuable resources, the concept of the circular economy offers opportunities for a more productive use of materials through recirculating their larger share through reuse and recycling, thus reducing waste in production and extending the lifetimes of products, and through associated policies  has been increasingly used . For a tDifferent materials have different potentials in reducing the weight of vehicles and different carbon footprints for production and recycling. For some metals, their energy-demanding manufacturing process affects the potential energy savings during their service in the vehicle. This is particularly valid for aluminum and magnesium, known by their large energy input required during the primary metal production.2 emissions.The automotive industry is going through an accelerated transformation with advancements in innovative technologies and changing of consumer preferences. Its business model that was valid for the last century to design, manufacture, sell, and service vehicles is anticipated to experience radical change through the involvement of intelligent mobility technologies. Such directions of sustainability, technology advancements, electrification, autonomous driving, consumer expectations, and personal mobility will drive changes over the next decade. It is predicted that the future transportation will be dominated by autonomous, connected, electric, and shared (ACES) vehicles that will alter the way consumers interact with vehicles. A lightweight vehicle is seen by automakers as a core aspect for sustainable mobility, improving both the fuel consumption and COmobility into recent literature may cause some terminology confusion by creating an impression that it aims to sound superior to the existing term transportation ..46]. WitLightweight materials are the essence of the weight reduction strategy and their typical list includes aluminum, magnesium, beryllium, titanium, titanium aluminides, structural ceramics, and composites with polymer, metal, and ceramic matrices . CurrentAluminum offers a lower-weight alternative to steel and it fits greatly into a circular economy since it is highly recovered and reused in new products. The current North American Light Vehicle Aluminum Content and Outlook report reveals that aluminum is the fastest growing automotive material . Since 2The major technology of manufacturing the automotive components from aluminum is casting a inset. The development history of aluminum sheets for the automotive industry covers Al–Mg, Al–Cu, and Al–Mg–Si within 2000, 5000, and 6000 series ,52. The The novel application example of aluminum in electric vehicles concerns the aluminum sheet battery enclosure that can help extend the driving range, allowing vehicles to travel up to 10% further on a single charge . The encAluminum is also considered for EV brakes, where regenerative braking sends back most of the car energy into its battery rather than dissipating it in the form of heat from the friction of a conventional braking system . The aluTo improve the part quality and simultaneously preserve the low cost rate typical for casting, semisolid processing technologies were developed. Instead of the fully liquid alloy, it explores a semisolid slurry where a solid fraction has a spheroidal morphology as a result of liquid-metal engineering. Such a slurry has thixotropic properties and therefore flows during die filling in a more laminar mode, forming low porosity (high integrity) parts after solidification and having better properties. During heat treatment, components do not experience blistering, as frequently seen in conventional castings. Between two essential routes of the semisolid processing, namely thixocasting and rheocasting, the latter is more developed commercially . It is oFor cast aluminum alloys with an application in and around the combustion engine, its thermal stability, determining the material ability of retaining its properties-required temperatures over extended service times, is of key importance . Current2 emission savings in both ICE and EV, with the aluminum electric vehicle emitting 1.5 tons less of greenhouse gases over its complete life cycle  contributed to the popularity of magnesium injection molding . The injAs shown earlier in Currently, there are still barriers to using magnesium in high-volume vehicle applications, as manufacturing and processing, in-service performance, and cost are seen as obstacles . Quite oA large range of emissions from the primary magnesium production depends on its geographic location and the process type used to generate the primary metal is what makes it difficult to precisely determine the emission scale ,81. AccoAs has been proven in aerospace, composites have extensive capabilities in contribute to lightweighting. However, the application of a composite structure is generally driven by the trade-off between its lightweight performance and production costs. As a result, the wide use of advanced composites in the automotive industry is still thwarted by their high cost. For example, lightweight carbon-fiber composites weigh about one-fifth of that of steel but are as good or better in terms of stiffness and strength. However, the cost of carbon-fiber composites is at least 20 times as much as steel, which prevents their use in cars.Metal-matrix composites (MMC), exploring the discontinuously reinforced aluminum matrix, have a potential for automotive applications due to their low density, good strength and ductility, and excellent thermal conductivity and corrosion resistance . The rei2O3 that reduce the weight and increase the engine efficiency, as well as replace other structural automotive components. Aluminum MMC with SiC can optimize high-performance automotive applications, including powertrain engine components, engine pistons, cylinders, connection rods, elements of vehicle braking systems (rotors), suspension systems, and chassis ..86]. In Sheet composite materials based on the aluminum matrix, reinforced with internal components such as an expanded steel mesh inlay, have great potential in the automotive industry. Although the steel reinforcement of aluminum sheets results in an increased density, it improves the strength and impact energy absorption in comparison with conventional aluminum alloys. An example of the reinforcement geometry is shown in Fiber metal laminates (FML), defined as a hybrid material consisting of alternating layers of monolithic metallic sheets and pre-impregnated fiber layers, take advantage of both metals and composites, and have shown great promise as lightweight structural materials in transport vehicles a 90]. O. O90]. OAn automated, large-scale production process of lightweight car structures with a high stiffness-to-weight ratio was proposed through the combination of high-strength steel and carbon fiber reinforced plastics (CFRP) prepregs in a hybrid material/fiber metal laminate . Carbon An application of fiber metal laminates in an automotive vehicle when preforming CFRP reinforcement resulted in an improvement in both the crashworthiness of the car body and the weight reduction . The strConsider the example of a natural fiber metal laminate consisting of two layers of woven fabric of a tropical plant of the mallow family, namely kenaf, in the polypropylene matrix and with aluminum 5052-O as the skin of the car front hood, as described in . The kev® was manufactured with the outer skins made of steel and the inner layer of a low-density, conductive, reinforced polymer core with a of density less than aluminum [The three-layer laminate termed as Smart Steelaluminum . The ligA sandwich-structured composite consists of two thin high-strength skins that are separated by the thick and lightweight core ,100,101.Sandwich composites belong to anisotropic materials, with their strength properties changing depending on the applied load direction. Since bending stresses reach maximum levels at the exterior, the material located further away from the centerline has a higher impact on bending strength and stiffness. Sandwich composites are becoming increasingly popular in the automotive sector and the challenge concerns how to replace the monolithic metals through this form without compromising the mechanical performance . The claAn aluminum foam sandwich (AFS) is comprised of a highly porous aluminum alloy foam core and two aluminum alloy face sheets b. The laThe example of a sandwich structure proposed in  consistsTo further reduce the specific weight, ARPRO, a propylene-based foam, sandwiched between two thin sheets of aluminum, was developed and its proposed application for the entire automotive sub-frame  is shown in Biomimicry, which include innovations inspired by nature, explores the strategies found in nature and adapts these biological models, systems, and elements to solve engineering problems. Bio-inspired concepts are increasingly used to design both vehicles and the materials used for vehicles.Cellular materials are a special class of lightweight materials that are found in nature but are also increasingly used in technological applications . They haHoneycomb structures, inspired from bee honeycombs, are attractive candidates to be widely used in lightweight automotive designs due to their high stiffness-to-weight ratio, high strength-to-weight ratio, cost efficiency, multi-functionality, and extraordinary energy absorption capacity.The honeycomb-inspired cellular structure for electric vehicle battery protection during collisions was designed this way . During In another example, a bio-inspired design strategy for aluminum alloy thin-walled structures was proposed to improve the performance of out-of-plane crashworthiness by altering the material distribution . In thisCellular foams represent a bio-inspired material that has received increased attention for vehicle crashworthiness due to their lightweighting and excellent energy absorption capabilities that allow for significant weight reductions without compromising the structural safety aspects. It was found that the cellular foams, when used as a filler material in thin-walled energy absorbers, improve the crashworthiness performance through favorable changing of the deformation mode .Manufacturability is an important limitation when designing lightweight structures. Advances in manufacturing technologies have led to the development of a new approach to material selection, in which complex designs can be created to achieve a specific mechanical objective. The new opportunities in the design of ultralight components are provided by additive manufacturing (3D printing), which allows for alternative, radical, and new design approaches for component internal structures. AM technologies make it possible to fabricate parts of any complexity . TherefoThe idea of reducing weight in high-strength elements using replicative structures is shown in Cellular lattice structures have been at the forefront of lightweighting through AM due to their ability to tailor mechanical responses through the tuning of the topology, surface thickness, cell size, and cell density. It can be designed for specific performance characteristics and has numerous advantages due to their large surface area, low weight, regularly repeated structure, and open interconnected pore spaces . The curThe lightweighting trend in the automotive industry is highly influenced by the entire transportation sector. In particular, aerospace and car racing industries are drivers of the technological development in mainstream automotive vehicles, reaching well beyond the subject of materials, for example, as seen in the radar-based driver assistance features of four-wheel steering.Although the there are many differences between the aerospace and automotive industries, and both have their distinct paths of development, historically, aerospace material innovations continuously penetrated into the automotive industry.As an expedition into technology transfer, serve the luxury and high-end performance automotive brands because the product cost and its affordability were not the primary constraints. With fewer regulations and cost considerations than in the mainstream automotive industry, car racing became an open test ground for changing industry boundaries and generating innovations that have far-reaching impacts on the future of mobility. When considering the fuel economy, in auto racing, this factor controls the difference between winning and not finishing the race. One of the reasons racecars are able to reach such impressive track times is because they are light. Thus, racecar designers routinely utilize lightweighting strategies to help make their cars fast.The interconnection between aerospace and automotive industry is schematically portrayed in As a challenge to overall technology, progress remains the material development line, as showed in this figure. During the past two decades, carbon-fiber composites have transformed aerospace manufacturing. Newer aircrafts, such as the Boeing 787 Dreamliner and the Airbus A350 XWB, are built mainly out of carbon fiber or other composite materials instead of heavier metals. Before carbon fibers, aluminum was used to build aircrafts, as it was lighter compared to steel. Although the carbon-fiber composite cost exceeds the cost of steel by up to two orders of magnitude, it is found in a variety of applications in luxury and high-end performance automotive brands.At the top of the material progress chain of the Ashby’s illustration, the additive manufacturing is shown . It is sThe automotive lightweighting strategy is becoming the mature growth trend, driven by sustainability, cost, and performance, and creating an enormous demand for modern lightweight materials and design concepts. The lightweighting strategy is growing as a part of the circular economy and is the solution for both modern mobility and transportation; its objectives are not exclusively focused on the reduction of weight but also cover other aspects such as structural efficiency as well as economic and environmental impacts. It appears that the emergence of electric vehicles creates even more pressure on lightweighting.In current lightweighting strategies, in addition to design, the materials represent the key part of the trend. A quest for lightweight materials creates many challenges and opportunities not only for existing conventional metallic alloys but also for novel strategies of achieving lightweighting goals through structural engineering, including metal-matrix composites, laminates, sandwich structures, and bionic-inspired archetypes.Lightweighting design combined with the use of advanced lightweight materials leads to structural optimization, maximum weight reduction, and fulfilled required performance and safety standards. Manufacturability is still an important limitation to the design of lightweight structures but with progress in additive manufacturing, this constraint will gradually be eliminated.


An approach called cell-free therapy has rapidly developed in regenerative medicine over the past decade. Understanding the molecular mechanisms and signaling pathways involved in the internal potential of tissue repair inspires the development of new strategies aimed at controlling and enhancing these processes during regeneration. The use of stem cell mobilization, or homing for regeneration based on endogenous healing mechanisms, prompted a new concept in regenerative medicine: endogenous regenerative medicine. The application of cell-free therapeutic agents leading to the recruitment/homing of endogenous stem cells has advantages in overcoming the limitations and risks associated with cell therapy. In this review, we discuss the potential of cell-free products such as the decellularized extracellular matrix, growth factors, extracellular vesicles and miRNAs in endogenous bone and dental regeneration.  Regenerative medicine, and, in particular, tissue engineering, are considered to be promising strategies for the repair of lost/damaged tissues, and aims to improve a patient’s quality of life. Approaches to tissue reconstruction are based on the use of stem cells (SCs), growth factors, signaling molecules, scaffolds and gene therapy. Stem cells, primarily mesenchymal SCs (MSCs) or progenitor cells, obtained from various tissues are attractive therapeutic agents. Their advantages are not only their rapid buildup in required amounts but also differentiation into various cell types to enable the modeling of various technologies for the reconstruction of lost or damaged tissues and organs ,2. CompaAn approach known as cell-free therapy has rapidly developed in regenerative medicine in the past decade, due to the growing volume of knowledge of the SC mechanisms of action. Together with an understanding of the paracrine effects of exogenously administered SCs, the molecular mechanisms and signaling pathways involved in the intrinsic potential of tissue regeneration started to be understood. This prompted the development of novel strategies to control and intensify these processes during regeneration. The use of SC mobilization/homing technology for regeneration based on endogenous healing mechanisms has become a new concept in regenerative medicine and is called endogenous regenerative technology (ERT) , endogenThe development of regenerative approaches in ERM/ERT requires, aside from the knowledge of biological SC homing–regulating signals, requires a comprehensive idea of the characteristics of the resident SCs’ microenvironment/niche, as well as of the extracellular factors involved in SC self-maintenance, to manipulate these cells. The key function of SC niches is to maintain a constant number of slowly dividing cells to balance the proportion of quiescent and activated cells. In a niche, as it is known, SCs are under the spatio-temporal control of an enormous number of factors, including chemokines, cytokines, growth factors, ligands, insoluble transmembrane receptors, proteases, adhesion molecules (selectins and integrins) and extracellular matrix (ECM) molecules . AdditioAn ever-increasing amount of currently emerging data indicates that the use of cell-free therapeutics leading to endogenous SC recruitment/homing has advantages for overcoming restrictions and risks associated with the use of cell-free therapy, including tumorigenesis, unwanted immune responses and transfer of pathogens. Additionally, it has significant advantages in production, storage and standardization ,14,15. TThis review deals with the potential of such cell-free products as decellularized ECM (dECM), growth factors, extracellular vesicles and miRNAs in bone and dental regeneration. We discuss the important roles of these cell-free products in forming a favorable niche for resident SC homing. As we mentioned above, the leading strategy in ERM is the use of various factors  that stiIt is known that, as well as growth factors and various signaling molecules, the traffic of SCs, their oriented migration, survival, self-renewal and differentiation can be regulated and enhanced by the ECM . ECMs are highly specialized and dynamic three-dimensional frameworks that aid the adhesion and functioning of various cells that form the basis of tissues. ECMs consist of numerous fibrillar components such as collagens, fibronectin and elastin, and nonfibrillar molecules such as proteoglycans, hyaluronan and glycoproteins, including matrix cell proteins. They interact with one another via numerous receptors, including integrins, discoidin domain receptors (DDR), proteoglycan surface receptors and hyaluronan receptors such as CD44, RHAMM, LYVE-1 and layilin, creating a multicomponent structural network . For insThe ECM molecular composition and structure differ in different tissues and change noticeably at the reconstitution of normal tissue, as well as in the progression of various diseases. ECMs in tissues such as cartilage and bone differ in their composition and structure from ECM in connective tissue, as they bear significant mechanical loads. The bone contains a specialized ECM, which essentially consists of collagen I, III and V fibrils . CollageIn view of the organization of various organs as three-dimensional structures, it is essential to choose for their regeneration an underlying scaffold mimicking the ECM in native tissue. The choice of scaffold materials and design impacts the therapeutic potential and the number and invasiveness of associated clinical procedures . As scafOverall, scaffolds should meet four main criteria with respect to (1) their shape ; (2) function ; (3) formation (contribution to regeneration); and (4) fixation (light interaction and integration with adjacent tissues) .Biomimetic frameworks actively developed at present in tissue engineering are formed based on purified ECM components and synthetic or natural polymers . BiomimeAlong with biomimetic frameworks, a strategy, which aims to use decellularized matrices that possess the advantage of a great similarity with the tissue to be replaced, is also being actively developed in tissue engineering. It is crucial to choose proper decellularization methods for obtaining decellularized matrix biomaterials , which wIn general, decellularization techniques preserve the capability of bone ECM scaffolds to induce the osteogenic differentiation of cells in vitro and to promote angiogenesis and cell infiltration in vivo ,47. MoreThe approach using only scaffolds is often insufficient for reconstructing a biologically suitable extracellular SC microenvironment/niche. In this case, combinations of ECM molecules and growth factors are used . Growth Promising results of preclinical and clinical research led to the subsequent introduction of various growth factors to the commercial market for regeneration of soft and hard tissues . HoweverThe combination of recombinant human BMP-2 (rhBMP-2) on an absorbable collagen sponge carrier was shown to induce bone formation in a number of preclinical and clinical investigations . The maiA particularly intriguing approach is the modification of known growth factors with so-called superaffinity domains, which allows these growth factors to achieve effects at a lower effective dose through better binding affinity to their carrier material or ECM proteins . Thus, the main tendencies in acellular bone tissue engineering today are directed to the creation of an ECM-based bioscaffold, usually by including several key growth factors for mimicking the natural bone structure and developing an environment for maintaining osteogenesis, osteoconduction and/or osteoinduction . AlthougAs noted above, cell-free therapy is an approach in regenerative medicine that makes use of SCs and progenitor cells as a source of therapeutic molecules, but not as therapeutic agents. SCs secrete various factors called secretomes. These factors can be found in a medium where SCs are cultured, i.e., in a conditioned medium. A conditioned MSC medium for cell-free therapy was recently considered to be a source of various factors. As some studies showed, the secretome can, without SCs, cause a restoration of tissues/organs during damage ,66,67, ig [Although growth factors and cytokines are a significant part of the SC secretome, these cells also produce extracellular vesicles , which represent nanosized vesicles enclosed in a lipid membrane. Extracellular vesicles are present in all body fluids and are secreted by all types of cells in the human body. They are classified by biogenesis and size ,81. The g ,81. Thisg . Purer fg ,81. The g . An analg . Given tg ,85. In ag ,87,88. Ig . For insg . In addig . In addig . Moreoveg . It is ag ,90.Mechanisms of tissue repair in vivo mediated by extracellular vesicles originating from MSCs include immune modulation, enhanced angiogenesis, the inhibition of apoptosis and the reduction in fibrosis . TherefoThe delivery routes of extracellular vesicles into the body include intravenous, intraperitoneal and subcutaneous injections. Extracellular vesicles can also be injected directly into the site of injury. Local delivery, as opposed to systemic delivery, can help ensure that any effects of bioactive factors are not widespread . ExtraceTo date, the clinical evaluation of secretomes, and particularly those of extracellular vesicles obtained from MSCs, is limited, but significant trials are needed to establish the effectiveness of this approach. Several clinical trials and case studies explored the potential of conditioned media and reported the safety and potential efficacy. Leveraging the knowledge base established by the successes and challenges in manufacturing cells, the MSC-derived extracellular vesicle field is well-poised for a quick translation from research to the clinic ,100. HowAs mentioned above, extracellular vesicles, aside from proteins and lipids, contain regulatory noncoding RNAs. In many preclinical studies, therapeutic effects mediated by extracellular vesicles are associated with the contents of their nucleic acids. Interestingly, the treatment of extracellular vesicles with RNase prevented their effect on kidney recovery in a mouse model of acute kidney injury, indicating the presence of RNAs as the main therapeutic component . Among regulatory noncoding RNAs, small interfering RNAs (siRNAs) and microRNAs (miRNAs) are distinguished. siRNAs and miRNAs have much in common, but their mechanisms of action and clinical applications are different . siRNAs To target cells, siRNAs and miRNAs are delivered by exosomes; into exosomes, they can be successfully loaded by electroporation . In addiThe most studied class of RNAs enclosed in extracellular vesicles are miRNAs. The complete complementarity of sequences between miRNA and its potential target, mRNA, is not required to suppress gene expression, and a match of only six base pairs is sufficient . ConsequIn recent years, the role of miRNAs in the posttranscriptional regulation of genes has come to the fore, with convincing evidence indicating the important role of miRNAs in regulating a wide range of fundamental biological processes, including the regulation of maintenance and differentiation of MSCs and/or other progenitor cells, as well as mechanisms of endogenous tissue repair . The regThe modulation of miRNA signaling in in vitro or endogenous SC populations as part of a tissue engineering strategy can provide a useful tool for managing tissue regeneration . HoweverThe technology of mobilization/homing resident SCs for the regeneration of damaged organs/tissues based on endogenous healing mechanisms has become a new concept in regenerative medicine, known as ERM. The accumulated data indicate the possibility of resident quiescent SCs of various tissues to activate the physiological regenerative ability of a tissue. Taking these data into account, it is possible to circumvent the costs and complexity associated with the exogenous regenerative approach, which includes the cultivation of SCs and the creation of functional tissues in vitro by using an endogenous regenerative approach, in which the organism is used as an in vivo bioreactor for tissue regeneration. Since the natural endogenous regenerative process is usually too limited, strategies are being developed for the successful regeneration of many tissues that promote the recruitment of resident SCs to the damaged area. This approach opens a new direction of research focused on the use of the latent regenerative potential of the patient’s own cells, which makes this type of tissue engineering safer, simpler, and more practical and economical than other approaches, while achieving effective and successful results. Nevertheless, ERM remains an emerging field of research, and many details concerning the cellular and molecular events that drive the homing of endogenous cells, and their recruitment from tissue-specific niches remain unknown. This concerns both the engineering of biomaterials in the creation of matrices necessary for the proliferation and differentiation of recruited cells, and, consequently, the regeneration of new tissues, and a combination of growth factors, cytokines and other biological signals specific to each tissue. Aside from this, the ability of the organism to regenerate can be limited in patients with an insufficient number of resident cells  or in tissues with an internally insufficient pool of endogenous SCs and/or low regenerative potential. Even in cases when endogenous SCs alone fail to realize their therapeutic promise, the identification of key regulators involved in SC homing is highly valuable for understanding the native regenerative process and directing future tissue-engineering design. Future expanding opportunities in this field will continue to foster strong collaborative efforts among cell biologists, clinicians, material scientists and engineers.


Since African swine fever (ASF) virus in wild boar populations can spill over to domestic pigs, it is crucial to understand the disease determinants in the wild compartment. However, the imperfect detection sensitivity of wild boar surveillance jeopardizes our ability to understand ASF spatial distribution. In this study, we used national surveillance data of ASF in wild boars collected in the Republic of Korea from 2019–2020 to model the spatial distribution of ASF-positive carcasses for two successive study periods associated with different surveillance intensity. The model allowed us to identify disease risk factors in the Republic of Korea, determine the spatial distribution of the risk of ASF, and estimate the sensitivity of surveillance. The outputs of this study are relevant to policy makers for developing and improving risk-based surveillance programs for ASF in wild boars.In September 2019, African swine fever (ASF) was reported in South Korea for the first time. Since then, more than 651 ASF cases in wild boars and 14 farm outbreaks have been notified in the country. Despite the efforts to eradicate ASF among wild boar populations, the number of reported ASF-positive wild boar carcasses have increased recently. The purpose of this study was to characterize the spatial distribution of ASF-positive wild boar carcasses to identify the risk factors associated with the presence and number of ASF-positive wild boar carcasses in the affected areas. Because surveillance efforts have substantially increased in early 2020, we divided the study into two periods  based on the number of reported cases and aggregated the number of reported ASF-positive carcasses into a regular grid of hexagons of 3-km diameter. To account for imperfect detection of positive carcasses, we adjusted spatial zero-inflated Poisson regression models to the number of ASF-positive wild boar carcasses per hexagon. During the first study period, proximity to North Korea was identified as the major risk factor for the presence of African swine fever virus. In addition, there were more positive carcasses reported in affected hexagons with high habitat suitability for wild boars, low heat load index (HLI), and high human density. During the second study period, proximity to an ASF-positive carcass reported during the first period was the only significant risk factor for the presence of ASF-positive carcasses. Additionally, low HLI and elevation were associated with an increased number of ASF-positive carcasses reported in the affected hexagons. Although the proportion of ASF-affected hexagons increased from 0.06 : 0.05–0.07) to 0.09 (95% CrI: 0.08–0.10), the probability of reporting at least one positive carcass in ASF-affected hexagons increased from 0.49 (95% CrI: 0.41–0.57) to 0.73 (95% CrI: 0.66–0.81) between the two study periods. These results can be used to further advance risk-based surveillance strategies in the Republic of Korea. African swine fever (ASF), caused by the African swine fever virus (ASFV), is a highly contagious viral disease that affects both domestic and wild pigs. Symptoms of ASFV infection include fever, hemorrhage, vomiting, and diarrhea, and nearly 100% mortality can occur with some strains, including the ASFV genotype II that is circulating in the Republic of Korea ,3.Sus scrofa) and domestic pigs, it is crucial to understand the disease dynamics in both species. Therefore, many countries have developed surveillance systems for wild boars [Since ASFV can spill over between wild boars  identify the risk factors associated with the presence of ASF and those associated with the reporting rate of ASF-positive carcasses, (2) estimate the prevalence and sensitivity of the surveillance system, and (3) understand the dynamics of ASF infection among the wild boar population. To do so, a spatial zero-inflated Poisson model (SZIP) was adjusted to the temporal patterns of reported ASF-positive wild boar carcasses in the Republic of Korea.The reported data for wild boars were retrieved from the surveillance system database developed by the Ministry of Environment, Republic of Korea. Passive surveillance was performed in wild boars right from the beginning of the epidemic (August 2018); however, it is expected that the effectiveness of this surveillance stream is highly dependent on the search efforts and public awareness. Consequently, in November 2019, as the cases of ASF in wild boars had been continuously reported in South Korea, the government decided to expand the surveillance system into active and passive surveillance: (1) active surveillance included hunting, trapping, and active carcass search by the Ministry of Environment, the Forest service, and the Ministry of National defense; (2) passive surveillance include wild boar carcass reporting by the public with financial incentives. Accordingly, the carcasses were reported by both the active and passive surveillance system. Since the expansion of the wild boar surveillance system, there has been intensive hunting activity in South Korea , reachinThe collected data included the type of report (public reporting or active searching), report date, diagnosis date, species , type of specimen , administrative addresses, and geographic coordinates. All cases were diagnosed as infected with the detection of ASFV with polymerase chain reaction in National Institute of Environmental Research. For the sake of consistency and homogeneity of the data collection process, only the cases derived from carcasses were included in this study.During the whole study period, the number of reported ASF-positive wild boar carcasses increased substantially after the implementation of the enhanced surveillance protocols in January 2020 . ConsideThe study region was located in the northern regions of South Korea, bordering North Korea . The regConsidering the imperfect detection in the surveillance of wild boars, the regions that reported ASF-positive carcasses and their neighboring regions were selected as the study sites and were marked using the second-level administrative regional (si-gun-gu) boundaries. These regional boundaries followed the 2019 Administrative District Boundary for the Republic of Korea from Statistics Korea . Since tZero-inflated count models have been applied in veterinary epidemiological research to identify risk factors of animal diseases while adjusting for imperfect detection ,30,31. Thexagons . vi was The sensitivity of the surveillance system for each hexagon ( follows :(4)PrevOConsidering the symptoms of ASF-infected wild boars, such as fever, dehydration, and hemorrhage, the behaviors of infected wild boars would be associated with those of the feverish animals’ preference for a cool, humid, and aqueous environment. Thus, the covariates were selected based on these characteristics and previous studies ,21. ManyBecause the distribution of ASFV-positive carcasses was expected to be dependent on the distribution of wild boar distributions, we considered as covariates the wild boar habitat suitability, representing the probability that the conditions are suitable to the wild boar. Moreover, to reflect the resting sites for ASF-positive wild boars, enhanced vegetation index (EVI) as an indicator of forestation level and area of rice paddy was used. The covariates to be associated with the symptoms of ASF included area of surface water, presence of wetland, median normalized difference water index (NDWI), median land surface temperature, median rainfall, and median heat load index (HLI). Moreover, the surveillance activity was dependent on human resources, which could make the sensitivity of surveillance heterogeneous by the level of human accessibility. Consequently, we also considered median human density, median elevation, and median slope as putative explanatory variables. Finally, given that more than 50% of ASFV-positive wild boar carcasses were found at less than 10 km from the North Korean border, we also included the distance to North Korea as a putative explanatory variable.The habitat suitability for wild boars was retrieved from the species distribution model to reflect the distribution of wild boars presented in . The modThe median of distributions of time-varying variables, such as EVI, LSTN, LSTD, rainfall, and NDWI, were extracted from each source at the highest temporal resolution for the total study period. Consistent variables, including habitat suitability for wild boars, elevation, slope, aspect, area of rice paddy, surface water and wetland, minimal distance to North Korea, HLI, and human density were extracted from each source and equally analyzed for both the study periods. All values of the variables, spatially corresponding to a hexagon, were extracted, and the median of the values was assigned to the hexagons.Given that wildlife ecosystems have been considered to be nonlinear , all covThe models were built using the following process: univariable analysis, collinearity analysis, and multivariable analysis, with a forward selection procedure. In the univariable analysis, all variables were tested independently using the Poisson and the logistic parts of the SZIP regression model. In the univariable analysis for both time periods, besides habitat suitability for wild boars, the spatial and nonspatial random terms were included in the logistic part of the regression analysis. In particular, for univariable analysis of the second study period, the spatiotemporal and temporal autocorrelations were adjusted; this was achieved using the binary variable, indicating whether ASF-positive carcasses were reported in the first study period in the hexagon and their neighborhoods (ST_variable), and the count variable for the number of reports during the first study period in the hexagon (T_report) as a confounder in the logistic and Poisson parts, respectively. Variables associated with at least one coefficient for which zero was not included in the 80% credible interval (CrI) of its posterior distribution were included in the multivariable analysis. Collinearity between the variables identified as significant at 20% in univariable analysis was assessed using the Kendall rank correlation test . If the R2OpenBUGS” package [All analyses were performed with Bayesian Markov Chain Monte Carlo simulation (MCMC). The MCMC was performed in R software with the “ package . The weaThree chains of 100,000 iterations were sampled with a 20,000 burn-in. Convergence was assessed by checking the trace plot visually and using the Gelman–Rubin–Brooks diagnostic . The posTo compare the hexagon-level prevalence of ASF-positive wild boar carcasses, the hexagon-level sensitivity of the surveillance system and the hexagon-level proportion of false-negative reports between the two study periods were plotted against each of the posterior distributions. A scatterplot for the probability of the presence of ASF-positive wild boar carcasses between the first and second periods was created.parallel” and “dclone” [Because of substantial computational demand, the simulations were run with parallel computing using ““dclone”  packages“dclone” .Among the 569 wild boar cases that were reported between 2 October 2019 and 24 April 2020, 551 cases were from carcasses, 12 cases from trapped wild boars, and seven cases from hunted wild boars. During the first period (from 2 October 2019 to 18 January 2020), the total number of reports of ASF-positive carcasses was 79, distributed among 37 hexagons. For the second period (from 19 January 2020 to 28 April 2020), 472 of the ASF-positive carcasses were reported in 80 hexagons.The results of univariable analyses for the first and second periods are presented in 2 was statistically significant .The results of the SZIP for the first study period are presented in ST_variable, T_report, HLI, and habitat suitability for wild boars were identified as significant risk factors for the second period . Only thThe assessments of the discriminatory performance of the models were conducted for the training sets  hexagon-level prevalence of ASF-positive carcasses increased between the two periods as well as the hexagon-level sensitivity of ASFV-positive carcass reporting.For the first study period, our results emphasized that the infection risk of ASFV is significantly increased with decreasing distance from the North Korean border, suggesting that the ASFV could have been introduced from North Korea. This is consistent with the fact that North Korea reported an ASF outbreak on 30 May 2019, before the ASF epidemic in South Korea . South KAs expected, the results also showed that the habitat suitability for wild boars was associated with the number of reports of ASF-positive carcasses in the affected hexagons. This is likely due to higher densities of wild boars leading to higher contact rates, resulting in a higher incidence and therefore in an increased number of reports of ASF-positive carcasses. Moreover, more ASF-positive carcasses were reported in affected hexagons with low heat load index (HLI). We identified three factors that could explain this: first, wild boars prefer high-moisture and cool-temperature environments ,54, leadDuring the second study period, the fact that the carcasses were already reported during the first period in a hexagon or its neighboring hexagons was a strong risk factor for the presence of ASF-positive carcasses. Unlike during the first study period, the distance to North Korea was not associated with the presence of ASF-positive wild boar carcasses, suggesting that disease distribution was driven by the previous phase of the epidemic rather than by potential reintroductions of ASFV from North Korea.Moreover, HLI was found to be positively associated with the number of reported carcasses in the affected hexagons, while no such observation was noted during the first study period. This could be due to seasonal effects of HLI. Unlike during the first period, the second period included the spring season. As the regions with high HLI receive more solar radiation, they would have more dense vegetation than the other regions ,62, and The results also suggested that the increased number of reported ASF-positive carcasses from the first to the second study periods was the combined results of the increased prevalence of ASF and an improved sensitivity of the surveillance system. Taken together with the maps for the probability of presence of ASF-positive carcasses and its relationship between the first and second study periods, the probability of false-negative reports, and the increased prevalence for both periods, it can be stated that ASF infection had spatially spread centered on the previously affected regions, especially in the southward direction. Although it is favorable that the overall sensitivity of the surveillance system increased in the second period, it should be noted that some regions remained undetected, and those numbers are considered to be unchanged. These might have contributed to the spatial spread. The movement of the hotspot towards the southeastern direction in the second study period may be explained by the following possibility: there were hexagons with low surveillance sensitivity around the central north hotspot in the first period. Thus, ASFV could have been introduced into these regions and remained undetected during the first study period. The undetected ASF-positive carcasses could have contributed to the infectious events in these regions, which could have generated the hotspot identified in the second study period. Similarly, the undetected hexagons in the second period might contribute to spatial spread in the future: the carcasses undetected in the northeast regions in the second period could contribute to the spread of ASFV in the southern direction because of low surveillance sensitivity in these regions. Furthermore, the “Taebaek mountain ranges” are present around these regions, starting from North Korea and extending to the middle of South Korea. Since ASFV infection among wild boars could follow the boundary of these mountain ranges , controlConsidering that the study regions include the border with North Korea, there are areas with unique characteristics: the DMZ (2 km from the border) and CCZ (10 km from the DMZ), which correspond to the reference level of the variable of the distance to North Korea. In these regions, there were no residents because of military reasons. Moreover, there are landmines in these regions. Thus, even if the probability of the presence of the ASF-positive carcasses was high, it would have been difficult to search for such carcasses. Therefore, during the first period, it can be assumed that there were some number of undetected cases in these regions. These undetected carcasses could be a driver of the endemicity of ASF infection among wild boars.From the standpoint of the fact that the ASF wild boar surveillance systems have limited detection sensitivity, our findings give suggestions for the improvement of ASF wild boar surveillance systems: it is necessary to take actions to deploy more surveillance efforts in the regions that have limited accessibility but are suitable for wild boars, such as less-populated and high-elevation regions in South Korea, and thus have been less surveyed. Moreover, considering that the environmental characteristics of the distribution of ASF-positive carcasses have changed, the surveillance efforts should be guided based on scientific evidence of the seasonal and human-mediated effects on the distribution of wild boars and dynamics of ASF, as well as the geographical proximity of previously reported cases.In this study, only ASF-positive wild boar found-dead carcasses were included for the statistical analysis. The reasons why we only included ASF-positive found-dead carcasses are that the wild boar is a terrestrial mammal that can move around within its home range. Thus, based on the geographical locations where the wild boars are trapped or hunted, it is difficult to understand the characteristics of the location of ASF-positive wild boars. Moreover, it is highly likely that ASF-positive wild boars are hunted during the incubation period of ASF infection before symptom onset, which indicates that that the environmental characteristics of the geographical locations where the ASF-positive animals were hunted or trapped are not associated with the symptoms of ASFV infection. Furthermore, the main driver of ASF spread among wild boar populations is ASF-positive carcasses. Thus, the surveillance for ASF-positive carcasses can indicate the spatial distribution of ASF and would also reduce the risk of ASF in the population. That is, the detection of wild boar carcasses is the pivotal axis of ASF control strategies in wild boars. Thus, we focused only on ASF-positive carcasses. The impact of not including hunted or trapped animals is expected to be negligible, as these cases account for only 3% of the wild boar cases. Moreover, the sensitivity of surveillance using trapped or hunted wild boars is considered to be lower than that of surveillance using carcasses, suggesting that the sensitivities estimated in this study are the maximum values ,20,21,68This study had two main limitations. First, because of military restrictions, many types of spatial data were unavailable for distances less than 25 km from the North Korean border, which covers 54% of the study region. Consequently, many variables that are potentially related to observed distribution of ASF-positive carcasses, such as road length, density of domestic pig farms, and landmine distribution, could not be included. However, the effects of these variables would be accounted by the human population density, associated with the road density, density of domestic pig farms, and landmine distributions. Second, we did not account for the death time point of the carcasses in the analyses. This might result in bias in the results, since carcasses found during the second study period could be due to the death of a wild boar during the first period. However, the data of time of death was not available, as this estimation is incredibly challenging owing to its dependence on many interrelated factors .In this study, we analyzed the spatial distribution of ASF-infected wild boars for successive periods, while also accounting for imperfect detection. The epidemiological situation of ASF among wild boar populations seems to have changed into an endemic status, and further, appears to be getting worse. Although the performance of the existing surveillance system has improved, it is possible to improve the sensitivity based on the results of this study to suppress the further spread of ASF. We believe that the factors identified in this study could be useful for developing and improving risk-based surveillance systems.


As the efforts of the Global Age-friendly Cities and Communities movement mature and continue to grapple with society’s shifting dynamics, blind spots and knowledge gaps are exposed. This research applies critical discourse analysis to examine the evolution of Age-friendly NYC using an intersectional lens committed to an ethics of representation. Over 1,000 pages of public records were analyzed to trace the history of this movement in relation to age, race, sexuality, gender, ability, and class. Findings suggest that Age-friendly NYC is a global leader of the age-friendly movement, yet social identities are represented neither equally nor universally in its initiatives. Discussions of race, sexuality, and gender are subtle. They also overlook how these identities may intersect and shape the aging experience for differently positioned older adults. A comprehensive understanding of the aging experiences of those with multiple intersecting identities is needed to inform future age-friendly policies and programs.


The neurodegenerative and neurodevelopmental hypotheses represent the basic etiological framework for the origin of schizophrenia. Additionally, the dopamine hypothesis, adopted more than two decades ago, has repeatedly asserted the position of dopamine as a pathobiochemical substrate through the action of psychostimulants and neuroleptics on the mesolimbic and mesocortical systems, giving insight into the origin of positive and negative schizophrenic symptoms. Meanwhile, cognitive impairments in schizophrenia remain incompletely understood but are thought to be present during all stages of the disease, as well as in the prodromal, interictal and residual phases. On the other hand, observations on the effects of NMDA antagonists, such as ketamine and phencyclidine, reveal that hypoglutamatergic neurotransmission causes not only positive and negative but also cognitive schizophrenic symptoms. This review aims to summarize the different hypotheses about the origin of psychoses and to identify the optimal neuroimaging method that can serve to unite them in an integral etiological framework. We systematically searched Google scholar (with no concern to the date published) to identify studies investigating the etiology of schizophrenia, with a focus on impaired central neurotransmission. The complex interaction between the dopamine and glutamate neurotransmitter systems provides the long-needed etiological concept, which combines the neurodegenerative hypothesis with the hypothesis of impaired neurodevelopment in schizophrenia. Pharmaco-magnetic resonance imaging is a neuroimaging method that can provide a translation of scientific knowledge about the neural networks and the disruptions in and between different brain regions, into clinically applicable and effective therapeutic results in the management of severe psychotic disorders. Psychosis is not a nosological entity, but rather a clinical condition consisting of numerous symptoms that may be a common clinical outcome of a variety of causes. While the concept and definition of psychosis is defined by the core clinical symptoms of delusions, hallucinations, and disorganized thinking, these symptoms are most likely the common final consequences of a variety of different etiopathogenetic pathways, which may all lead to an analogous clinical picture .Schizophrenia and other psychotic disorders are a heterogeneous group of mental illnesses that are frequently categorized together for practical reasons. However, schizophrenia is the most prevalent, debilitating, and socially significant disorder among this group . SchizopThe diagnosis of schizophrenia is purely clinical, most often made after the first manifestation of psychotic symptoms . In pracDespite all the described shortcomings, psychiatry is currently in its “heyday” due to the variety of neuroimaging techniques that offer opportunities to study structural and functional aberrations in the central nervous system (CNS). Combining psychopharmacology with functional magnetic resonance imaging (fMRI) in the study of central psychopharmacological mechanisms, could be a successful translational strategy in the search for biomarkers for the validity of psychiatric diagnosis and treatment monitoring in clinical practice.This review will examine the etiological theories of schizophrenia, the current methods for identifying biomarkers by neuroimaging tools, the possibilities of incorporating research findings into clinical practice, and the potential benefits of applying interdisciplinary efforts in the management of schizophrenia, emphasizing translational neuroscience. We will visualize our desire to combine psychopathological, psychopharmacological and neuroimaging techniques with the ultimate goal of finding the optimal therapeutic method that could successfully treat not only the positive but also the negative and cognitive symptoms that cause severe disability among schizophrenic patients.Studies were searched via Google Scholar and PubMed databases without taking into account the date of publication. Potential candidate studies were identified first using the following search word combinations: etiological theories-relevant , and MRI-relevant , functional imaging, connectivity, rest, or resting, task, pharmacological MRI). Reference lists of retrieved studies were also searched manually to find additional potential studies of relevance to match the initial keywords set.Various theories on the origins of schizophrenia have been proposed in the past, including the supernatural, somatogenic, and psychogenic theories. According to the supernatural theory, psychotic phenomena are attributed to spells, sins, and the soul’s possession by evil and demonic spirits. According to the somatogenic theory, behavioral disturbances arise as a result of somatic disease, genetic anomalies, brain injury, or metabolic imbalance. Psychogenic theory is concerned with psychotraumatic or stressful events that result in maladaptive behavior .In modern times, with the understanding of the basic and specific biological mechanisms in the CNS, several etiological directions have been formed, which are supported by the relevant genetic, clinical, neuroimaging and especially psychopharmacological observations on the course of psychotic disorders.Since Bender  coined tNumerous longitudinal studies, on the other hand, have discovered a progressive decrease in cortical thickness over the course of the disease, which correlates with the affected individuals’ ongoing impairment in cognitive and social functioning ,26,27. TSome scientists propose a conceptual model that consists of a set of pathological mechanisms that occur during the stages of neurodevelopment, as well as later emerging (during the first psychotic episode) brain-degenerative processes, which, when combined with the same causal factors, eventually at some point lead to the clinical manifestation of schizophrenia .In the second half of the twentieth century, the focus shifted from psychogenic to neurobiochemical theory, thanks to the advent of neuroleptics. Their action on dopamine D2-receptors in mesolimbic and mesocortical structures underlies the “dopamine hypothesis”  for schiThe classical dopamine hypothesis for schizophrenia suggests that hyperdopaminergia in the mesolimbic system causes psychotic symptoms  and hypoThe classical dopamine hypothesis is presented on Although the dopamine hypothesis has contributed significantly to the understanding of the clinical effects of psychostimulants, as well as to the introduction of many molecules with antipsychotic effects, it has nevertheless led to certain limitations . For exaN-methyl-D-aspartate (NMDA) type [About four decades ago, an alternative etiological formulation for schizophrenia was postulated based on the action of “dissociative anesthetics,” a class of psychomimetic drugs that includes phencyclidine (PCP) and ketamine. These substances are glutamatergic antagonists that act by blocking the glutamate receptor of the DA) type . Unlike DA) type ,47,48,49DA) type ,51. AmphDA) type . In addiDA) type ,53,54,55Another interesting point of view for psychosis was presented back in 1986 by Robinson and Becker  who suggNeuronal sensitization is a universal characteristic in the development of schizophrenia. Incentive learning is considered to be at the root of psychostimulant-induced context-dependent sensitization, which may play a role in the development of addiction, dyskinesia, and amphetamine-induced psychosis and it occurs when dopaminergic neurons are activated, for example by rewards. As a result, neutral stimuli gain incentive salience as well as the ability to trigger future attraction or other stimulus-seeking reactions . SchmidtAlthough scientists declared glutamatergic neurotransmission as a targeted strategy for the development of treatments for schizophrenia 40 years ago ,60, the The “dysconnection hypothesis” ,69 descrFunctional connectivity is a term that describes observable interactions between parts of the brain, but it does not specify how these connections are mediated and in what direction they interact. An effective connectivity, which is closer to the intuitive concept of connection, is utilized for a more thorough definition of the integration in the system . In electrophysiology, there is a tight connection between effective connectivity and synaptic efficiency at the synaptic level .Analyses of functional connectivity reveal various brain networks that represent distinct functions and diverse spatial topologies. Among the different brain networks that have been found to be malfunctioning in schizophrenia are the salience network (SN), the default mode network (DMN), and the central executive network (CEN), which together form the so-called “triple network” . The SN Impaired synchronization between the anti-correlated DMN and CEN is postulated as a key pathophysiological feature of schizophrenia . The “trThe concept that schizophrenia represents disintegration or fragmentation of the mind is as ancient as the term “schizophrenia” itself, which was coined by Bleuler  to highlThe typical onset of schizophrenia in the transition phase between late adolescence and early adulthood is one of its main characteristics. Studies with rats demonstrate that ketamine and PCP are not neurotoxic until late adolescence. Furthermore, human investigations have shown that ketamine anesthesia does not cause psychotic symptoms in prepubertal children when compared to anesthesia in adults . Olney eIt has been suggested that glutamate may serve as a “bridge” uniting neurodevelopment and neurodegenerative theories due to its active participation in neuronal processes during all periods of human development. In early development, glutamate plays a role in neural migration, in adolescence it plays a role in the plasticity and pruning of neurons, and later in life, it is involved in neurodegeneration through the process of excitotoxicity .Neurotransmitters tend to alter the excitability of neurons not only by directly affecting the postsynaptic membrane potential but also through modifying their responsiveness to other neurotransmitters. In the PFC, for example, dopaminergic terminal axons contribute to the development of synaptic complexes including excitatory (glutamatergic) projections on the pyramidal cells . This syIn summary, schizophrenia can be considered as a mental disorder of impaired brain connectivity, the course of which is modeled by complex etiopathogenic factors, and at each stage of development, certain abnormal neurobiological processes contribute to its clinical manifestation. These processes originate from a genetic predisposition embedded in the genome, which is a prerequisite for the further development of the disease .Later, during early development, the abnormalities stay dormant, followed by the prodromal phase, during which neuronal maturation occurs, then, due to endogenous neurochemical dysfunction and environmental factors, the full clinical manifestation of the disease occurs, reaching the residual phases of schizophrenia, during which neurodegenerative disorders predominate .The integral model of schizophrenia is presented in Understanding the complex dynamics of interactions between different brain areas at rest and during conditional task performance is a relevant subject in research about the underlying pathophysiological mechanisms of psychotic disorders. Disruptions in communication between and within brain networks, and the pathophysiological processes of their nodes enable translational neuroscience to obtain biological insight into schizophrenia and to describe it as impaired connectivity disorder .A wide range of scientific fields and new methodologies are part of the translational approach in psychiatry. Magnetic resonance imaging (MRI) such as quantitative structural imaging, voxel-based neuromorphometry (VBM), functional neuroimaging, and spectroscopy are commonly used in research. Structural and functional MRI has the potential to refine diagnoses, assist in making therapeutic decisions, and be incorporated as a method of monitoring the effect of treatment by directly assessing the improvement of disease-related brain dysfunction. The different imaging modalities report diverse and specific CNS impairments, some of which will be presented in the following lines.Structural MRI investigations in psychotic individuals have revealed a variety of anatomical abnormalities in the CNS. Reduced GM volumes have been detected in several brain regions, including the frontal, temporal, parietal areas, the cingulate gyrus, and limbic structures  . AccordiA recent study performed by our research group, consisting of a multivariate analysis of different MRI modalities, using artificial intelligence (unsupervised machine learning method) comparing paranoid syndrome in schizophrenia and depressive syndrome in the context of mood disorder, found that regions located in the left and right opercular part of the inferior frontal gyrus (IFG), right supramarginal gyrus, left STG, left anterior orbital gyrus, supplementary motor cortex, and several occipital areas are highly discriminatory for convergent cross-validation of biological features of disease .One of the most consistent anatomical findings in schizophrenia is the abnormal insula structure. According to meta-analyses, the GM volume of the bilateral insula is reduced, and while evident in other mental illnesses, the reduced insula volume, is most pronounced in psychotic disorders ,101,102.fMRI research results collected during the performance of various tasks (task-related fMRI) while identifying activations in different brain areas when applying various sensory stimuli constitute a large part of the data published in the literature related to neuroimaging. Numerous task-related neuroimaging studies with emotionally charged visual stimuli have demonstrated reduced accuracy in recognizing emotions and prolonged response time in patients with schizophrenia ,105,106.In addition, task-related hyperactivation in the components of the DMN is observed in psychotic patients, while in healthy controls, deactivation in the same network is reported .Studies have shown that impaired coordination of DMN/CEN/SN is associated with disorientation between internally and externally focused attention and cognitive impairment, which are typical signs of psychotic disorders . ImpaireOur research team, led by Stoyanov, has developed and integrated an innovative neuroimaging paradigm  aimed atIn this sense, psychiatry acquires a psychometric tool that is evidence-based and can be freely used in clinical practice. PDS can be implemented not only for initial diagnostic assessment, but also for monitoring the progress of the disease, as well as for monitoring the therapeutic effect, as the initial establishment of this scale was precisely in order to assess the effectiveness of treatment.fMRI at rest (resting-state fMRI) examines the complex interactions between predefined ROIs using general linear model (GLM) and dynamic causal modeling (DCM) analysis. The study of functional connectivity at rest reveals a number of neural networks that represent specific patterns of synchronous activity . RestingIn healthy individuals, SN activation is often observed throughout a variety of cognitive tasks . Its majStudies conducted by our team on resting-state effective connectivity prove an aberrant brain connectivity in schizophrenia ,111, i.eWe suggest that the observed task-related hyperactivity of the DMN may be a consequence of the inhibition from the PFC on the insula, which disrupts its balancing function as a dynamic switch between the anti-correlated DMN and CEN.In addition, the SN hyperconnectivity points to the conclusion that schizophrenic patients stay in a “resting-state of aberrant salience”, instead of a “resting-state of default mode”. Such a conceptual model helps understanding of schizophrenia as a behavioral disorder caused by disintegration in key brain networks. Abnormal SN hyperconnectivity and fronto-insular inhibition at rest prevent SN function from acting as a dynamic switch between resting-state (DMN) and event-related (CEN) activity. The fundamental disruption of SN in schizophrenia prevents switching between anti-correlated DMN and CEN, thus interfering with their basic functions.This concept is presented in Given the controversial efficacy of standard therapies (psychopharmacology and psychotherapy), a significant proportion of schizophrenic patients do not achieve full remission  or maintain symptom relief. This lack of efficacy has prompted the search for alternate treatments, which include the use of more invasive procedures for treatment-resistant cases of schizophrenia . As a reUnconventional therapeutic instrumental methods have been shown to be beneficial for a variety of psychiatric disorders . Unfortunately, their usage for schizophrenia is still limited in standard clinical protocols, and these technologies remain in the shadow of psychopharmacology .However, we remain positive about the possibilities for improving the therapeutic approach to psychosis, as some of the modern neuroimaging techniques can provide available resources for non-invasive analysis of complex interactions and biochemical imbalances that cause the characteristic manifestation of the disease. The study of the pharmacokinetic and pharmaco-dynamic processes occurring in the CNS under the load of various chemicals could help both to identify psychosis-specific biomarkers and to develop an effective strategy for monitoring and predicting the effect of drug treatment.One of the most essential elements of comprehending inter-individual differences or clinical results is to investigate the neurochemical substrates of brain function. Positron emission tomography (PET) has allowed for a direct assessment of brain chemistry in vivo. The dynamics of regional uptake of neurotransmitter-specific radio-ligands in PET can be used to identify regional neurochemical modulation of brain activity. PET mostly uses 18FDG, a direct reflection of regional glutamate transmission, to offer a quantifiable measure of glucose metabolism . PET is Therefore, the focus is on pharmacological MRI (ph-MRI), which is an accessible instrument as an alternative for studying the chemical imbalances in the brain. ph-MRI is an innovative technology for assessing regional network effects and treatment response to specific medications. In general, there are two types of ph-MRI. The first is usually done as a drug challenge study, in which MRI signal changes are evaluated after an acute administration of the substance of interest. Apparently, there are several adaptations on this fundamental paradigm, such as drug antagonistic effects or investigating the acute effects of one medication on the chronic effects of another (useful perhaps for studying drug addictions). The second type of ph-MRI is the observation of pharmaco-modulatory effects of drugs on a traditional task-related fMRI study, such as dopaminergic medicines’ effects on cognitive tasks .The main purpose of phMRI is to recognize the location of drug action fingerprinting in order to measure the connection between drug dose, neural reaction, and treatment significance over time (pharmacokinetic/pharmacodynamic modeling), and to assist in making go–nogo decisions about the efficacy of drug treatment in clinical trials, all with the goal of accelerating drug discovery. By enabling a controlled regulation of a specific pathway and analyzing its causal influence on other signals and systems, pharmacological probing tests can be useful for fundamental neuroscience and validation studies .L-DOPA, while ketamine, phencyclidine (PCP), and LY2140023 are appropriate substances for studying the glutamate systems [The dopamine and glutamate neurotransmitter systems are the main targets for ph-MRI in schizophrenia. Suitable ligands for examining the dopamine system are cocaine, amphetamine, and  systems . The mai systems . As a re systems . Because systems .Given the intricacy of the clinical presentation and the underlying malfunctioning brain circuits, ph-MRI investigations can assist in determining the initial treatment response, mechanisms of therapeutic efficacy and adverse effects, and potentially accelerate CNS drug development. ph-MRI studies reveal stable and reproducible alterations on disease-relevant networks, as well as sensitivity to early pharmacological impacts on disease-related functional architecture. Improved disease phenotyping, or biomarkers, utilizing sophisticated imaging techniques will substantially assist future CNS medication research and development.Schizophrenia and other psychotic disorders affect a huge number of people around the world, thus destroying the lives of patients, burdening their loved ones and society, and leading to significant and global economic losses. Theories about the origin of schizophrenia have changed over the years, starting with the supernatural, going through the psychodynamic “schizophrenogenic mother” and reaching modern interpretations of the etiology of this destructive disease. For more than half a century, neurobiology has been able to provide explanations for the central brain mechanisms of the disease through the neurodevelopment hypothesis, the neurodegeneration hypothesis, and the biochemical dysfunction represented by the dopamine and glutamate hypotheses. In recent decades, thanks to neuroimaging, new insights have been gained about the disrupted integration in communication between and within the brain networks, emphasizing the disrupted connectivity between the components of the triple network, the default mode network, salience network and central executive network, which form the concept of schizophrenia as a brain dysconnectivity syndrome. At this stage, neuroscience has the task of combining different concepts into an integral model with the clear goal of contributing to the development of new treatments for schizophrenia. A suitable tool for this is pharmacological magnetic resonance imaging which has the ability to measure the connection between drug dose, neural reaction, and treatment significance over time, thus providing a “system evaluation” of networks underpinning a drug’s behavioral effects, irrespective of its pharmacological mechanism of action.According to the validation theory as conceived back in 2007, the cross-validation of clinical psychological self-assessment tools with fMRI may well underpin pharmaco-psychological monitoring strategies .Advances in neuroscience are expected to provide new horizons in the near future by incorporating neuroimaging findings into clinical practice, including non-traditional neuromodulation methods in the therapeutic approach of schizophrenia.


Cellular protein kinases remain the target of choice when the intention is to intervene in a particular signaling pathway leading to cancer progression. Their reversible mode of action, tight regulation, and molecular structure allows for the design of specific inhibitors. However, from the more than 500 protein kinases identified, many potentially involved in important cancer-related signaling cascades, only a few have received most of the attention over the years. This is either due to their central role on essential processes, the facility of intervention, or their early discovery. This Special Issue tried to offer new insights into some of the lesser-known human protein kinases, their substrates, regulation, and involvement in cancer progression. The published articles offer good examples of the important cellular functions that the so-called non-canonical kinases develop and their contribution to cancer. They also discuss some of the therapeutical opportunities and challenges.The vaccinia-related kinase (VRK) proteins are structurally related to the casein kinase family and the viral protein B1R. This family of protein kinases has revealed itself as an important mediator of tumor progression and cell proliferation. Although a role for VRK1 in normal cell division is granted, the high expression and activity of this protein in some cancers, including now pediatric neuroblastoma, is essential for malignization . It is nAnother family of pleiotropic protein kinases associated with cancer is dual-specificity tyrosine-regulated kinases (DYRK). Their molecular functions leading to tumor progression are discussed in another contribution to this Special Issue . InteresSpecific tyrosine kinase inhibitors are being used with success in the treatment of some types of cancer. In addition to major signaling players, tyrosine kinase inhibitors also offer specificity against other tyrosine kinases. A revision of their use and targets could offer new opportunities for the treatment of tumors with poor prognosis and few therapeutic tools available . For exaCancers shows good examples of the functionality and therapeutic values that the study of non-canonical kinases or domains, their substrates, and inhibition can offer. With research on these lesser-known proteins, we will expand not only our knowledge about cancer progression, but our possibilities to halt it.In summary, this Special Issue of