The growing number of end-of-life vehicles (ELVs) engenders a genuine concern for achieving sustainable development. Properly recycling ELV is paramount to checking pollution, reducing landfills, and conserving natural resources. The present study evaluates the sustainability of India's ELV recycling system from techno-socio-economic and environmental aspects as an instrumental step for assessing performance and progress. This investigation has performed the Strength-Weakness-Opportunity-Threat (SWOT) analysis to evaluate ELV recycling in the long-term viability and examine the critical factors and potential. This research makes practical recommendations for effectively encountering persistent challenges in the ELV recycling system based on Indian values. This research adopts an explorative and Integrated bottom-up mixed approach; it interfaces qualitative and quantitative data and secondary research. This study reveals that the social, economic, technological, and environmental aspects of the sustainability of India's ELV recycling system are comparatively limited. The SWOT analysis demonstrates that potential market size and resource recovery are more significant strengths, whereas lack of an appropriate framework and limited technology are major challenges in the recycling of ELVs in India. Sustainable development and economic viability have emerged as great opportunities, while informality and environmental impact have surfaced as primary potential threats to ELV recycling in India. This paper offers insights and yields critical real-world data that may assist in rational decision-making and developing and implementing any subsequent framework. After a specific period, the vehicle becomes unfit for the road and generates scrap automobiles proportionally4. The vehicles that have been retired from service and are no longer in use, end-of-life vehicles (ELVs), ELVs impose numerous threats in several aspects of society; hence proper handling of ELVs is of paramount importance6. ELV recycling has received enormous momentum. It offers excellent potential to extract as much value from ELVs and sustainable hazardous waste disposal9. Proper and efficient ELV recycling enables the recovery of a significant quantity of different materials, including Iron, Aluminium, Lead, Copper, Glass, and several rare materials12. Therefore, ELV recycling is regarded as a secondary source of materials that can preserve the finite natural resources in this world14. Besides the secondary source of materials, proper ELV recycling disposes of harmful and toxic materials in ELVs in an environmentally sound way that can reduce pollution and landfills17.As a consequence of rapid globalization and tremendous industrialization, the number of vehicles is proliferating on the road exponentially in recent times18. The phenomenal expansion of India's automotive industry requires an enormous amount of distinct, precious, and scarce materials to expedite the ongoing development20. The dramatic decline of primary resources causes struggles to maintain a steady supply of raw materials for the automobile industry21. As ELVs incorporate a plethora of distinct ranges of materials, the recovery of materials from ELVs can assist significantly in maintaining the steady supply of materials to the material-thirsty Indian automobile sector24.The burgeoning automobile industry in India manufactures and yields a growing number of vehicles to society every year. Figure 25. Consequently, informality in this sector prevails, which causes the bleeding of resources to waste and aggravates environmental quality26. The effective and practical legal and technical frameworks for ELV recycling can expedite the value extraction from ELVs in environmentally friendly ways. Countries like Japan, the USA, the EU, and China, are toiling to establish a sustainable ELV recycling system and have enacted practical regulations to govern the ELV recycling system30. As a result, they have evinced significant advancement in establishing a sustainable ELV recycling system with an excellent material recovery and recycling rate because they adopt sophisticated technology to enhance material extraction rates31. The material recycling and recovery rates are limited in the sector of ELV recycling in India; ELV recycling in India can only recycle certain parts, including engines, transmission systems, chassis, batteries, gearboxes, tires, rims, axles and few other economically viable body parts32. A significant value is squandering landfills because of the absence of advanced and cutting-edge technologies. Additionally, the de-pollution process of ELV does not adhere to environmentally friendly standards, which contributes substantially to environmental degradation25. The stringent legal framework and practical guidelines can enhance materials recovery rates and reduce potential greenhouse gas emissions, not to mention road and vehicle safety.The recycling of ELVs in India is at the nascent stage and is highly chaotic and poorly managed because of the absence of legal and technical frameworks33. The inadequacy of insightful recommendations that steer stakeholders toward a greater recycling rate and authority to implement legal and regulatory frameworks hinders the sustainability of ELV recycling. This issue prompts a thorough investigation.Little research sheds light on ELV recycling in India; it necessitates more explorative analysis to develop a thorough understanding of current ELV recycling practices from techno-socio-economic and environmental aspects. The absence of real-world data for the authority is stymieing rational decision-making and developing and implementing any subsequent regulatory and legal framework that succinctly embraces the techno-socio-economic and environmental aspects; it warrants more in-depth investigation on real ground. Identifying and assessing the critical factors and potential of the recycling of ELVs in India is crucial for providing future directives toward sustainability in ELV recycling; the lack of investigation in this facet demands deeper insights. The literature analysis, field investigation, and stakeholder interaction reveal that the absence of a practical framework thwarts India's ELV recycling sustainabilityThe mentioned research inadequacies and knowledge deficiencies regarding the recycling of ELVs have inspired the current investigation. The present study evaluates the sustainability of India's ELV recycling system from techno-socio-economic and environmental aspects as a significant step to advancing understanding of the current practice and evaluating performance, and assessing progress. It offers insights and yields critical real-world data that may assist the authority in rational decision-making and developing and implementing any subsequent regulatory and legal framework. This investigation has performed the Strength-Weakness-Opportunity-Threat (SWOT) analysis to evaluate ELV recycling in the long-term viability and assess the critical factors and potential. This study's findings may assist India's authority in introducing an appropriate regulatory framework and strategic decision-making and might have significant social influence in Indian society.35. Figure 25. After collecting ELVs, legal paperwork needs to complete for recording details as evidence. After that, ELVs undergo depollutioning operation; in this stage, several pollutants and harmful substances, including engine oil, brake oil, coolant, and air conditioning gases, are disposed of in an environmentally sound way. In the next step, dismantling the operation, numerous recyclable and reusable parts are recovered from ELVs, such as the engine, gear system, chassis, and wheels; maximum material recovery from ELVs occurs in this stage36. Consequently, the remaining car hulk undergoes shredding operation for further value recovery. The shredding operation leaves automotive shredder residue that is metal-rich and contains a high calorific value37. Therefore, proper treatment of ASR is instrumental for higher material recovery and recycling rates38. Figure 39.ELV recycling system is very intricate that involves numerous complicated processes beginning from collecting ELVs and ending with automotive shredder residue (ASR) treatment40. Figure 25. As the informal sector is solely driven by economic gain, the operations for value recovery from ELVs disregard the environmental impact, which aggravates environmental quality. In the informal sector, after perfunctory depollutioning operation, through dismantling, certain specific parts are recovered from ELVs as the value recovery; after that remaining car hulk is sold to the shredding company for further value recovery as the informal sector lacks modern and sophisticated equipment and techniques, it leads the draining of resources to waste. Whereas the formal ELV recycling facility centers are well-organized and equipped with modern and sophisticated equipment and techniques compared to the informal sector, even though the number of formal ELV recycling facility centers is insignificant. In the formal ELV recycling facility center, the operations for value recovery from ELVs adhere to standard guidelines; after dismantling operation for parts recovery from ELVs, ELVs undergo the shredding process for further value recovery, which leaves ASR, ASR is metal-rich and carry a high calorific value, partial ASR treatment is carried out for further value recovery; however, the landfill is relatively high compared to developed nations.In India, the proper treatment of ELVs is a critical issue because ELV recycling is still in the nascent phases and is very disorganized and poorly managedThis research explores India's ELV recycling system by adopting an explorative and integrated bottom-up mixed approach; It interfaces qualitative and quantitative data and secondary research.This investigation shined the spotlight on critical automotive industrial zones in India to evaluate the sustainability of India's ELV recycling system from techno-socio-economic and environmental aspects and to perform the SWOT analysis to evaluate the ELV recycling system in the long-term viability and assess the critical factors and potential. This research developed a structured questionnaire to perform the objective evaluations that it sought. This questionnaire was evaluated and endorsed by experts and had three sections, demographic information, sustainability evaluation from techno-socio-economic and environmental aspects, and SWOT analysis. The demographic part of the questionnaire sought basic information about survey respondents, and Table This investigation employed a quantitative research method to perform objective measurements through a structured questionnaire. Secondary research was an integral part of the methodology of this study. This investigation conducted secondary research to explore and analyze the present level of information about ELV recycling, develop comprehensive insights, gain detailed information, and evaluate the research limitations and gaps in the ELV recycling system in India. The literature review enabled the development of the robust foundation of this research. It significantly assisted in factors selected for evaluating sustainability from techno-socio-economic and environmental aspects and the SWOT analysis and making practical recommendations based on Indian values to resolve the persistent issues to expedite the sustainability of the ELV recycling system in India. The questionnaire items were drawn from literature reviews. Initially, more items were selected from the literature to conduct this study. Eventually, after a thorough review to assess the importance, relevance, and significance of the factors, a few factors were dropped from the questionnaire to make the questionnaire more precise, pertinent, and applicable; experts advised and recommended this exclusion. Furthermore, the relevancy, applicability, and subjectivity of all selected factors were checked and verified by the ELV stakeholders consultation. Social awareness and understanding of ELV recycling, current practices in society, and government-sponsored awareness-raising campaigns were considered for selecting factors for assessing sustainability from the social dimension. Satisfaction with the received monetary value for ELV, economic gain of stakeholders, expansion of the sector, investment for advanced types of equipment for energy-efficient operations, and financial assistance from authority determined the factors for evaluating sustainability from the economic dimension. The factors for assessing sustainability from the technological aspect were derived from equipment upgradation, application of energy-efficient equipment, recycling capacity, and facility of glass and plastic recycling and ASR treatment. The factors for evaluating sustainability from the environmental dimension were decided based on the amount of landfill, ecological degradation, energy consumption, carbon emission, and hazardous waste management.For the SWOT analysis factors selection, for strengths, India's internal resources and tangible assets, distinctive qualities, and technological development were taken into consideration; for weaknesses, the lacking qualities, resource limitations, and malpractices were taken into account; for opportunities, emerging economy, investment, future goals, and initiatives were considered; for threats, potential vulnerabilities, legislation, environmental quality, and globalization were taken into account.Table Data analysis is a significant phase that entails interpreting and analyzing the obtained quantitative as well as qualitative data. All the data collected for objective measurement for the present study was based on the five-point Likert scale. Microsoft Excel and SPSS software programs were employed to analyze the quantitative data, whereas ATLAS and Nvivo software programs were used to interpret and rationalize the qualitative data. To evaluate the sustainability of India's ELV recycling system from techno-socio-economic and environmental aspects, this study calculated the mean value of collected data and arranged the items in the social, economic, technological, and environmental aspects in an ascending way for visualization. For the SWOT analysis, the mean value of the parameters in the SWOT analysis was calculated and arranged the parameters in an ascending way for visualization. Figure As this research evaluates the sustainability of India's ELV recycling system from techno-socio-economic and environmental aspects by performing objective measurements, this section delineates the critical findings of this study.43. Figure Social awareness is of paramount importance for establishing an effective and sustainable ELV recycling system, as it encourages individuals to recycle their abandoned vehicles. A greater awareness level in society is more conducive to adopting and implementing any subsequent ELV recycling framework14. Figure 57. This research unveils that investment in energy-efficient operations in the ELV recycling sector (ECA5) is poor, 1.8 out of 5 scales. It implies that ELV recyclers have not yet upgraded their equipment. Incentives and financial assistance authorities are conducive to developing a sustainable industrial sector; this exploration demonstrates that the ELV recycling sector receives inadequate financial assistance from the authority (ECA6), 1.5 out of 5 scales. It suggests that the ELV recycling sector is running without sufficient incentives and assistance from the authority.Economic gain is a great motivator; receiving appropriate monetary values for ELV inspires individuals to recycle their scrap vehicles. Conversely, making more profit from ELV recycling prompts stakeholders to invest in energy-efficient operations and higher material recovery from ELV58. Figure 59. The informal sector dominates India's ELV recycling sector, and a recycling center is incapable of recycling all kinds of vehicles; this study demonstrates that the capacity for recycling all types of vehicles, including two-wheeler, three-wheeler, private vehicles, commercial passenger and goods vehicles, military vehicles, and others (TEA3) is poor, 1.6 out of 5 scales. Glass and plastic are the significant part of the vehicle, which can be recycled61. This exploration exhibits that the capability for recycling glass and plastic components (TEA4) is very limited, 1.5 out of 5 scales. It implies that material recovery and recycling rates can be elevated by emphasizing glass and plastic components recycling. ASR is a metal-rich mixture that contains a high value; through effective ASR treatment, significant further value can be recovered37. This study delineates that the ASR treatment facility in India's ELV recycling sector (TEA5) is scarce, 1.2 out of 5 scales. It indicates that most of the ELV recycling sector in India operates without an ASR treatment facility.Advanced and sophisticated technology is instrumental, as it enables higher material recovery and recycling rates, lower energy consumption, and reduces the emission of greenhouse gases62. Figure 53; this awareness of pollution caused by improper recycling is conducive to adopting an efficient ELV recycling framework. As mentioned, India's ELV recycling system operates with relatively lower materials recycling and recovery rates; therefore, landfill is relatively higher. This investigation unveils that the reduction in landfills (ENA2) is limited, 2.5 out of 5 scales. It indicates that still further value can be recovered by reducing landfills. Higher energy consumption is one of the persistent issues in industries; higher energy consumption degenerates the environment. This research demonstrates that the effort to reduce energy consumption (ENA3) is poor, 2.3 out of 5 scales. The reduction in carbon emissions is a global challenge; the United Nations (UN) has taken numerous initiatives to reduce carbon emissions. This study delineates that the endeavor to minimize carbon emissions from recycling operations (ENA4) is poor, 2.1 out of 5 scales. ELVs encompass several detrimental and hazardous substances, and sustainable disposal of these harmful materials and waste is paramount49. This exploration finds that following proper guidelines for disposing of hazardous waste (ENA5) is scarce in India's ELV recycling sector, 1.8 out of 5 scales. It indicates that the generated harmful waste is not disposed of in an environmentally sound way, which is a potential environmental threat.ELV contains several hazardous and harmful substances, and proper disposal of these toxic substances is imperative to safeguard the environmentThis research has performed the SWOT analysis to evaluate the competitiveness of India's ELV recycling system by assessing critical factors as well as present and future potential. The SWOT analysis investigates strengths, weaknesses, opportunities, and threats in India's ELV recycling system, yielding a fact-based analysis, fresh perspectives, and profound insights.Figure Figure Figure Figure This study evaluates the sustainability of India's ELV recycling system from techno-socio-economic and environmental dimensions. This research finds that knowledge and understanding of ELV recycling are mediocre in society, but individuals express great support for ELV recycling, which is considered substantial backing for the implementation and adaptation of an effective ELV recycling system. This investigation unveils that the practice of abandoned vehicle recycling in society is limited; lack of awareness prevents individuals from properly ELV recycling their abandoned vehicles. The lack of support for enhancing public awareness from authorities has emerged in this investigation. The authority should endeavour to enhance the awareness level in society, which will drive people to recycle their abandoned vehicles. This research underlines the social aspects of the sustainability of India's ELV recycling system for elevating the lives of people in Indian society. This study might have a profound impact on people to save energy, reduce landfills, and safeguard the environment.Moreover, the findings of this study demonstrate that the amount paid to the end-user of the vehicle for the ELV is insufficient because the monetary value of ELVs in India depends on the market price of iron only. The insufficient monetary value of ELV discourages the end-user of the vehicle from recycling vehicle. The authority should devise an appropriate legal framework to govern the ELV recycling system. This investigation finds that ELV recycling is still one of India's more profitable businesses. However, the ELV recycling sector is not growing rapidly. This research reveals that the investment for enhancing materials recovery and recycling and energy-efficient operations is limited, which leads to poor materials recovery rates and high energy consumption. It indicates that financial constraint is impeding the development of the ELV recycling sector. Lack of assistance and incentives from authorities has surfaced as a prominent issue in the ELV recycling sector. The authorities should take the initiative for financial assistance for ELV stakeholders to grow the ELV recycling sector sustainably.63; nonetheless, the glass and plastic components are not recycled at most of the ELV recycling centers, leading to significant value waste. ASR treatment is a crucial step for value recovery from ELVs64. Still, the lack of modern techniques and machinery prevents most ELV recycling centers from treating ASR, which also leads to significant value waste. Increasing landfills causes great concern in society, but very little effort has been put forward to reduce landfills. This study finds that minimal effort has been made to reduce carbon emissions and maintain the proper guidelines for disposing of hazardous wastes generated from ELV recycling. Hazardous and harmful wastes from the ELV recycling sector are required to dispose of in an environmentally friendly way49. The Indian authority should establish a safe center for hazardous waste handling to reduce the substantial environmental threat. The energy used in the ELV recycling sector, and its supportive and dependent industries comes from finite non-renewable energy sources, which have several inevitable implications for the environment and public health, including greenhouse gas emissions and air and land pollution. Renewable energy can play a crucial role as it offers a low-emission, clean and infinite energy source. The application of renewable energy can reduce carbon emissions from the ELV recycling sector significantly and facilitate the achievement of sustainability65.Most ELV recycling centers operate with rudimentary machinery, leading to low materials recovery, a persistent issue in the ELV recycling sector. There are different types of abandoned vehicles in the community, including two-wheeler, three-wheeler, private vehicles, commercial passenger and goods vehicles, military vehicles, and others; one ELV recycling center can recycle only a specific type of vehicles, not all kinds of vehicles. The glass and plastic components can be recycledIn addition, this research has performed the SWOT analysis to evaluate ELV recycling in the long-term viability and assess the critical factors and potential. The SWOT analysis demonstrates that the potential market size and skilled and cheap labor are the superior strengths of India's ELV recycling sector, while the lack of appropriate framework, knowledge and awareness are more severe weaknesses of the ELV recycling system. The combination of the growing automobile market and cheap and skilled labor draws significant foreign investments that keep India's automobile sector expanding constantly. Resource recovery, growing demands, and waste management system initiatives are significant strengths that can improve the performance of the ELV recycling system in India. The lack of an appropriate framework makes India's ELV recycling chaotic and disorganized; the authority should develop an appropriate framework to assist the ELV stakeholders in advancing and providing standard guidelines. Besides the lack of an appropriate framework, the authority should address the issues, including lack of awareness and knowledge, vehicle deregistration and ELV collection, limited technology, and pollution, to establish an efficient ELV recycling system.66. As a result, stakeholders engaged in ELV recycling cannot recycle modern vehicles with conventional technology until car manufacturers share their contemporary technologies, which leaves numerous vehicles untreated and make ELV recycling arduous and inefficient. The findings of the SWOT analysis might have significant practical impacts on society as it emphasizes maximizing strengths while reducing weaknesses and benefits from opportunities, and eventually, it underscores the potential threats to the ELV recycling sector. The SWOT analysis findings may enable the current ELV recycling system to be more productive and improve the decision-making process.Towards circular economy and sustainable development and economic viability have emerged as the greater opportunities for ELV recycling, whereas informality in the ELV recycling sector and market barriers have appeared as the greater threats to the ELV recycling system. Establishing an efficient ELV recycling system can create significant opportunities, including developing a circular economy, achieving sustainable development goals, resource recovery, reduction in energy consumption, economic prosperity and job creation. Informality, absence of policy and regulation, and different value chains are palpable potential threats to India's ELV recycling system; these threats can thwart the achievement of sustainability in the ELV recycling sector. The value chain in the automotive industry and the ELV recycling sector should be interconnected; nonetheless, no collaboration exists between vehicle manufacturers and the stakeholders involved in ELV recycling; lack of cooperation prevents information flowThis study sheds light on India's ELV recycling system and yields critical and insightful interpretations of factors contributing to sustainability. The findings of this investigation reflect the ground-level practice of ELV recycling; hence this study's outcomes may assist the Indian authority in the appropriate decision-making and implementing and designing policy, regulation and framework for ELV recycling. As this research evaluates sustainability from techno-socio-economic and environmental dimensions by underscoring group-level practices, therefore outcomes of this investigation may assist in subsequent research. This research may facilitate the authority to transform the informality-dominated India's ELV recycling sector towards a more sustainable ELV recycling system.This study makes practical recommendations as the reflection of insights gained from observation and analysis have been performed in the previous section.Designing a practical framework is imperative to achieving sustainable goals. Informality-dominated India's ELV recycling sector unveils the absence of practical frameworks. By developing practical frameworks, Indian authorities can provide directives for achieving sustainability in the ELV recycling sector by enhancing material recovery, recycling, and extraction rates while respecting the environment. In addition, providing practical frameworks to stakeholders will assist the government in governing the ELV recycling sector systemically. As practical frameworks offer resolutions to numerous persistent issues in India's ELV recycling system, authorities should urgently design appropriate guidelines and provide them to stakeholders.Public awareness plays a critical role in sustainability in the ELV recycling system. In India, public awareness is relatively low, which impedes ELV recycling significantly. Increasing public awareness level is a demanding task. The authority in India should immediately take appropriate actions to enhance awareness levels. The government can tailor awareness-raising endeavours through a systematic training program, education, reaching targeted audiences, and awareness-raising activities.The government should develop a mutual fund immediately with the collaboration of car manufacturers, stakeholders, and car owners, as the ELV recycling system is associated with several expenses, such as recycling fees, the cost of awareness-raising initiatives, financial assistance, and informal stakeholders, subsides and waste management. This fund ought to be used for promoting sustainability and green technology.The lack of stakeholder cooperation is palpable in India's ELV recycling system. The Indian government should immediately establish an information-sharing center to collect and share the required information with all stakeholders. The information-sharing center will make ELV dismantling operations easy and more effective.ELVs encompass several hazardous substances, including poisonous electronic materials, waste liquids and oils, automotive shredder residue, and other detrimental residues, that should be disposed of in environmentally sound ways. Hazardous waste management will deal with harmful wastes and dispose of these wastes in sustainable practices. India's 2070 decarbonization goal is a significant and ambitious target, requiring a combination of government policies and framework for stakeholders, private sector initiatives, and societal awareness to achieve. An appropriate waste management system can significantly contribute to a decarbonization plan by reducing greenhouse gas emissions, promoting sustainable land use, and promoting a circular economy. By implementing measures such as composting, recycling, waste-to-energy, and sustainable land use, a waste management system can help reduce carbon emissions and promote a more sustainable future. The Indian government should urgently form a hazardous waste management board as the quality of the environment is deteriorating dramatically in India.Performance evaluation plays an imperative role in enhancing product quality, standardizing ELV operations, safeguarding the environment, and promoting sustainable development and green technology. Currently, there is no performance evaluation facility in India. The Indian government should immediately design a performance evaluation system to evaluate the progress towards sustainability.67, and circular economy business model68 principles is required to support the development of ELV recycling in India, which prompts in-depth investigation Environmental degradation has become a significant challenge in India, and the evaluation of emissions from ELV recycling sectors and air quality in the vicinity of the ELV recycling sector needs further investigation. ASR is a metal-rich mixture and is not treated for value recovery in the ELV recycling sector in India because of the lack of technique and machinery. An in-depth investigation is required for ASR treatment. Stakeholders are the key players in establishing an effective ELV recycling system in India; the lack of collaboration between stakeholders is evident, which impedes material flow and information flow, which requires in-depth investigation. Economic gain inspires stakeholders to invest in energy-efficient operations and higher material recycling and recovery; material recycling and recovery rates are limited; hence the study of the economic feasibility of ELV recycling in India prompts a deeper investigation. As India's environmental quality is degenerating continuously, hence the study of the impact of ELV recycling on environmental and public health necessitates further research. Also, in recent years, India started witnessing an electric vehicle (EV) boom; this would create an entirely different set of ELVs , and the sustainable transition could depend on various other conditions. Some evidence from European Union suggested that EVs sustainable transition can't be achieved unless conditions like the use of renewable sources, local development, and battery recycling are met69. This might be true in the case of India too, so detailed further research focusing on India's EV-based ELVs could be considered. Localizing ELV recycling facilities in remote and sub-urban areas in India has advantages and disadvantages; this depends on the specific circumstances and perspectives. While it may reduce the potential negative impacts on public health and the environment, it may also increase transportation emissions and face infrastructure limitations. It is essential to carefully evaluate the benefits and drawbacks of locating ELV recycling facilities in remote areas, considering factors such as public health, environmental impact, economic development, and sustainable infrastructure. This issue requires a thorough investigation before moving forward with the localization of ELV recycling to especially remote areas and sub-urban regions in India.The present study has evaluated the sustainability of India's ELV recycling system from techno-socio-economic and environmental dimensions and performed the SWOT analysis based on ground-level practice. Based on this research and the research gap in the literature review, subsequent research can be conducted. Structural equation modeling (SEM) can be performed to investigate the impacts of social, economic, technological, and environmental aspects on sustainability, respectively, which requires further in-depth investigation. The fourth industrial revolution (IR 4.0) emphasizes automation, the internet of things (IoT), artificial intelligence (AI), smart factory, digital business models, and digitization and integration of vertical and horizontal value chains. The drivers and barriers to adopting and implementing IR 4.0 in ELV recycling, automobile, and manufacturing industries in India, require further explorations. This exploration will reveal the readiness for IR 4.0. The development of ELV recycling has been impeded by the absence of a practical framework; an effective framework equipped with the features mentioned in IR 4.0, blockchainThis research has evaluated the sustainability of India's ELV recycling system from techno-socio-economic and environmental aspects as an instrumental step for assessing performance and progress. The findings of this paper unveil that the knowledge and understanding of ELV recycling are moderate; in contrast, individuals show significant support for ELV recycling. The practice of abandoned car recycling is limited in society. ELV recycling is still one of the more profitable businesses but growing gradually. Investment in enhancing material recovery and energy saving is limited. The ELV recycling sector in India operates with conventional equipment and machinery, leading to limited material recovery rates from ELVs. Increasing landfills is a great challenge for authority. The generated harmful waste from ELV recycling is not disposed of in an environmentally sound way, which is a potential environmental threat. This study has performed the SWOT analysis to evaluate the competitiveness of India's ELV recycling system and yield a fact-based analysis and fresh perspectives. Potential market size, economic viability, and increasing demand are favourable factors; on the contrary, lack of appropriate framework, limited technology, and informality in the ELV recycling sector are critical concerns in India's ELV recycling sector. This investigation makes practical recommendations for effectively encountering persistent challenges in the ELV recycling system, enhancing materials recovery, recycling, and extraction rates, and expediting sustainable development. This research yields critical real-world data that might be instrumental for rational decision-making and developing and implementing any subsequent regulatory and legal framework that succinctly embraces the techno-socio-economic and environmental aspects. This study may assist India's government in enacting the following policy for achieving sustainable goals in ELV recycling.To the authors' best knowledge, this research represents the initial study for evaluating the sustainability of India's ELV recycling system from techno-socio-economic and environmental aspects and performing the weighted SWOT analysis to emphasize the most critical factors and prioritize the elements according to their significance and importance to assess the competitiveness of India's ELV recycling system and to overcome the limitations of the simple SWOT analysis. Consequently, this paper will assist in the future advanced study of India's ELV recycling.We also highlight a few potential drawbacks of this research study. This research interviewed 263 selective individuals to evaluate the sustainability of India's ELV recycling system from techno-socio-economic and environmental aspects and perform the SWOT analysis; the greater sample size might have given more precise outcomes. Secondary research is crucial for providing the ground for the research. This research has performed objective measurements through predefined items. The lack of contemporary literature reviews about India's ELV recycling system made the items selection for evaluating sustainability from techno-socio-economic and environmental aspects and performing the SWOT analysis very difficult. India nurtures great diversity in the world; different states have different cultures, languages, inspirations, and economic conditions; it is a cumbersome task to divide the sample size equally among people of different cultures. This study focused on the significant automobile hubs in India only. As mentioned in this paper, India's ELV recycling sector is dominated by the informal sector, and informal ELV recyclers are very suspicious of disclosing information about their practices to researchers because of fear of legal proceedings. It was an arduous task to obtain information about their perspectives and practices.


Nonspecific gastrointestinal symptoms remain a problem for pediatricians because, out of a thousand trivial cases, there are rare diseases that require in-depth diagnostics and extensive knowledge to identify them. These complaints may be caused by a neoplastic process. We present the case of a 5-year-old boy whose diagnostic pathway lasted about 3 months. He was admitted to hospital due to severe abdominal pain. Physical examination revealed a bloated, hard, and painful abdomen. In the standing X-ray, the features of intestinal obstruction were visualized. An ultrasound examination showed a possible malignant lesion in the location of the left adrenal gland. After the surgical removal of the pathological mass and histopathological examination, the diagnosis of ganglioneuroblastoma intermixed was made. This tumor, along with neuroblastoma, ganglioneuroma, and ganglioneuroblastoma nodular, belongs to neuroblastic tumors (NTs), which originate from primitive cells of the sympathetic nervous system. NTs are quite rare, but they are still the majority of extracranial solid tumors in children, and their symptoms often appear relatively late when the neoplastic process is already advanced. The purpose of this review is to present current information about ganglioneuroblastoma, with a special emphasis on nonspecific gastrointestinal symptoms as first sign of this tumor and its diagnostics. Ganglioneuroblastoma intermixed (GNBI) is, in addition to neuroblastoma (NB), ganglioneuroma (GN), and ganglioneuroblastoma nodular (GNBN), one of the four types of neuroblastic tumors (NTs) according to the International Neuroblastoma Pathology Committee (INPC). NTs are the most prevalent extracranial solid tumors in children and originate from primitive cells of the sympathetic nervous system . HoweverWe present a clinical case of a child with nonspecific gastrointestinal symptoms as the first sign of GNBI. The aim of this study is to illustrate similar cases, highlight the diagnostic challenges associated with nonspecific gastrointestinal symptoms in children, and present the current state of knowledge about GNBs—its morphology, diagnostic, and treatment options.The paper was created based on the PubMed and Google Scholar databases. The literature was reviewed using the following key words: ganglioneuroblastoma, high-risk neuroblastoma, abdominal pain, and rare tumors. We also reviewed similar case reports from the last 30 years, where gastrointestinal symptoms were the first sign of GNB in children.A five-year-old male patient presented to the Pediatric Emergency Department (ED) due to severe abdominal pain. Since three months prior to admission to the hospital, the patient had periodically been suffering from constipated stools, which were mostly passed daily, but with increased hardness. Over the past three months, there had been three episodes when the boy did not pass stool for a week. During these times, an increase in paroxysmal abdominal pain was observed. The boy was then treated with trimebutine prescribed by the general practitioner. Three days before his admission to the hospital, the child had passed stool for the last time, and abdominal pain had intensified. In primary care, trimebutine and macrogol therapy were ordered, but due to the lack of improvement, the mother took her child to the ED for the first time. During this visit, the child underwent an examination by a pediatrician and had an enema performed. At that time, the boy’s condition improved, and the child was discharged home. On the next day, the mother and the boy were again admitted to the ED, because the child had developed severe abdominal pain since the morning hours.The patient was in average general condition. Physical examination revealed that the abdomen on palpation was bloated, hard, and painful on the entire surface. A standing abdominal X-ray  was perfBased on imaging studies, a neuroblastoma-like lesion was suspected. The child was transferred to the Department of Surgery for the resection of the tumor and then to the Department of Pediatric Hematology and Oncology with the aim of further diagnostics and treatment. The additional laboratory tests  showed tDuring hospitalization, the boy complained of abdominal pain, accompanied by loose stools and pain in the lower limbs, which required opioid analgesics—nalbufine. Due to the boy’s deteriorating condition, pending the result of the histopathological examination, the decision was made to start chemotherapy. The diagnosis of neuroblastoma was suspected because of the location of the tumor ; the patient’s age; the presence of metastatic lesions in the bone marrow and in the T3 and T6; and high NSE, ferritin, and OB. Therefore, the patient was classified as being at high risk of neuroblastoma (HR-NBL), and chemotherapy was started according to the COJEC protocol. The tolerance to chemotherapy was generally good. There was a tendency towards thrombocytopenia and anemia, which required a transfusion of 1 unit of RBC concentrate. The following histopathological result was obtained: ganglioneuroblastoma intermixed with a partial tumor differentiation of paraganglioma with bone marrow, bone, and periaortic lymph node involvement. 131I-Metaiodobenzylguanide (131I-MIBG) scinthygraphy was performed, which showed two distinct foci of accumulation of 131I-MIBG within the T5 and T6 vertebrae. The patient continued chemotherapy and underwent autologous peripheral blood stem cell transplantation (auto-PBSCT). He was also treated with radiotherapy (21 Gy) and immunochemotherapy with 13-cis-retinoic acid and dinutuximab. In a follow-up scintigraphy study, the regression of previously identified lesions with residual tracer accumulation at T6 was visualized. The boy has been facing complications from intensive treatment: leukopenia (grade IV according to WHO), anemia (grade III according to WHO), toxic liver damage (grade II according to WHO), eating disorder, and infection requiring broad-spectrum antibiotic therapy.Abdominal pain is one of the most frequent complaints reported by children in pediatric healthcare units. While most of the complaints are relatively mild and are associated with functional gastrointestinal disorders, it is very important to always remember about organic causes of abdominal pain that may be life-threatening . The diaIn addition to the patient’s history and detailed physical examination, imaging studies are extremely valuable tools in the search for organic causes of abdominal pain. These tests can be helpful in finding a pathological mass, and their primary role is to confirm its presence and recognize prominent imaging characteristics that can narrow the range of differential diagnoses. The preferred initial modality to determine the origin of the mass is US . HoweverWe reviewed the case reports of GNB in children, where the primary complaints were those from the gastrointestinal system .In the nine case reports, the first sign of GNB was chronic watery diarrhea caused by excessive VIP secretion. All of these children were under 2 years of age, and all complaints were resolved after the surgical removal of the tumor. According to Soga et al., pediatric patients with VIP-secreting GNBs have a good survival rate of 90% . AlthougThe majority of extracranial solid tumors in children and adolescents, comprising 7–10% of all pediatric tumors, are NTs ,27,28. NThe histological characteristics of the GNBI subtype encompass small regions of neuroblastic cells at various levels of maturation, the presence of neuropil, and Schwannian stroma constituting more than half of the structure. In comparison to the nodular subtype, GNBIs usually lack hemorrhagic and/or necrotic nodules. Tumors in this category are classified into a Favorable Histology (FH) Group according to The International Neuroblastoma Pathology Classification (INPC) . ImmunohMultimodality imaging, including metabolic nuclear imaging, is required for diagnosis, staging, response assessment, and follow-up . US is nGNBs are easily misdiagnosed due to nonspecific symptoms in the early stages of the disease . The cliGNBI is widely seen as a malignant tumor that, depending on the stage, requires multimodal therapy ,52. The The International Society of Pediatric Oncology (SIOPEN) conducts trials on NB within Europe. In the current HR-NB protocol, cross-sectional imaging is mandatory for the response assessment of the primary tumor at staging, after induction chemotherapy, for preoperative planning and the evaluation of residual primary tumors after surgery and before radiation therapy, before maintenance, and at the end of treatment . The IntThe recurrence of GNB occurs mostly in the first 2 years after surgery, and it can be solved by subsequent surgery and chemotherapy ,56. OkamClinicians should be aware of classic manifestations of GNB, especially those caused by disseminated tumors, and must always pay particular attention to the possibility of a neoplastic cause of nonspecific gastrointestinal symptoms. In diagnosing functional gastrointestinal disorders, an organic cause should always be excluded. Imaging studies, such as CT, play a key role in the evaluation of children with nonspecific symptoms, enabling the detection of lesions that are rare and life-threatening. As a result, the likelihood of a timely diagnosis and the early implementation of effective therapeutic protocols increases, ultimately leading to improved survival rates and reducing permanent damage.


The aging of the population is an increasingly serious issue, and many age-related illnesses are on the rise. These illnesses pose a serious threat to the health and safety of elderly individuals and create a serious economic and social burden. Despite substantial research into the pathogenesis of these diseases, their etiology and pathogenesis remain unclear. In recent decades, rodent models have been used in attempts to elucidate these disorders, but such models fail to simulate the full range of symptoms. Nonhuman primates (NHPs) are the most ideal neuroscientific models for studying the human brain and are more functionally similar to humans because of their high genetic similarities and phenotypic characteristics in comparison with humans. Here, we review the literature examining typical NHP brain disease models, focusing on NHP models of common diseases such as dementia, Parkinson’s disease, and epilepsy. We also explore the application of electroencephalography (EEG), magnetic resonance imaging (MRI), and optogenetic study methods on NHPs and neural circuits associated with cognitive impairment. In recent years, as the world population has aged, the prevalence and incidence of cognition-related diseases  have increased, which places great stress on society and families. Some of these diseases have high mortality rates, and their etiology and pathogenesis are unclear, while their main manifestations include deficits in learning and memory function, language, visuospatial function, executive function, personality, and attention, among others ,2,3,4.Alzheimer’s disease (AD) is the most common type of dementia, accounting for 60–70% of cases , and hasParkinson’s disease (PD) has a prevalence of 2–3% among people aged 65 years and older, and it is the second most common neurodegenerative disease in the world . With th5. Based on this, it is estimated that there are approximately nine million epilepsy patients in China. Meanwhile, there are approximately 400,000 new epilepsy patients added each year, making epilepsy the second most common disease in neurology after headaches in China.Epilepsy is a common neurological disorder that affects approximately 1% of the world’s population; it is characterized by long-term and unpredictable seizures caused by abnormal neuronal electrical activity. Epilepsy is caused by the sudden abnormal discharge of brain neurons, which leads to temporary brain dysfunction . AccordiWith the aging of the world population, it is particularly important to select appropriate, safe, effective, and ideal experimental animal models for the study of senile diseases. Based on the principle of selecting similarity in experimental animals, the advantages of nonhuman primate models are becoming increasingly prominent.Due to the connection between shared sequences and the evolution of environmental forces, NHPs have many anatomical and functional similarities to humans. Compared to rodents, NHPs have cortical folding, segmentation, and expansion that are more similar to humans, and these features increase the complexity of their anatomy, cognition, and behavior, making it difficult to find perfectly consistent models of many human neurological diseases in rodents. Macaques are the most studied NHPs ,12. The The emergence and development of techniques such as electroencephalography (EEG), magnetic resonance imaging, and optogenetics have revealed new horizons for neuroscience research, and these methods have resulted in some breakthroughs in rodents. Therefore, understanding the application of these research methods in NHPs is of great significance for future disease research. In this review, we retrieved the keywords AD, PD, epilepsy, EEG, MRI, or virus vectors in the PubMed database and discussed studies on NHP models of cognition-related diseases; the application of EEG, magnetic resonance imaging, optogenetics, and other research methods; and research on disease-related neural circuits see .Nonhuman primates are ideal neuroscience models for studying the brain. In this review, we summarize three models of common diseases: (1) Alzheimer’s disease; (2) Parkinson’s disease; and (3) epilepsy. In addition, we list studies using EEG, magnetic resonance imaging, and optogenetics in NHPs. The study of neural circuits can fully reveal how the brain performs complex functions; recombinant viruses have become the most commonly used tool for studying neural circuits, and we summarize the common viral vectors applied to neural circuits and discuss their advantages and disadvantages while listing the neural circuits associated with cognitive impairment.Of all animal research models, NHPs are the closest to humans in terms of physiology, anatomical structure, and immunity. Long-term practice has demonstrated that NHPs provide appropriate models of human disease and have natural advantages in this function. NHPs are the most suitable for exploring human disease mechanisms and new treatment modalities. Therefore, NHPs are a highly reliable experimental model species in which to study the etiology, pathogenesis, and potential treatment of brain diseases.The cognitive impairment of AD patients mainly manifests as learning and memory impairment, language impairment, visuospatial impairment, and executive dysfunction, among other deficits. The main pathological manifestations of AD are extracellular β-amyloid (Aβ) deposition, tau protein abnormalities, intracellular neurofibrillary tangles, and neuronal loss . The valThe AD models that exist at present include natural aging models, transgenic animal models, models constructed by physical or chemical methods, and models constructed by a combination of methods. However, these models are mostly based on C57BL6/J mice, while there have been few studies on macaques. Yang et al. used macaques as research subjects. Juvenile male macaques were chronically fed 3% methanol for 6 months, and a variable spatial delayed-response task was administered. The results showed a persistent decline in the memory capacity of these macaques, which was consistent with the abnormal increase in tau protein phosphorylation of T181 and S396 residues in cerebrospinal fluid during methanol feeding, as well as an increase in tau protein phosphorylation aggregates and amyloid plaques. The phenomena are present in four regions of postmortem brains: the prefrontal cortex (PFC), the parietal cortex, the temporal cortex, and the hippocampus. Subsequently, the researchers fed macaques methanol for 6 months and found persistent changes in phosphorylated tau protein in the brain after consuming methanol, suggesting that methanol feeding leads to long-term pathological changes related to the development of AD in macaques . This reThe core symptoms of PD are bradykinesia and clinical manifestations such as static tremor, myotonia, and abnormal posture . TypicalIn 1959, Senoh and Witkop  first isLi et al.  combinedIn approximately one-third of epilepsy patients, these seizures cannot be controlled through drugs; this condition is known as refractory epilepsy. Patients with refractory epilepsy have significantly greater mortality, physical trauma, and risk of psychological disorders than the overall population of epilepsy patients . The cliSystemic convulsants are often used in the development of models of temporal lobe epilepsy in primates. However, this usually leads to diffuse brain damage that affects multiple lesions outside the limbic system. Perez-Mendes et al.  induced In cognitive studies of humans and NHPs, the cerebral cortex is recognized to consist of anatomically and functionally distinct cortical regions. However, these cortical regions complete tasks independently in use or rapidly and selectively in a flexible way to achieve different effects. Neural network theory proposes two basic characteristics of brain function, namely, functional separation and functional integration ,32. For An EEG signal is the spontaneous, rhythmic electrical activity of brain cell clusters recorded by electrodes. EEG is an effective method for examining functional changes in the brain and is highly sensitive to changes in the neural activity of the brain at the millisecond level . AccordiScalp EEG represents the electrical activity of a large brain region recorded from the scalp surface. Because of its noninvasive nature and portable, easy-to-use apparatus, it is safe for patients and is increasingly used in various neurodegenerative and neuropsychiatric diseases, such as AD, schizophrenia, depression, Huntington’s disease, PD, multiple sclerosis, and brain injury ,35. For ECoG is a technique that uses subdural electrodes to record neural activity on the cortical surface, allowing simultaneous recording of neural activity from several of these electrodes without penetrating the cortical tissue. ECoG has higher spatial resolution , wider bandwidth , higher amplitude  ,39, and LFPs are the low-frequency component of the electrophysiological signal recorded invasively in the brain, which can capture neural oscillations at approximately 1–300 Hz. LFP recording has become an important technique for neurophysiological recordings in the cerebral cortex. Because LFP recording is suitable for simultaneous measurements from different regions, it enables the study of neural interactions in different brain regions. LFP can capture the traditional single-unit activity (SUA) to record otherwise unmeasurable synaptic processes .Spike signals and LFP signals can be separated from the electrophysiological signal recorded by the implanted electrode. Spikes primarily represent a series of action potentials emitted by a single neuron and are the output from neurons within a radius of approximately 200 μm around the tip of the microelectrode . LFPs arOne sign of LFPs is that the oscillations of various frequencies are modulated between different times and different brain structures. LFP oscillations at different frequencies are related to different sensory and cognitive processes and information transmission between brain regions . Yan et EEG has also been applied to study the correlations of different parts of the brain. Some studies have shown that both action selection and spatial working memory are associated with the frontoparietal network of the primate cerebral cortex, particularly with direct interactions between the frontal and parietal lobes , but howAlthough some researchers have made great contributions regarding the interaction between the frontal and parietal lobes, the neural mechanism underlying the control of the frontoparietal network remains unresolved. Dotson et al.  simultanOther researchers have proposed that the coherent oscillation in neuronal activity constitutes a hypothetical dynamic mechanism for regulating the interaction between different brain regions ,57. SimuMRI is a technique that uses the phenomenon of magnetic resonance to obtain electromagnetic signals from the human body and reconstruct body information, which plays a crucial role in neuroscience research involving NHPs. Before the appearance of MRI, neurophysiologists relied on postmortem histological evaluation of brain sections under a microscope to identify target areas by recording or injection. The emergence of MRI provided a new perspective to further explore the internal structure of the brain and the pathogenesis of brain diseases. Recently, the combined application of MRI and other techniques has greatly improved the accuracy and efficiency of neurophysiological experiments in NHPs , offerinsMRI uses the nuclei of hydrogen atoms arranged in a certain sequence under the action of a magnetic field; in this imaging modality, the changes in some structures can be clearly observed. In NHPs, sMRI can be combined with invasive experimental conditions that cannot be achieved in human research, such as drug intervention, histological research, high-density electrophysiological recording, and injection of viral vectors for optogenetic manipulation or calcium imaging; thus, sMRI provides a unique way to understand the human brain and its pathology . sMRI haPelekanos et al.  observed2) in the functionally active area of the brain leads to enhancement of the magnetic resonance signal. BOLD-fMRI imaging has the advantages of noninvasiveness, strong repeatability, high spatial and temporal resolution, and easy localization of signals. fMRI has developed very rapidly in the field of functional neurological studies of the brain and has been widely used to examine the functioning of brain networks behind various cognitive, emotional, and motor functions in NHPs  clozapine. The study demonstrated that low-dose [11C] clozapine activated hM4Di in the dorsal amygdala, producing a significant reduction in anxiety-related behaviors in NHPs.Clozapine-N-oxide (CNO) was originally considered an ideal activator of designer receptors exclusively activated by designer drugs (DREADDs), with high affinity and selectivity for DREADDs, and has been widely used in rodent studies to mediate amygdala inhibition to regulate anxiety. Some studies using rAAV5/hSyn-hM4D-mCherry to transfect the amygdala of rhesus monkeys have revealed that CNO reduces the resting-state functional connectivity between the amygdala and the frontal cortex by binding to the receptor DREADD of hM4Di. However, this study did not use DREADD-free mice as a control group. Recent pharmacokinetic evidence shows that CNO has poor brain permeability, but CNO can be reversely metabolized to clozapine. Therefore, some doubt was expressed as to whether the observed effect is due to the intrinsic effect of CNO or reverse metabolism to clozapine . SubsequFear, a vital emotion for the survival of animals, can be generated when individuals are in danger or when they see their companions in danger . HoweverThe amygdala, PFC, and hippocampus have been identified as three key brain regions involved in the learning, regulation, and regression of the animal fear response . The amyMontardy et al.  studied Cognition refers to a complex set of brain functions, ranging from attention, language, and visuospatial processes to learning, memory formation, and execution , includiPerception is a series of processes of awareness, sensation, and attention directed towards internal and external information. Up to half of the regions in the macaque cortex and approximately one-quarter of the human cortex are involved in the processing of visual sensory information . In primIn addition, both human and NHP studies have revealed the existence of a third visual pathway on the lateral surface of the brain. The third pathway projects from the early visual cortex to the superior temporal sulcus (STS) through the motor selection area. STS is used to calculate the movement of the moving face and body , indicating that the third visual pathway is dedicated to the dynamic aspects of social perception .The hippocampus and PFC are considered of critical importance for cognition. The hippocampus is an important component of the limbic system in the human brain and plays an important role in spatial navigation and the integration of information from short-term to long-term memory . ExtensiThe dorsolateral prefrontal cortex (dlPFC) is unique to primates and underlies their unique cognitive abilities. It is located at the core of advanced brain function through the neural circuit connecting the dorsal caudate nucleus (dCD) and the medial thalamus (MDI). Oyama et al.  transfecNHPs are of irreplaceable value in the field of cognitive research. In the clinic, brain cognitive-related diseases still have a high mortality rate, and there is no effective treatment. Although many scholars have conducted extensive research in the field of neuroscience and achieved a series of great achievements, some NHP brain disease models cannot effectively simulate the common clinical symptoms and typical pathological markers of the diseases. In the future, more attention should be given to the exploration of NHP disease models.In addition, electrophysiological, optogenetic, chemogenetic, and other techniques have made positive achievements in the study of brain function in NHPs. Major breakthroughs will be made in the cognitive field when the cognitive control mechanisms of the brain for different tasks are revealed by studying specific brain areas/neurons and identifying neural networks corresponding to behaviors, neural circuits, and causal interactions between neurons. However, there are still some problems in the study of NHPs. For example, the primate brain is two orders of magnitude larger than the mouse brain, which makes it more difficult to research the deep brain in NHPs. Additionally, the behavioral response induced by the regulation of the primate brain is far more complex than that of rodents. We reviewed the methods of constructing animal models of some brain diseases in NHPs and the applications of neuromodulation and imaging techniques in NHPs. We hope that in the future, NHP neuromodulation techniques and imaging methods can be applied to the research of NHP brain diseases, thereby promoting the development and research of these diseases.


Neural circuits are remarkably well-organized systems that transmit and process incoming information. At the same time, neural circuits are highly flexible systems that demonstrate drastic refinement and remodeling depending on animal development, environmental cues, distress, or lesion. Accumulating evidence suggests that precise refinement and remodeling are crucial for appropriate higher brain functions, and disturbance of these processes could account for psychiatric disorders  evoked and AP-independent, “spontaneous” transmission at the Drosophila larval neuromuscular junctions. AP-evoked neurotransmission is considered the primary mode of inter-neuronal communication, whereas spontaneous transmission is required for neuronal development, homeostasis, and plasticity. However, the functional interdependence of both transmission modes remains unknown. The results in the article indicate that the level of spontaneous activity is a predictor of their responsiveness to AP-stimulation. Thus, this seemingly stochastic transmission mode may very well serve as a reference signal to keep connection strength in check and constantly adjust the presynaptic neurotransmitter release machinery. In another study, San Segundo et al. elucidate the significance of the multivesicular release. In the CNS presynaptic terminal, the univesicular and multivesicular synchronous release of neurotransmitter release occurs. They examine the association of glutamate release with excitatory post-synaptic currents by expression of fluorescent glutamate sensor iGluSnFR in the astrocyte which contacts with synapses. Measuring signal of iGluSnFR together with electrophysiological post-synaptic currents at the autaptic hippocampal neuronal cultures, they found that all measured presynaptic terminal possesses a mixed population of univesicular or multivesicular neurotransmitter release and that the terminals showing a preference for multivesicular release display greater strength as well as short-term synaptic depression.Two of the studies treat the presynaptic transmitter release properties using electrophysiology and live imaging of CaFeng et al. studied the effects of temperature on the function of the CNS synapses. They show that hypothermia and hyperthermia trigger bidirectional re-organization of presynaptic architecture, synaptic strengthening, and weakening, respectively, at the hippocampal neurons. Interestingly, induction of hypothermia in vivo enhances inhibitory synapses in the hippocampus but not in the cortex, suggesting a region-specific form of environmental synaptic plasticity with a mechanism distinct from the classic temperature shock response. Chequer Charan et al. applied cutting-edge serial block-face electron microscopy to study the developmental structural change of the giant presynaptic terminal with multiple active zones, the calyx of Held, located at the medial nucleus of the trapezoid body (MNTB) of the C57BL/6J mouse. By reconstruction of circuitry-level volumes of mouse MNTB at different ages, they found that MNTB neurons reduce in density with age, which is consistent with a type of age-related hearing loss in the mouse. It has been assumed that the mature MNTB neuron is innervated by a single calyx of Held, but they surprisingly observed an average of ~10 % of poly-innervated MNTB neurons along the mouse lifespan.In addition to the functional analysis by electrophysiology or live imaging, the morphological analysis of the synapses under different conditions is crucial to understand the refinement/remodeling of the neural circuit. The aim of this Research Topic was to highlight recent advances in the field of neural circuit adaptation, refinement, and remodeling, both from functional and morphological perspectives. Moreover, we tried to notify the readers of the many open questions that remains to be elucidated to understand neural circuit refinement and remodeling. We hope this Research Topic fulfilled our aim to some extent. We would like to thank all the contributing authors and hope that the readers will share our excitement and enthusiasm to explore the neural circuit refinement and remodeling.All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.


Lungs are important respiratory organs primarily involved in gas exchange. Lungs interact directly with the environment and their primary function is affected by several inflammatory responses caused by allergens, inflammatory mediators, and pathogens, eventually leading to disease. The immune architecture of the lung consists of an extensive network of innate immune cells, which induce adaptive immune responses based on the nature of the pathogen(s). The balance of immune responses is critical for maintaining immune homeostasis in the lung. Infection by pathogens and physical or genetic dysregulation of immune homeostasis result in inflammatory diseases. These responses culminate in the production of a plethora of cytokines such as TSLP, IL-9, IL-25, and IL-33, which have been implicated in the pathogenesis of several inflammatory and autoimmune diseases. Shifting the balance of Th1, Th2, Th9, and Th17 responses have been the targets of therapeutic interventions in the treatment of these diseases. Here, we have briefly reviewed the innate and adaptive i3mmune responses in the lung. Genetic and environmental factors, and infection are the major causes of dysregulation of various functions of the lung. We have elaborated on the impact of inflammatory and infectious diseases, advances in therapies, and drug delivery devices on this critical organ. Finally, we have provided a comprehensive compilation of different inflammatory and infectious diseases of the lungs and commented on the pros and cons of different inhalation devices for the management of lung diseases. The review is intended to provide a summary of the immunology of the lung, with an emphasis on drug and device development. Lungs are important respiratory organs involved in providing oxygen to the body. Every day, the lungs interact directly with a myriad of different-sized particles from the environment. Most of these particles are filtered through the mucosal barriers present in the upper respiratory tract. These barriers thus efficiently protect the body from pathogens, allergens, and various foreign bodies. Large particles are removed by physical barriers and forces such as coughing and sneezing, triggered by the muscular-nervous system. Smaller particles are entrapped, degraded, and processed by epithelial and a battery of cells in the mucosal lining of the trachea. Interactions of these external substances with specific Toll-like receptors present on the inner epithelium of the respiratory tract and phagocytosis of these substances activate the innate immune system . This syIn this review, we have summarized various aspects of pulmonary immune homeostasis mediated through regulated activation of innate and adaptive immune responses. We have elaborated on the pathogenesis of inflammatory autoimmune diseases and infectious diseases. Further, we have highlighted the advances in novel therapies and drug delivery devices that can help in developing drugs to treat lung diseases.Homeostasis is a state of balance. Homeostasis within the lung is maintained by harmonious coordination of different immune pathways, which includes the active participation of alveolar epithelial cells (AECs) and macrophages Figure 1In contrast to AMs, IMs have a regulatory function within the lung tissue . While AA detailed understanding of the pathogenesis of inflammatory diseases and lung infections has given insights into the multifactorial components of the immune system in regulating lung functions. We have reviewed these two conditions and listed the immunological pathways that contribute to the immunopathogenesis of various inflammatory diseases and infections. There are several learnings of immunological pathways from these diverse pathologies that have yielded novel therapies. We have outlined the advances in delivery devices for therapeutic interventions that have been developed to treat lung diseases.Every day, the respiratory system, processes 10,000–12,000 L of air. Due to this, the lung epithelium is exposed to several particulates mixed with a complex mixture of gases . The pulThe respiratory adaptive immune system consists of cellular components like T lymphocytes, B lymphocytes, and antigen-presenting cells, along with soluble mediators like cytokines, chemokines, lactoferrin, defensins and sIgAs . Followi+ T cells and AEC apoptosis which is a prominent observation in lung biopsies of patients with idiopathic pulmonary fibrosis (IPF). Further, we discuss the role of inflammation in chronic obstructive pulmonary disease (COPD) and asthma. The role of inflammation in IPF is considered somewhat controversial and reviewed extensively elsewhere  proteins in the lung tissue, which makes the lungs unable to transport oxygen into the bloodstream efficiently and often leads to lung failure. Although the etiology of IPF is unknown, several risk factors such as cigarette smoking, occupational factors, genetic polymorphisms, and environmental exposure can contribute to the development of IPF. IPF is a clinically heterogeneous disease with an overall prognosis being very poor; typically, it has a median survival of 3–4 years , 53. RepCD4+ T cells in IPF: One of the main challenges in lung fibrosis is that the exact molecular and cellular mechanisms underlying the disease remain largely unknown. However, damage to the airway epithelium (apoptosis) is considered as an early pathogenic event, with an irregular repair process by epithelial-mesenchymal interactions, rather than an inflammatory response   , and inh (LABAs) .β-defensins can contribute to the severity of asthma. In fact, Baines et al., demonstrated that airway β-defensin-1 was elevated in severe asthma patients regardless of the inflammatory phenotype and may act as an effective biomarker and potential therapeutic target . Asthma affects over 300 million people worldwide . The prec target . Recent Th2 immune responses in asthma: The pathophysiology of asthma is complex and involves various host-environment interactions and inflammatory responses occurring at various levels. There are two subtypes of asthma: allergic and non-allergic. Allergic asthma is the most common form of disease that affects many individuals. Allergic asthma may get triggered in response to house dust mites, animal dander, mold, and pollens, whereas non-allergic asthma might be the result of respiratory viral infections, cold air, and tobacco smoke leading to chronic airway inflammation  cells  cells . It has ecretion , 114.Role of thymic stromal lymphopoietin in asthma: Our understanding of the airway epithelium in driving asthma pathogenesis has progressed extensively in recent years. In response to allergic and non-allergic triggers, airway epithelial cells release cytokines, known as “alarmins,” such as TSLP, IL-33, and IL-25  or bronchopneumonia (affecting patches of the lobe). Further, it can be etiologically classified as community-acquired pneumonia  or hospital-acquired pneumonia .Etiology:Bacterial pneumonias- S. pneumoniae is the most common cause of CAP and a leading cause of illness in children below 2 years of age, the elderly, and immunocompromised individuals  and Klebsiella pneumoniae are more common among patients over 50 years old with chronic obstructive lung disease or alcoholism, whereas pneumonia due to Mycoplasma pneumoniae and Chlamydophila pneumoniae are more common in school-aged children. Other less common agents causing pneumonias include Francisella tularensis, Legionella pneumophila, Yersinia pestis, and Neisseria meningitidis (Mycobacterium tuberculosis (Mtb) causes pulmonary pneumonia; however, the incidence of tuberculosis is low in industrialized countries. Nonetheless, it remains to be a significant public health problem in the United States.ividuals . Pneumonngitidis . MycobacViral pneumonias- Pneumonias by RSV and Adenoviruses are rare in the healthy population. Pneumonia caused by influenza viruses is still a cause of high mortality in the elderly and in patients with underlying diseases. A serious complication of influenza is a secondary bacterial pneumonia which can be fatal in infants.Other pneumonias- Actinomyces and Nocardia spp can cause pneumonitis. Aspergillus and Candida spp cause pneumonias in severely ill or immunosuppressed patients and neonates, whereas Pneumocystis carinii causes life-threatening pneumonia in patients with HIV.Pathogenesis and clinical manifestations: The onset of pneumonia is quite abrupt; it develops with a shaking chill, fever, malaise, cough, and dyspnoea. Left untreated, this toxic illness can progress to acute respiratory failure, septic shock, multiorgan failure, and death within several days from onset  receptors that promotes release of viral RNA into the host cell, initiating replication and further dissemination  that can be conveniently aerosolized and delivered to the patient using nebulizers and pressurized metered-dose inhalers (pMDI) –193. ThrThe physicochemical and pharmacokinetic properties of drugs, such as half-life, molecular weight, solubility, lipophilicity, charge, and protein binding are important in determining their clearance from the lungs . Lipid-sThe choice and suitability of an aerosol delivery device for a particular patient depends on the recommendations of the physician, available types of formulations, and compliance with the personal ease and comfort of the patient Figure 3pMDIs were the foremost among the extensively used inhaler devices  has been successfully used to treat patients with pulmonary arterial hypertension using an ultrasonic nebulizer   were originally available for the administration of ipratropium/albuterol, which later became available for other bronchodilators  are excellent alternatives to pMDIs as they help to circumvent many limitations associated with pMDIs such as low lung deposition of drugs and the need for propellants. In 1967, Fisons  launched the Spinhaler® device. Thereafter, striking advances have been made in DPI design. and a wide variety of medications are available as dry powder formulations, making them extremely useful to patients with respiratory tract diseases. Some of the commercially available DPI designs are Genuair, Breezhaler, Podhaler, Dreamboat, Conix, Twincer, Twincaps, and Staccato. They are compact and easily portable and can help impart short treatment times. The TOBI® Podhaler®  holds merit over jet nebulizers for the treatment of cystic fibrosis. Administration of Tobramycin Inhalation Solution (TIS™)  using a jet-nebulizer posed several problems. For example, the device requires long inhalation times cleaning of the nebulizer is required after every use, which increases the chances of lung infection from devices that are not cleaned properly (properly . Moreoveproperly , and thevia other sources. The merit of a passive DPI is that it averts the need to synchronize the actuation and inspiration maneuver by the patient. However, this requires a pronounced inspiratory effort on the part of the patient, which might be difficult for the elderly and children, and those suffering from COPD or asthma (However, there are some demerits of DPIs. Due to inter-particulate forces like electrostatic interactions and van der Waals forces , micronir asthma . Becauser asthma . The perA wide variety of inhaler devices are commercially available today; however, knowledge of correct device use, device maintenance, and stringent compliance to the instructions provided by the medical practitioner are pivotal in achieving maximum and timely therapeutic benefits. Newer models of inhalers are constantly on the horizon to make them more user-friendly and convenient. Effective communication and coordination among doctors, nurses, and patients and being updated with the latest developments in the field of inhaler device designs and applications can help in the effective and timely implementation of treatment regimens.Exosomes are naturally occurring nanoparticles present in most bodily fluids such as serum, plasma, urine, breast milk, saliva, ascites, and synovial and amniotic fluids. These extracellular vesicles are like bacterial outer membrane vesicles and vary in size from 20 microns to 200, assisting in cell-cell communication and intercellular transport , 214. ThThe normal functioning of the lung requires complex interactions of many different cell types embedded in a precise architecture of the lung. Normal human lungs are constantly exposed to a plethora of inflammatory molecules, allergens, pollutants, and microbes from the environment and can induce cough, shortness of breath, chest pain, and fever. The nature of the immune responses to these foreign entities involves a coordinated action of the innate and adaptive immunity, which enables a balanced response and minimize lung pathology.In this review we have described various aspects of lung homeostasis and innate and adaptive responses required to maintain a balanced state. We reviewed lung inflammatory responses and infectious diseases contributing to lung disease pathogenesis with a brief description of COVID-19 lung pathology. Further, we reviewed currently available therapies to treat lung diseases and devices used to deliver drugs including exosomes, directed to the airways of the respiratory tract. The review provides a guide to lung immunology expanding on the interplay of different aspects of the immune system, inflammation and lung associated infectious diseases and how various strategies are used for lung pathology treatment. It aims to provide a technical insight into the current landscape of drugs and devices used to treat various lung diseases and discusses their limitations to initiate a colloquy about future targets of therapeutic interventions.IG: Wrote the Lung Inflammation Section; RD: Wrote the Infectious Diseases Section; VB: Wrote the Therapy and Devices Section; VG: Wrote the Lung Immunology and Exosomes as drug delivery Section; NC: Conceived the concept and directed the writing. All authors contributed to the article and approved the submitted version. IG, RD and VB contributed equally to the manuscript.