Antibodies are not only an important class of biotherapeutic drugs, but also are targeting moieties for achieving active targeting drug delivery. Meanwhile, the rapidly increasing application of antibodies and Fc-fusion proteins has inspired the emerging development of downstream processing technologies. Thus, IgG Fc affinity ligands have come into being and have been widely exploited in antibody purification strategies. Given the high binding affinity and specificity to IgGs, binding stability in physiological medium conditions, and favorable toxicity and immunogenicity profiles, Fc affinity ligands are gradually applied to antibody delivery, non-covalent antibody–drug conjugates or antibody-mediated active-targeted drug delivery systems. In this review, we will briefly introduce IgG affinity ligands that are widely used at present and summarize their diverse applications in the field of antibody-involved drug delivery. The challenges and outlook of these systems are also discussed. L), constant light (CL) and variable heavy (VH), constant heavy 1 (CH1) segments, and the Fc region is a heavy chain dimer composed of constant heavy 2 (CH2) and constant heavy 3 (CH3) segments (Antibodies (Abs), also known as an immunoglobulin (Ig), represent one of the most important classes of biotherapeutic drugs . They arsegments . The FabTraditionally, IgG Fc affinity proteins, which could non-covalently bind with Fc regions, have been widely explored in antibody purification processes . ProteinWith the wide development of affinity ligands, it is gradually realized that they are not only limited to the purification of antibodies, but also gradually applied to more and more fields, such as researches including recombinant proteins, biomedical engineering, and electronic engineering. For example, there are studies on the use of affinity peptides to immobilize antibodies in the appropriate orientation to the sensor and the use of affinity proteins to increase the half-life of fusion proteins ,13. It iIn this review, we will briefly introduce IgG affinity ligands that are widely used at present and summarize the advanced applications of affinity ligands in the field of antibody delivery, non-covalent antibody–drug conjugates (ADC), and antibody-mediated active targeting drug delivery systems. We will highlight some representative work and present the challenge and outlook of the future research and development of antibody-involved drug delivery.IgG Fc affinity ligands have already been reviewed in the earlier literature . TherefoIgG affinity proteins were initially developed for application in antibody purification, and the most widely used were the natural affinity proteins of bacteria, such as pA and pG . However−9 M to 1 × 10−4 M, which means that different ligands can be selected according to different application scenarios. High selectivity and stability, low toxicity and cost, and selectable affinity capacity provide prerequisites for affinity ligands to be used in the field of drug delivery.As shown in Monoclonal antibodies (mAbs) are now applied as targeted therapies for cancer, autoimmune and infectious diseases, as well as a range of new diseases. However, systemic administration of mAbs carries the risk of immune reactions, such as anaphylaxis and the production of anti-drug antibodies . In addiCompared with systemic administration, local administration at the site of disease allows delivery of higher “effective” doses while enhancing the stability of therapeutic drugs and minimizing side effects. Hydrogel systems, including peptide hydrogels, have proven to be highly biocompatible materials for disease-initiated in situ assembly, programmed degradation, and drug release. However, there are still limitations in current hydrogel-based delivery systems, such as the burst release of drugs . Peptide4+ and CD8+ T cells and Foxp3+ regulatory T cells in mice. The pG_EAK/EAK gels can be used to retain IgG locally in vivo and can be tailored as a scaffold to control molecular and/or cellular therapy deposition. This localized delivery system can reduce immune-related adverse events for many of the immunomodulatory agents currently approved for use in humans. Li et al. [The EAK16-II, consisting of the sequence AEAEAKAKAEAEAKAK, which self-assembles into crosslinking fibrils in ionic solutions, is often used for local delivery and release of antibodies. However, IgG antibodies are rapidly released. As shown in i et al.  developeCompared to gels that achieve controlled release of antibodies through biotin, heparin, and divalent metal ,49, gelsThe development of antibodies against intracellular drug targets is an effective way to treat diseases. However, the large size and high surface charge of antibodies limit the development and application of intracellular targeting antibodies . To deliAs shown in Du et al.  synthesiCompared to electroporation and microinjection, non-covalently delivered antibodies avoid disrupting cell membranes or reducing cell viability. Moreover, compared to covalent coupling strategies, this “mix-and-go” method not only avoids the complex step of antibody purification, which causes the structural and functional impairments of antibodies, but also allows delivery of more than one antibody or Fc-fusion protein simultaneously in a facile way . Due to Over the past ten years, antibody–drug conjugates (ADCs) have made considerable progress in the field of cancer therapy. ADCs utilize the high binding specificity and affinity of antibodies to target antigens and specifically direct potent cytotoxic payloads into cancer cells . The strTherefore, an alternative approach to the production of homogeneous ADCs using unmodified antibody scaffolds would be advantageous . As discAs shown in There are also many studies to construct non-covalent ADC systems using the affinity properties of protein A/G and its variants. Maso et al.  construcRapid generation of homogeneous ADCs by simply mixing antibodies with the payload of the modified affinity sequence avoids the need for antibody modification and destruction. In addition, this strategy can be extended to a wide range of therapeutic molecules as well as diagnostics, with potential uses beyond the treatment of cancer.Drug delivery systems (DDSs) are widely used in pharmaceutical research and clinical settings to improve the effectiveness of diagnostic agents and drugs. There are various types of DDSs, including simple macromolecules  and particulate multicomponent structures  . The useTake antibody-modified liposomes, for example, also known as immune-liposomes. They can selectively deliver encapsulated drug “carriers” to cells through the interaction of cell surface proteins with antibodies . HoweverBionanocapsules (BNCs) are hollow nanoparticles composed of protein L (the hepatitis B virus surface antigen) that have a specific affinity for human hepatocytes and are a safe DDS . HoweverIn another studies, Dostalova et al.  used theIn recent decades, the increase within the variety of therapeutic antibodies has led to requirements for optimized antibody purification processing. More and more kinds of Fc affinity ligands are screened and developed, which promotes the success of antibody affinity chromatography. With the continuous emergence of optimized ligands, their applications are not limited to protein purification. Emerging studies have applied IgG affinity ligands to antibody-involved drug delivery. The choice of affinity ligands in different applications has both similarities and differences. The requirements for the antibody-binding specificity and affinity ability of affinity ligands are consistent in the applications of drug delivery and affinity chromatography for antibody purification. The key differences mainly involve the binding stability of antibody affinity ligand complexes and their controlled dissociation in related conditions. In the context of antibody purification, the complex is expected to remain stable in the stage of antibody capture and dissociate under a specific and mild elution condition, while in the case of drug delivery the affinity ligands should bind stably to antibodies during preparation and in storage. When in use, the complex should be stable until they reach the target site in vivo. It would be better that the complex in the site of the disease could dissociate in a controlled manner. Moreover, in order to explore the full targeting capability in drug delivery or disease treatment, it is crucial that the Fab region of the antibody should not disturbed. Despite tremendous progress in antibody-involved drug delivery, including antibody delivery, drug delivery, and active targeting carriers using non-covalent affinity with antibodies, there are still many issues to be addressed. The stability of the complexes in vivo is less explored, and the current applications mostly remain validated in in vitro experiments. Whether the non-covalent affinity strategy can be stably applied to in vivo circulation needs to be further explored in detail. Secondly, antibody aggregation is also a non-negligible problem in its application in drug delivery. Several mechanisms have been proposed for protein-induced nanoparticle aggregation . TherefoIn addition to issues such as stability and aggregation, for intracellular delivery of antibody applications, non-covalent affinity strategies still suffer from issues such as low cytoplasmic delivery efficiency. Whether the delivered antibody can reach the effective dose is an issue to be considered for future applications. For non-covalent ADCs, the stability of the preparation process and the availability of a highly productive, scalable, and robust synthesis process is also an issue to be explored from the perspective of future applications and industry.In most cases, the binding of affinity ligands to IgG masks the Fc region of the antibody and perhaps prevents the ADCC or CDC effect of the antibody. Therefore, in the future, it will be necessary to screen an alternative non-covalent binding strategy to ensure that the antibodies attach in a favorable orientation while maintaining their biological function and avoid non-specific protein adsorption. In addition, the controlled dissociation of ligands and antibodies at the target site is also a potential strategy to address the issue of Fc function loss.Although the application of affinity ligands in drug delivery is at the initial stage, there are still some achievements that are something to be proud of, such as the half-life of non-covalent ADCs in blood after intravenous injection being equivalent to that of antibody, nearly 7 days. More importantly, with the development of more types of antibody drugs and the continuous improvement of downstream processes, more and more affinity ligands will be developed in the future, which provides more alternative ligands for antibody-involved drug delivery.Following with their wider applications and success in antibody purification, Fc affinity ligands have been gradually used in various fields including drug delivery. In this brief review, we have described the emerging of Fc affinity ligands and highlighted their application in antibody-involved drug delivery. By means of the binding affinity of Fc affinity ligands with the antibody Fc region, the retention of antibody drugs in hydrogels could be improved for more prolonged antibody release. In the respect of intracellular antibody delivery, the cell-penetrating peptides or polymers are facilely introduced into antibodies and facilitate their internalization into cells. In addition, Fc affinity ligands have been applied in the modification of antibodies on many kinds of drug carries as well as in the development of antibody–drug conjugates, both of which for active targeting delivery of the potent cytotoxic payload into the antigen-overexpressed cells. Although some progress has been made in these directions, some problems remain, such as the uncertainty about the stability and safety of this affinity system application in vivo. Overall, the Fc affinity ligand-based drug delivery is still in its infancy. Future research needs to explore the stability and controllability of the non-covalent antibody complexes or systems, and also could develop versatile platforms to expand the application field of Fc affinity ligands in drug delivery.


Epilepsy is a chronic non-infectious disease of the brain, characterized primarily by recurrent unprovoked seizures, defined as an episode of disturbance of motor, sensory, autonomic, or mental functions resulting from excessive neuronal discharge. Despite the advances in the treatment achieved with the use of antiepileptic drugs and other non-pharmacological therapies, about 30% of patients suffer from uncontrolled seizures. This review summarizes the currently available methods of gene and cell therapy for epilepsy and discusses the development of these approaches. Currently, gene therapy for epilepsy is predominantly adeno-associated virus (AAV)-mediated delivery of genes encoding neuro-modulatory peptides, neurotrophic factors, enzymes, and potassium channels. Cell therapy for epilepsy is represented by the transplantation of several types of cells such as mesenchymal stem cells (MSCs), bone marrow mononuclear cells, neural stem cells, and MSC-derived exosomes. Another approach is encapsulated cell biodelivery, which is the transplantation of genetically modified cells placed in capsules and secreting various therapeutic agents. The use of gene and cell therapy approaches can significantly improve the condition of patient with epilepsy. Therefore, preclinical, and clinical studies have been actively conducted in recent years to prove the benefits and safety of these strategies. Epilepsy is one of the most common diseases of the nervous system (more than 50 million cases have been reported worldwide). This condition is characterized by recurrent unprovoked seizures that result from abnormally excessive firing of neurons due to an imbalance in levels of excitation and inhibition in the brain . Epileps1).The production of effective methods of treatment is an urgent problem that requires an immediate solution since epilepsy is a serious medical and social problem. The risk of premature death in people with epilepsy is three times higher than in the general population  preferentially binds to three G-protein coupled receptors . Furthermore, the antiepileptic effect of NPY in the hippocampus is mediated by binding of NPY with presynaptic Y2 or Y5 receptors, which subsequently suppress glutamate release at excitatory synapses . Bindingin vivo studies that have not yet been further developed. For example, the introduction of AAV encoding the glial cell line-derived neurotrophic factor (GDNF) gene or the γ-aminobutyric acid decarboxylase 67 (GAD67) gene reduced the seizure frequency in the TLE model . DREADD technology is based on mutated human muscarinic receptors, which, when expressed in cells, can only be specifically bound and activated by the pharmacologically inert compounds, such as clozapine-N-oxide (CNO). Systemic administration of CNO leads to the opening of Gi-protein gated inwardly rectifying potassium channels, resulting in membrane hyperpolarization and neuronal inhibition. The efficacy of DREADDs has already been confirmed in a number of therapeutically relevant animal models of epilepsy . For exain vivo animal systems. To date, there are no registered clinical trials aimed at investigating gene drugs for the treatment of epilepsy. In this regard, we can say that gene therapy is at an early stage of development and obviously requires more attention from researchers.In gene therapy for epilepsy, the use of AAVs encoding potassium channel or NPY genes are the most investigated. However, the evaluation of the effectiveness of these therapeutic agents has not gone beyond Cell therapy for epilepsy includes a variety of approaches, including the use of MSCs , mononucPromising approaches for epilepsy treatment are aimed at replenishing the neuronal loss in the hippocampus by transplanting cells of the nervous system. The neural stem cell is capable of self-renewal and differentiation into neurons, glial cells, and oligodendrocytes as well as expression of neurotrophic factors. Transplantation of neural stem cells into the hippocampus of epileptic rats led to an increase in the number of GABAergic neurons and cells expressing GDNF, which resulted in the suppression of seizures .in vitro, have also been studied. Intravenous administration of neurospheres into epileptic rats has been shown to reduce oxidative damage by significantly increasing the level of antioxidant enzymes such as glutathione, superoxide dismutase and catalase  can differentiate into functional GABAergic interneurons. Transplantation of MGE precursors into the cortex of model mice with a deletion of potassium channels led to a significant reduction in the duration and frequency of spontaneous electrographic seizures, which is achieved due to GABA-mediated synaptic inhibition (GABA is an inhibitory neurotransmitter) .GABAergic interneurons can be derived from induced pluripotent stem cells (iPSCs). It has been shown that transplantation of pluripotent stem cell-derived GABAergic interneurons into the hippocampus of model animals led to a decrease in seizures and other behavioral abnormalities .Mesenchymal stem cells (MSCs) have many therapeutic properties useful in epilepsy, including neuroprotection, immunomodulation, neurogenesis support, inflammation, and oxidative stress damage suppression. These effects are achieved due to the fact that MSCs secrete various neurotrophic factors, anti-inflammatory cytokines, growth factors and other biologically active molecules . It is aNumerous studies have shown that the administration of undifferentiated MSCs can significantly decrease the frequency of seizures , improveIt has been shown that MSCs begin to secrete BDNF, NT3, and NT4 after neuronal differentiation. Their transplantation into the hippocampus of rats with kainic acid-induced epilepsy led to an increase in the level of BCL-2 and BCL-XL anti-apoptotic proteins and a decrease in the level of BAX pro-apoptotic protein in the hippocampus. Suppression of seizure activity and restoration of learning ability have also been noted .The results of clinical studies also confirm benefits of MSC transplantation. For example, phase I/II clinical trials have demonstrated that the administration of antiepileptic drugs along with one or two intravenous and intrathecal administrations of MSCs has been safe and effective in treating patients with drug-resistant epilepsy. Combined use of levetiracetam (an antiepileptic drug) and MSCs led to a decrease in the frequency of seizures, and a repeated course of MSC administration contributed to a further improvement in the patients’ condition (NCT02497443) , 2021.A combination therapy has also been used for pediatric patients with drug-resistant epilepsy. The intrathecal and intravenous administration of autologous bone marrow nucleated cells, followed by four intrathecal injections of MSCs every 3 months, resulted in neurological and cognitive improvement in all patients, including a decrease in the number of seizures .Intrathecal administration of adipose-derived regenerative cells  into patients with autoimmune refractory epilepsy (3 times every 3 months) has also been reported. Only 1 out of 6 patients achieved complete remission (there were no seizures for more than 3 years), in 3 out of 6 there was a slight and short-term decrease in the frequency of seizures, and in two out of six no effect was found . In all Not only MSCs, but also exosomes derived from them, exhibit immunoregulatory, anti-inflammatory and trophic effects , which mBone marrow mononuclear cells (BMCs) also possess immunomodulatory and neuroprotective properties  due to tIt has been shown that after intravenous administration to animals with status epilepticus, BMCs can migrate to the hippocampus, reduce the frequency and duration of seizures, maintain neuronal density , increasPhase I/II clinical trials have investigated the safety and efficacy of intra-arterial injection of BMCs in TLE patients. Researchers demonstrated safety, improved memory, a decrease in theta activity, and a decrease in spike density .Despite the proven efficacy, gene and cell therapy methods have a number of known disadvantages and side effects. It should be noted that these methods of therapy are irreversible and unregulated, and some of them can lead to an immune response and malignant transformation.In the case of cell therapy, as mentioned above for gene therapy, the major limiting factor is safety, specifically the possibility of a significant immune response induction and oncogenic transformation. In some cases, long-term immunosuppressive therapy and monitoring of the cells after the administration are required . It is iOne of the approaches to overcome some of the difficulties of cell-based therapy is encapsulated cell biodelivery (ECB). ECB usually involves the implantation of a capsule with a semipermeable membrane containing genetically modified cells that secrete therapeutic substances. In this case, the cells do not leave the capsule, but the therapeutically active molecules leave and spread in the area of transplantation. This method allows (1) preventing an immune response and transplant rejection, since the cells are physically isolated, (2) locally delivering therapeutic substances, and (3) stopping treatment by removing the capsule from the brain. To suppress epileptic activity, such capsules were designed to contain cells expressing GDNF , BDNF K, or galain vivo models have shown the potential benefit of viral vectors  encoding genes of therapeutic agents. Thus, the effectiveness of viral delivery of (1) neuro-modulatory peptides, such as NPY or galanin, (2) potassium channels to inhibit increased internal excitability of neurons, (3) GDNF, (4) GAD67, (5) preprosomatostatin, as well as (6) miR to suppress ADK expression has been shown.This review discussed recent developments in gene and cell therapy for epilepsy. To date, Cell-based therapy has made more progress with documented clinical trials showing the benefits and safety of MSC or BMC transplantation. The therapeutic effect can be achieved due to the neuroprotective, anti-inflammatory, immunomodulatory properties of these cells, which is also shown for MSC-derived exosomes. Researchers are also focusing on the transplantation of neural stem cells into the hippocampus to reduce neuronal loss in animal models. ECB, which is the injection of capsules with cells expressing BDNF, GDNF or galanin in the hippocampus, has shown an antiepileptic effect.The majority of gene and cell therapies have not yet reached clinical practice, but they have made significant progress. To date, preclinical studies in animal model are ongoing and new clinical trials are being registered to confirm both the effectiveness and safety of these approaches. Considering the heterogeneous nature of the onset and manifestation of epilepsy, the development of methods of gene and cell therapy can make a significant contribution to progress in the treatment of this disease.AS, DC, VS, and AR: conceptualization. AS and DC: writing-original draft preparation. VS, AM, RG, ZA, and AR: writing-review and editing. AS: visualization. VS and AR: supervision. All authors have read and agreed to the published version of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Taking university-enterprise collaborative innovation in five southern coastal provinces of China as subjects, empirical research is implemented by constructing a theoretical model of the effects of interface resource integration, interface conflict management, interface connection mechanisms, and enterprise absorptive capacity on the university-enterprise collaborative innovation performance with the partial least squares structural equation modeling and fuzzy-set qualitative comparative analysis. A total of 245 valid questionnaires were collected from five coastal provinces in south China. The research results show that the interface resource integration, interface connection mechanisms, and enterprise absorptive capacity has direct significant positive impacts on the collaborative innovation performance. Interface conflict management has no significant impact on school-enterprise collaborative innovation performance. Moreover, the interface connection mechanism acts as an intermediary. Therefore, it is suggested that university-enterprise should integrate resources with complementing, interacting, and sharing resources; construct the profit and risk-sharing mechanism, communication and trust mechanism, and organizational learning mechanism. University-enterprise collaborative innovation is a systematic project of joint action by both sides, which aims to integrate the resources of enterprises and universities and improve the innovation ability of enterprises . The keyInterface as an interdisciplinary term first appeared in engineering and technology to describe the interfaces between various mechanical components (assemblies.) In the 1970s, it was introduced into the management discipline to describe the connections between functions or between organizations in management activities. For example, it concentrated on the study of enterprise research and development (R&D) and supplier interfaces, production interfaces, and marketing interfaces. Souder and Chakrabarti found that when there are serious problems in the management of the R&D a marketing interface, it leads to the failure of 68% of R&D projects in terms of commercialization . The exiThe university-enterprise collaborative innovation interface mainly consists of cross-border players , media , and linkage mechanisms . The degree of organizational resource integration is positively related to university-enterprise collaborative innovation performance.Hypothesis (H2). Interface conflict management is positively related to university-enterprise collaborative innovation performance.Hypothesis (H3). Enterprise absorptive capacity is positively related to university-enterprise collaborative innovation performance.Hypothesis (H4). The Interface connection mechanisms is positively related to university-enterprise collaborative innovation performance.Hypothesis (H5). Interface connection mechanisms play a mediating role in inter-organizational resource integration and university-enterprise collaborative innovation performance.To address the problems of conflicting goals, interests and cultures in the process of collaborative innovation, we need to play the role of “benefit distribution, communication and coordination” mechanisms to resolve conflicts and promote cooperation . Based oHypothesis (H6). Interface connection mechanisms play a mediating role in interface conflict management and university-enterprise collaborative innovation performance.Enterprises have a certain absorptive capacity, but they need to rely on organizational learning mechanisms in order to identify, acquire and digest, and apply the university’s innovative knowledge and carry out technological innovation activities . Based oHypothesis (H7). Interface connection mechanisms play a mediating role in enterprise absorptive capacity and university-enterprise collaborative innovation performance.Based on the synthesis of many research results, combined with the preliminary survey research and group interviews, the framework of this study was determined see , in whicIn this study, technology-based SMEs in the five southern coastal provinces that carry out collaborative innovation with universities were selected as the subjects of empirical research. Mainly by contacting universities and local government management departments of science and technology innovation and technology transfer to understand the situation of local enterprises, then questionnaires were distributed in the field and by email, and the questionnaires were sent to the heads of technology departments or top managers of enterprises. A total of 325 questionnaires were distributed and 269 were returned, with a return rate of 82.8%. The questionnaires were then screened according to whether the questionnaires were filled out in a standardized manner and whether the enterprises carried out collaborative innovation as important criteria. 245 valid questionnaires were screened out, with a valid rate of 75.4%. The characteristics of the enterprises are shown in Combined with the theoretical framework model in The results showed that the measurement model satisfies all general requirements see . First, The correlation matrix in R2 values of ICMS (0.517) and UCI (0.529) exceed the minimum value of 0.10 recommended by Hair which is a satisfactory level of predictability as shown in Q2 values well above zero , Enterprise absorptive capacity → University-enterprise collaborative innovation , Interface conflict management → Interface connection mechanisms , Interface conflict management → University-enterprise collaborative innovation , Interface connection mechanisms → University-enterprise collaborative innovation , Interface resource integration → Interface connection mechanisms , Interface resource integration → University-enterprise collaborative innovation  complex, (2) parsimonious, and (3) intermediate . Fiss , and 5% quantile of the sample data as the three calibration points of full membership, crossover point, and full non-membership of the result and conditional variables. The results and calibration information for each conditional variable are listed in Before the condition configuration analysis, it is necessary to check the “necessity” of each condition individually. The necessary condition leads to the occurrence of the result, but its existence does not guarantee the inevitable existence of the result. Consistency is an important test standard for the necessary conditions. When the consistency score is greater than 0.90, this condition is necessary for the result . The aboThe sufficiency analysis of conditional configuration explores whether the set represented by the configuration composed of multiple conditions is a subset of the result set from the perspective of set theory. When using fsQCA 3.0 software for configuration analysis, the relevant parameters should be set according to the research needs. In this study, the original consistency threshold was set to0.80, PRI consistency threshold was set to 0.5, and the case frequency threshold is set to 1. In software fsQCA Ver.3.0, three solutions were generated using the standard analysis program: complex solution, intermediate solution, and reduced solution. The core conditions of each solution can be identified by comparing the nested relationship between the intermediate and reduced solutions.We use the QCA results proposed by Ragin to analyze the configuration of enterprise performance. The results are listed in We used standard methods to conduct a robust analysis of QCA results. The commonly used methods are: Adjust the calibration threshold, change the consistency threshold, add or delete the shell, change the frequency threshold, and add other conditions. Method 1: Referring to the practice of Fiss, the robustness test is carried out by adjusting the crossing point of calibration. Specifically, the crossing point is adjusted from 0.5 to 0.55. The number of configurations and the neutral permutations with the same core conditions but different edge conditions all changed slightly, but the changes were not enough to support meaningful and completely different substantive interpretation method 2. Referring to the set relation and quasi-sum difference of configurations proposed by Schneider and Wagemann  as the jIn this study, the following findings were obtained by exploring the effects of inter-organizational resource integration degree of collaborative innovation interface, interface conflict management, and enterprise absorptive capacity on university-enterprise collaborative innovation performance, and the mediating role of interface connection mechanism between them.In the collaborative innovation interface between universities and enterprises, the path of “interface conflict management → interface connection mechanism → collaborative innovation performance” is formed, and the interface connection mechanism plays a fully of intermediary role. Therefore, it is important to build a reasonable linkage mechanism, especially the benefit distribution mechanism, communication and trust mechanism, to resolve the interface conflict.In the collaborative innovation interface between universities and enterprises, the path of “enterprises’ absorptive capacity → interface linkage mechanism → collaborative innovation performance” is formed, and the interface linkage mechanism plays a part mediating role. This indicates that the construction of reasonable connection mechanism, such as organizational learning mechanism, is of great value to bring into play the absorptive capacity of enterprises, timely absorb the innovation knowledge of universities, and promote the transfer of scientific and technological achievements.The degree of integration of organizational resources at the interface and the absorptive capacity of enterprises all have significant and direct positive effects on enhancing the performance of university-enterprise collaborative innovation, while interface conflict management does not have a significant positive effect on innovation performance. Therefore, targeted enhancement of the degree of complementarity of organizational resources, the degree of mutual sharing of resources and the degree of interaction of human resources to integrate resources; resolving goal conflicts, interest conflicts and cultural conflicts of university-enterprise collaborative innovation through the interface connection mechanism to promote the deep integration between universities and enterprises; targeted efforts on the links of identification, acquisition, digestion and application of university knowledge by enterprises will help to improve university-enterprise collaborative Innovation performance.Based on the above findings, this study proposes that the integration of inter-organizational resources should be emphasized, interface conflict management should be carried out by fully leveraging the mediating role of interface connection mechanism, and the university-enterprise collaborative Innovation performance should be enhanced by strengthening the absorptive capacity of enterprises.First. Establish an innovative resource integration model based on complementarity, interaction and mutual sharing. Focusing on the common goal of collaborative innovation, with the complementarity of resources as the premise, the interaction of human capital as the key, and the sharing of various types of innovation resources as the focus, we fully gather the advantageous resources of each innovation body to achieve complementary mutual use. Integrate resources with the premise of complementarity of resources . The comSecond. The mechanism of benefit sharing and risk sharing is to coordinate and resolve the conflict of interests and risk crisis between universities and enterprises across organizations, and seek a balance of mutual interests. Adhering to the basic principle of “benefit sharing and risk sharing,” the university-enterprise collaborative innovation benefit sharing and risk sharing mechanism is established on the premise of clear ownership of intellectual property rights, based on a reasonable benefit distribution method and guaranteed by a perfect benefit distribution system, which ensures mutual benefits and sustainable stability of cooperation from multiple aspects, and Manages intellectual property issues and how to deal with knowledge . For theAlthough universities and enterprises are both knowledge sources, the strong R&D capability of the cooperating universities and the insufficient absorption capability of the cooperating enterprises will make it difficult to absorb, digest, apply and transfer the innovative knowledge of universities into commodities in a timely manner. The establishment of efficient organizational learning mechanism can help the diffusion of knowledge in the process of university-enterprise cooperation and promote the integration and absorption of knowledge by enterprises. Exploratory learning and excavation learning mechanisms of organizations proposed by March have insights for the establishment of organizational learning mechanism of university-enterprise cooperation. On the one hand, exploratory learning mechanism is established. Exploratory learning mainly emphasizes the organization’s search for external knowledge to acquire new knowledge and discover new business opportunities in order to form the organization’s competitiveness. Due to the influence of organizational inertia, existing technologies and behavioral patterns, enterprises’ willingness to acquire knowledge through exploratory learning will not be strong. Therefore, enterprises are encouraged to cooperate with universities to conduct innovation experiments, and in the process of research experiments, both parties establish exploratory learning mechanisms by jointly tackling R&D challenges. On the other hand, an exploratory learning mechanism is established. Excavative learning means that universities and enterprises have defined R&D tasks and use the organization’s existing knowledge and skills to improve products and services in order to enhance innovation performance. For example, enterprises provide a certain technology to directly help university researchers to complete the subsequent development of the product; or university researchers provide a certain innovative knowledge to directly help enterprises to improve the quality of a certain product. Both learning mechanisms are needed for university-enterprise collaborative innovation and should be used at the right time according to the characteristics of the R&D tasks jointly undertaken by universities and enterprises. For example, exploratory learning should be favored when the university-enterprise collaborative organization needs to acquire new knowledge from outside the organization, and exploratory learning should be favored when it needs to use existing knowledge to improve a product.This study solved some gaps in the literature, but there are still some limitations that need further discussion. First, the data used in this study was collected only in China. Since different research Settings and other samples may lead to different findings, researchers may wish to use data from other emerging economies to examine various entrepreneurial actions. Secondly, this study can use the fuzzy set qualitative comparative analysis method to study the antecedents of university-enterprise cooperation path, and obtain the path of university-enterprise cooperation innovation performence.The original contributions presented in this study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.HD, DL, and XC: methodology and software, formal analysis, resources, data curation, and writing—review and editing. HD and DL: investigation. YC: writing—original draft preparation, supervision, and project administration. All authors read and agreed to the published version of the manuscript.


Coal dust is a major risk factor for the occupational health of coal miners, and underground workers with coal mine dust lung disease  may have a higher risk of developing Nodular thyroid disease (NTD). The aim of this study was to investigate the relationship between coal mine dust lung disease and the development of Nodular thyroid disease in coal miners.This was a clinical retrospective observational study that included 955 male coal miners from 31 different coal mining companies in Huainan, Anhui Province, China, who were examined in April 2021 at the Huainan Occupational Disease Prevention and Control Hospital to collect all their clinical physical examination data, including general conditions, laboratory test indices and imaging indices. Based on the presence or absence of Nodular thyroid disease, 429 cases with Nodular thyroid disease were classified as the diseased group and 526 cases without Nodular thyroid disease were classified as the control group. Logistic regression was used to analyse the correlation between the occurrence of Nodular thyroid disease in coal miners, and further single- and multi-factor logistic regression was used to screen the risk exposure factors for Nodular thyroid disease in coal miners.p < 0.05) The results of univariate and multifactorial logistic regression analysis showed that CMDLD  had the highest OR and CMDLD was the strongest independent risk exposure factor for the development of Nodular thyroid disease in coal miners.Age, coal mine dust lung disease (CMDLD), red blood cells (RBC), mean red blood cell volume (MCV), albumin (ALB), albumin/globulin (A/G), indirect bilirubin (IBIL), globulin (GLOB), total bilirubin (TBil) and myeloperoxidase (MPO) were associated with the development of Nodular thyroid disease in coal miners (There is a strong correlation between coal mine dust lung disease and Nodular thyroid disease in underground coal miners, and clinicians need to be highly aware of the high risk of NTD in coal miners with CMDLD and adopt individualized clinical prevention strategies. Coal is China's main energy resource and about 70% of China's electricity comes from coal-fired power plants, and there are currently >6 million  undergroThe lung diseases of coal miners caused by long-term inhalation of coal mine dust are collectively known as coal mine dust lung diseases (CMDLD). CMDLD includes coal workers' pneumoconiosis (CWP), silicosis, bronchiectasis, emphysema and cancer , 5. CWP In this study, we collected clinical examination data from 955 male coal miners operating in underground environments. Four hundred and twenty nine coal miners had Nodular thyroid disease, and their prevalence was as high as 44.9%. Therefore, we hypothesize that the prevalence of Nodular thyroid disease in coal miners is higher than in other occupational groups, which may be related to the long-term exposure of coal miners to coal dust environment, and coal miners with CMDLD may be at a high risk of developing Nodular thyroid disease Coal miners with CMDLD may be at high risk of developing Nodular thyroid disease, but there are no studies on the association between CMDLD and NTD in coal miners. This study investigated the association between coal mine dust lung disease and Nodular thyroid disease in coal miners by retrospectively analyzing clinical examination data from 955 coal miners with underground operations in Huainan, Anhui Province, China, in 2021, with the aim of providing precise prevention strategies for primary prevention of Nodular thyroid disease in coal miners.This is a clinical retrospective observational study that collected clinical physical examination data from 955 male coal miners from 31 different coal mining companies in Huainan City, Anhui Province, China, who were examined in April 2021 at the Occupational Disease Prevention and Control Hospital in Huainan City, Anhui Province, China. Inclusion criteria: (1) Male coal miners aged ≥18 years. (2) No serious organic lesions. (3) In addition to the routine physical examination, the physical examination also included thyroid and lung examinations, and the physical examination information was complete and free of defects. Exclusion Criteria: (1) Serious cardiovascular, cerebrovascular, liver, kidney or other serious primary diseases. (2) Those with severe mental disorders or who are unable to cooperate with the medical examination for various reasons. (3) Those with a history of surgery or chemotherapy for malignant tumors. (4) Those with malignant diseases or serious systemic infections. (5) Incomplete thyroid and lung physical examination data. Finally, 955 male coal miners met the study requirements and were included in the observation. All personally identifiable information was encrypted by the researchers, no personal privacy was disclosed, and the ethical requirements of the ethical review committee of the First Affiliated Hospital of Anhui University of Technology  were met.t-test for comparison between groups; non-normally distributed data were expressed as M  and wilcox test for comparison between groups. Qualitative data were statistically described using frequencies (%) and comparisons between groups were made using the χ2 test or Fisher's exact test. Factors influencing Nodular thyroid disease were analyzed using one-way and multi-way logistic regression analysis. Differences were considered statistically significant when bilateral p-values were <0.05.The study was statistically analyzed using 4.0.3 statistical software. Quantitative data were determined to be normal using the Shapiro normality test, with normally distributed data expressed as ((1) Diagnosis of coal mine dust lung disease: In this study, coal mine dust lung disease refers to a range of lung diseases caused by long-term exposure to coal mine dust, including pneumonia, pneumoconiosis, silicosis, dust-related diffuse fibrosis (DDF) and chronic obstructive pulmonary disease (COPD) , 15. Pul(2) Diagnosis of Nodular thyroid disease: The diagnosis of Nodular thyroid disease in this study was based on clinical manifestations, laboratory tests and imaging examinations of the coal miners, and the diagnosis of Nodular thyroid disease was in accordance with the diagnostic criteria of the Chinese guidelines for the diagnosis and treatment of Nodular thyroid disease . ThyroidP-value > 0.05), as shown in In this study, clinical physical examination data of 955 coal miners were summarized. The number of coal miners with Nodular thyroid disease was 429 and the number of coal miners without Nodular thyroid disease was 526. After statistical test analysis, Age, CMDLD, RBC, MCV, ALB, A/G, IBIL, GLOB, TBil, and MPO were statistically significant between the two groups of coal miners with Nodular thyroid disease, while the remaining variables were not statistically significant between groups (p < 0.05). All parameters included in the above univariate analysis were further analyzed by multi-factor logistic regression, with OR values suggesting the relative risk of developing Nodular thyroid disease in coal miners. The results showed that CMDLD , MPO , GLOB , ALB , A/G  and clinicians should focus on the risk of Nodular thyroid disease in coal miners with CMDLD.Univariate and multivariate logistic regression analyses were performed using whether the patient had Nodular thyroid disease as the dependent variable  and whether they had coal mine dust lung disease as the independent variable  . The res factors . TherefoCoal dust is the most significant risk factor for occupational health risks to coal miners . McBean p < 0.0001), GLOB , Age  were found to be 0.0001 as independent risk factors for the development of Nodular thyroid disease in coal miners, with CMDLD having the highest OR, much greater than the other two variables, indicating that CMDLD is the highest risk exposure factor for the development of Nodular thyroid disease in coal miners, and is statistically significant. Therefore, focusing on screening for Nodular thyroid disease in coal miners with CMDLD and adopting targeted prevention strategies are important measures to effectively reduce the occurrence of Nodular thyroid disease in coal miners.Nodular thyroid disease is one of the most common non-communicable diseases in developing countries . BecauseThere is a lack of research on the mechanism of the relationship between CMDLD and the development of Nodular thyroid disease in coal miners. This study suggests that there may be two main associations. Firstly, when exposed to coal dust for long periods of time, the body adjusts cortisol, thyroid hormone and insulin levels for protective adaptive regulation, and when endocrine gland function reserves are depleted and the body's ability to adapt decreases, coal miners are prone to develop pneumoconiosis  and consHowever, there are some limitations that need to be taken into account when interpreting the results of this study. First, the data we collected on physical examinations of coal miners were missing data on coal miners' history of alcohol consumption, smoking, family history of Nodular thyroid disease, body mass index, years of underground work, number of shifts per month and some thyroid hormone blood biochemical indicators, variables that may be associated with the occurrence of Nodular thyroid disease in coal miners. Secondly, due to the fixed nature of the medical examination package, we were unable to obtain further pathological follow-up of the association between Nodular thyroid disease and coal mine dust lung disease, which prevented an in-depth investigation into the pathogenesis of CMDLD and NTD. In the future, we will conduct experimental studies to further investigate the mechanisms by which coal dust causes Nodular thyroid disease and CMDLD in animals. Thirdly, the population in this study was exclusively from Huainan, Anhui Province, China, and no data from other coal miners of different geographical or ethnic origin were included, which may have biased the results of the study. In the next step, we will expand the sample size collection to include data from coal miners from different regions, countries and ethnicities in China, so that this study can have a wider clinical utility.This study found a high correlation between coal mine dust lung disease and the development of Nodular thyroid disease in coal mine workers, and that coal mine dust lung disease is a high risk factor for the development of Nodular thyroid disease in coal mine workers. With the exception of thyroiditis, any benign change in Nodular thyroid disease is associated with an increased risk of thyroid cancer . NodularMine miners who are chronically exposed to working in a coal dust environment are at high risk of developing nodular thyroid disease. It is worth noting that Age, CMDLD, RBC, MCV, ALB, A/G, IBIL, GLOB, TBil, and MPO are influential factors for the development of nodular thyroid nodular disease in coal miners, with CMDLD being the strongest risk exposure factor for nodular thyroid disease in coal miners. Therefore, clinicians should be highly concerned about the high risk of nodular thyroid in coal miners with CMDLD and take early and individualized preventive and therapeutic measures, which are of great clinical value to improve the occupational health and safety of coal miners with thyroid.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. Written informed consent from the patients was not required to participate in this study in accordance with the national legislation and the institutional requirements.FZ and HZ contributed to the writing of the manuscript, design of the study, and statistical analysis. DR and C-mL contributed to the conception and design of this study. YG, YW, DL, and ZZ contributed to data retrieval and manuscript review. QL, XS, and LY contributed to data collection and data collation. All authors made significant contributions to the research process of this manuscript, read, and approved the submitted manuscript.The authors carried out all the work in this study with the support of the Department of the Huainan Municipal Committee of Anhui Province and the Huainan Science and Technology Bureau. This study was funded by the Key Research Project of Anhui Provincial Education Department (No. KJ2019A0094), the Key Research Project of Anhui Provincial Education Department (No. KJ2019A0095), and the Research Project Plan of Bengbu Medical College (No. BYKY2019318ZD). This work was supported by the Huainan City Occupational Disease Control Institute, China, the School of Medicine of Anhui University of Technology, and the First People's Hospital affiliated to Anhui University of Technology .The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Extracellular RNA (exRNA) is a special form of RNA in the body. RNA carries information about genes and metabolic regulation in the body, which can reflect the real-time status of cells. This characteristic renders it a biomarker for disease diagnosis, treatment, and prognosis. ExRNA is transported through extracellular vesicles as a signal medium to mediate communication between cells. Tumor cells can release more vesicles than normal cells, thereby promoting tumor development. Depending on its easy detection, the advantages of non-invasive molecular diagnostic technology can be realized. In this systematic review, we present the types, vectors, and biological value of exRNA. We briefly describe new methods of tumor diagnosis and treatment, as well as the difficulties faced in the progress of such research. This review highlights the groundbreaking potential of exRNA as a clinical biomarker. Extracellular RNA (exRNA) is a class of nucleic acid molecules first discovered in serum and plasma , 2. Due EVs mainly have three forms: microvesicles, exosomes, and oncosomes. The difference between microvesicles and exosomes lies in the direction of membrane budding. Microvesicles are produced by the outward budding of the plasma membrane and released directly into the extracellular environment. In essence, exosomes are produced by the inward budding of the membrane. The first step is the inward budding of the membrane to form the multivesicular endosomes (MVEs). Then, intraluminal vesicles (ILVs) are formed in the lumen of MVEs. ESCRT components, ceramides, tetrasanins, and syntenins play a key role in this process. When the MVB membrane fuses with the plasma membrane, exosomes are released into the extracellular environment. There is also a class of specialized EVs released by tumor cells, which are called oncosomes. It is a large EV formed by cancer cells that carries several cancer-causing molecules. Studies have shown that the regulatory factors related to EV biogenesis are overexpressed in cancer, which may be related to the development, progression, and metastasis of cancer .Other studies have found that the loading of extracellular RNA involves a complex sorting mechanism. RNA-binding protein (RBP) can not only bind RNA to prevent the degradation of exRNA but also play an essential role in the process of RNA targeting EVs. Some RBPs can also perform miRNA classification by recognizing specific RNA motifs. For example, hnRNPA2B1, SYNCRIP, and ANXA2 can mediate miRNA sorting and then induce the entry and localization of extracellular RNA to EVs. The regulation of miRNA sorting involves the expression level of miRNA, the sphingomyelin pathway, and the posttranscriptional modification of its 3’ terminus. The main components of miRISCs (mirNA-loaded RNA-induced silencing complex) such as Agos and GW182 can influence the sorting and loading process of miRNAs by associating with the endosomal pathway and then further mediate RNA silencing to affect the sorting and loading process of miRNA. The inhibition of neutral sphingomyelinase 2 and ceramide production can prevent multiple miRNAs from loading into EVs. In addition, uridylation and adenylation at the 3’ end of miRNAs are also associated with the release and retention of miRNAs in exosomes. When the EV-carrying information molecules meet the receptor cells, first of all, by directly triggering the membrane fusion mechanism, the contents of EVs can be directly released into the receptor cells, and finally, the transmission of information between cells can be completed. In addition, EVs can be ingested into recipient cells by corresponding endocytosis. EVs can also bind to receptors on the cell membrane, triggering intracellular signal transduction pathways, and then cascade information transmission process. When RNA is released from EVs, it can activate a series of biological functions, such as affecting protein translation (including promoting and inhibiting effects) and changing gene expression patterns , 18.www.exoRBase.org), to include more samples and data; this provides a more detailed detection and analysis for exLRs. Simultaneously, the RNA mapping program in human EVs/exosomes will be examined to 1) establish a standard protocol for the detection and analysis of exLRs and 2) construct the exLR mapping for common diseases. Uman et al. . After inserting the reducing agent DTT, a large amount of EVs captured by THP is released, and the purity of exosomes can be effectively improved. In the case of breast-milk samples, the increase of dead cells after refrigeration interferes with exosome extraction. Therefore, exosomes will be extracted more efficiently by using fresher milk. Breast milk was centrifuged from high to low density, and then, the supernatant removed from fat and cells was taken to ensure further exosome extraction. If direct high-speed centrifugation is used, it is likely to cause the globulins in breast milk to agglomerate with extracellular vesicles, making the isolation of exosomes more difficult. Cerebrospinal fluid is the best biological fluid to judge the status of the central nervous system. For such small biological samples, filtration and molecular exclusion chromatography are usually more suitable.Some studies have found EVs associated with tumor cells in the biological samples of cancer patients, carrying relevant carcinogenic factors and substances that can promote the occurrence and development of tumors. These factors have a profound impact on the invasion, immune escape, metastasis, and other aspects of cancer. For example, in the metastasis of breast cancer, macrophages can release EV-containing miR-223 to transmit the “invasion ability” of tumor cells from cell to cell. EV-RNA released by tumor cells can also damage the vascular endothelial barrier and cause secondary changes in endothelial permeability. Finally, it promotes the endothelial infiltration of cancer cells, leading to the enlargement of cancer cell spread, and even causes metastasis through the circulatory system. In addition, the role of EV-RNA from tumor cells in enhancing endothelial cell proliferation and angiogenesis should not be underestimated. The growth of tumor cells depends on the rich blood supply and nutrition. The pro-angiogenic effect of EV-RNA in tumor cells provides a good basis for tumor growth and metastasis to a certain extent. This essentially provides a driving force for tumor migration and invasion. In the process of cancer development, the communication of information is bidirectional, and there is mutual interference between tumor cells and normal cells. Normal cells can inhibit the proliferation of cancer cells and induce the apoptosis of cancer cells by releasing EVs rich in inhibitory miRNA, thus inhibiting the malignant phenotype of cancer cells. However, EV-RNA from certain normal cells may also help tumors grow and metastasize. For example, EV-miRNA from hypoxic mesenchymal stem cells (MSCs) can improve the survival rate of cancer cells and promote proliferation, migration, and invasion. When the gene expression of normal cells is regulated by EV-miRNA from tumor cells, a cancer-promoting effect appropriate to the biological function of cancer cells may occur, such as cancer-associated fibroblasts (CAFs) and mesenchymal stem cells in the tumor microenvironment. Once the balance between normal cells and cancer cells in the body is disrupted, cancer is endowed with the ability to metastasize and invade. The EV-RNA of cancer cells mediated the antitumor immune response by activating the function of immune cells, but it may also play an inhibitory effect to mediate the immune escape of the tumor. Under the interference of tumor EV-RNA, tumor-associated macrophages in the tumor microenvironment will change the cell phenotype and promote cancer progression. Studies have also shown that immune cells associated with hypoxia release EV-RNA, which can promote tumor growth and migration. In addition, the EV-RNA-mediated gene reprogramming of immune cells is one of the main reasons why the function of T cells is hindered, which promote the escape of cancer cells , 18.Currently, the main clinical screening and diagnosis methods are endoscopies, imaging detection, and tumor marker detection . HoweverStudies have shown that host cells or tumor cells are involved in tumor genesis, growth, invasion, and metastasis through special signal transduction modes , 37. Durin vitro and in vivo. Tumor-derived exosomes contain components associated with tumor cell miRNAs and have demonstrated the ability to independently process precursor miRNAs into mature miRNAs  and SPCA-1 cells, thereby promoting the progression and oncogenic ability of SM in lung adenocarcinoma. This suggests that SM intervention is a potential novel therapeutic target in the early stage of lung cancer. Further, evidence suggests that exRNA has a strong potential as a diagnostic marker for lung cancer. In future research on lung cancer, the detection of exRNA expression profiles in lung cancer tissue is expected to become the principal force of non-invasive detection methods  and lung adenocarcinoma (LUAD) are the main subtypes –52. Chen methods Table 2.Esophageal squamous cell carcinoma (ESCC) is the sixth leading cause of cancer death worldwide , 58. To Gastric cancer (GC) is a malignant disease with high morbidity and fatality rates . Yuan etThe high morbidity and mortality of hepatocellular carcinoma (HCC) grants urgency to the development of more effective treatment programs for the disease –66. ZhanIn 2008, Kroh et al. first demonstrated the presence of miRNAs released from prostate cancer (PC) cells in the blood . The greBreast cancer in women surpassed lung cancer for the first time as the most common cancer globally in 2020, accounting for approximately 11.7% of incident cancer cases, according to the latest data on the global burden of cancer for 2020 released by the International Agency for Research on Cancer of the World Health Organization . CirculaAdvanced ovarian cancer usually spreads to the visceral adipose tissue of the greater omentum , 81. Au in vivo and in vitro showed that AdARB2 can act on linear NT5E precursors and relieve ADAR-1’s inhibition of circnt5E transcription. The highly expressed circnt5E can be adsorbed to miRNA-422a to relieve its inhibition of downstream target genes. Then Akt, Smad2, and other signaling pathways are activated to promote the proliferation, migration, and invasion of GBM cells. In general, exRNA can regulate the occurrence and development of GBM through regulatory intervention on downstream target genes. This is a novel mechanism for the study of GBM  is a hematologic cancer caused by the abnormal expansion of plasma cells. MM is characterized by the malignant proliferation of monoclonal plasma cells and the secretion of large amounts of monoclonal immunoglobulins, which then inhibit the normal function of both polyclonal plasma cells and polyclonal immunoglobulins –88. DengThis review introduces the great potential of exRNA as a novel biomarker. Each study of the formation process of exRNA and the complex mechanism of its role in body diseases provides new possibilities for the detection and treatment of future diseases. At present, most clinical diagnoses of the disease still include invasive procedures, such as biopsies. Based on the special physiological characteristics of exRNA, researchers foresee much potential in utilizing exRNA for non-invasive diagnostic methods , 8. In aThe study of exRNA could lead to the search for new diagnostic markers or new therapeutic targets. However, before translating its use into clinical practice, the mechanisms and pathways of exRNA treatment should be understood. It is still unknown how to introduce this biomarker into clinical disease surveillance , 91, 92.At present, there has been the formation of an exRNA database –98. The XZ and ZL conceived the work. DW wrote and drafted the manuscript. TT, PL, ZL, and XZ discussed the manuscript. EE revised the manuscript. All authors read and approved the final version of the manuscript.This work was supported partly by The National Natural Science Foundation of China (81972366); The Natural Science Foundation of Guangdong (2022A1515012606); The Shenzhen Science and Technology Innovation Commission projects .The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


In recent decades, “post-feminism” has become a recurrent theme and a buzzword of sorts in a variety of settings, from academia and politics to media discourses and popular culture. After decades of scholarship and public debate on the matter, the task of delimiting the boundaries of what “post-feminism” means seems intellectually futile, particularly because the ambiguity of the term is what makes it intriguing and compelling as a frame of analysis.In a particularly relevant interpretation, scholars of gender have taken post-feminism as promising conceptual lenses with which to interrogate the (un)doing of gendered subjectivities in our contemporary culture, where intersectional inequalities are (re)produced amidst the neoliberal celebration of individual agency and empowerment, as predicated on consumption and commodification of gender difference. Postfeminism extends understandings of the ways in which gender is performed, and highlights how neoliberal capitalism and market values intersect with identity, subjectivity and agency  and in light of the neoliberal emphasis on inclusion through consumerism Lazar, . It is aRens analyses popular Afrobeats music videos to parse the heteronormative dynamics of masculine and feminist characters. In the romances visually depicted alongside and in the songs, he argues that an ethic of “misogyrom” is in operation, which undermines the agency of the women characters in the videos.Dunn and Falkof explore how young women who post self-portraits on social media work to create a sense of authenticity, which operates at both the level of feeling and appearance.Ghosh analyses television shows about Indian matchmaking, and teases out the web of cultural politics regarding nationhood, conservatives, caste and class, while showing how postfeminist values shape the narratives.Boshoff and Mlangeni examine South African tabloid newspaper writings about older well-off women who have romantic relationships with younger men. The authors show that though the women seem putatively empowered, their agency women should be placed in historical and global context.The third set of articles examines how the current wave of right-wing politics and anti-feminist backlash sweeping the world poses critical and specific questions to post-feminist dynamics and imaginings in global south contexts. As scholars have showed elsewhere, the contemporary political climate has invited sexist revivals and reactionary understandings of gender and gender theory (Whelehan, Chakraborty writes about the “interstitial intimacies” that emerge in labor in an NGO's community-based program to prevent violence against women and girls in Mumbai's urban poor neighborhoods.Maryani et al. discuss the rise of anti-feminist discourse on social media in Indonesia. This is put into context of the religious and political complexities of Indonesian society.Through these 10 articles, this Research Topic collection put the spotlight on transnational thinking about postfeminism, revealed the cracks, complexities, and contestations that characterize debates about the economic empowerment of women in contexts of inequality. This collection also gestures toward new directions in the critical analysis of postfeminism, and theory building from the south. It has given full attention to the ways in which postfeminist practices, identities and intimacies intersect with race, ethnicity, indigeneity, and caste, including practices of resistance to oppression organized along such lines. Future work must continue to develop fuller understandings of how neoliberal femininities explicitly matter in relation to racial identities and racialized experiences of life.This special issue proposes that, in the global south, postfeminism demands an expansive and inclusive understanding of the feminine to include all femininities, in order to explore what the pre-fix “post” means in relation to this inherent diversity. While the articles have tackled these questions from various perspectives and locations, more work is required to integrate trans-femininities into the work of the study of global south postfeminism, as part of a broader politics of rejecting cis-feminist exceptionalism.Both authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.


Generally, axons located at the central end of the nerve system will sprout after injury. Once these sprouts cannot reach the distal end of the severed nerve, they will form a traumatic neuroma. Traumatic neuromas bring a series of complex symptoms to patients, such as neuropathic pain, skin abnormalities, skeletal abnormalities, hearing loss, and visceral damage. To date, the most promising and practical clinical treatments are drug induction and surgery, but both have their limitations. Therefore, it will be the mainstream trend to explore new methods to prevent and treat traumatic neuroma by regulating and remodeling the microenvironment of nerve injury. This work first summarized the pathogenesis of traumatic neuroma. Additionally, the standard methods of prevention and treatment on traumatic neuroma were analyzed. We focused on three essential parts of advanced functional biomaterial therapy, stem cell therapy, and human-computer interface therapy to provide the availability and value of preventing and treating a traumatic neuroma. Finally, the revolutionary development of the prevention and treatment on traumatic neuroma has been prospected. How to transform the existing advanced functional materials, stem cells, and artificial intelligence robots into clinical practical technical means as soon as possible for high-quality nerve repair and prevention of neuroma was further discussed. The traumatic neuroma is usually caused by the random arrangement of nerve branches at different sizes after nerve injury . MacroscThe clinical treatment of neuroma was mainly divided into conservative treatment and surgical treatment . Among tSupramolecular biomaterials have developed rapidly in biomedical treatment due to their incomparable characteristics. The complexity of biology, pathology, and related biomedical issues requires that supramolecular biomaterials should be practical and designable. The designability and modifiability of supramolecular biomaterials  endow thThis review has focused on the research progress in the cross field of supramolecular biomaterials, stem cells, human-computer interface, and neuroma medicine in recent years. We hope this can make contributions to the treatment of traumatic neuroma. In addition, based on many excellent basic research, the effect of various new technologies and surgical treatment schemes should be strictly compared to prevent and treat neuroma in the future.The occurrence of neuroma is actually a kind of transitional repair or body disorder in the process of nerve repair. The essence of improving or inhibiting the occurrence of neuroma is based on the research of biological mechanisms. Therefore, how to prevent the formation of neuromas requires profound understanding of neuroanatomy and neurobiological mechanisms after injury . As showThe perfect repair of damaged nerves inhibits the formation of inflammatory reactions, peripheral fibrosis, and scar tissue, thereby inhibiting or preventing neuroma formation. In the whole process of nerve repair, it was difficult to improve or block the occurrence of inflammation due to the significant differences between individuals. When the body was damaged, the immune system starts to collect granulocytes (neutrophils and mast cells) and agranulocytes (monocytes/macrophages and lymphocytes) to key positions in the first few hours  22). Ef. Ef22). In terms of damage types, it is also necessary to distinguish between minor and long gaps. The small space (< 30 mm) for clinical treatment of nerve injury generally adopts autologous transplantation, allograft transplantation, and hollow lumen cannula. However, it is limited clinically due to insufficient autologous supply and allogeneic immune response. The injured nerve site must be protected as a guiding substrate for further repair. In addition, nutrients and oxygen diffuse to the regeneration site, so the hollow catheter is more demanding for nerve repair . Considein vitro tissue model drug screening and bridging or substitutes for trauma tissue. Although many “systemic drugs” have been developed clinically to guide the treatment of neuroma, it is now clear that locally mediated modified new materials can rapidly adjust the surrounding pathological environment to recommend the repair. In this review, we discussed how “local” biomaterials affect or treat neuromas, how stem cells secrete factors or self-regulate the surrounding environment of neuromas, and how human-computer interfaces treat neuromas.In clinic, the treatment of traumatic neuroma is mainly surgical treatment, but after the initial surgical treatment, up to 42% of patients may have persistent symptoms, which requires additional intervention . They caIn the early clinical stage, the neuroma is mainly treated by surgical resection, but it is easy to recur. In addition, nerve axons buried in adjacent tissues may lead to direct contraction or traction of nerves. Using nerve conduits to bridge or covering injured nerves is a promising method. Nerve grafts have become the gold standard for nerve reconstruction and neuroma prevention, while donor incidence rate and immunogenic host response remain challenges. With the rapid development of biotechnology and biomaterials, various biomaterials are being used to promote the functional recovery of injured nerves, prevent the occurrence of neuromas, and treat neuroma pain. The materials have been endowed with biological functions, from simple biopolymers to blends of bioactive substances and polymers. Additionally, the modifiability of materials endows them with multifunction, such as adjustable mechanical properties, degradability, good biocompatibility, convenience, and non-immunity. During the treatment period, biomaterials should also avoid swelling and not elicit inflammatory responses during degradation. Notably, the modified biomaterials should have the ability to maintain cell vitality and guide directional tissue growth.In recent years, many researchers have been committed to replace promising alternative biomaterials to autologous or allogeneic nerve transplantation, and simulate the macro or micro ring structure of peripheral nerves to improve the therapeutic effect and inhibit the occurrence of neuroma , 26. YanThe traditional casing manufacturing process is complex, time-consuming, and single in practicability. The emerging 3D printing technology is a revolutionary change for the effective prevention and treatment of neuroma . AdditioApF/PLCL/GO) nanofibers were used to prepare multicavity nerve conduits  Customize the geometry of the stent to match the inherent tissue anatomy ;(2) Combine the biological manufacturing method with the calculation modeling of design, analysis, and optimization;(3) Use physical and biochemical functions of space control to enhance equipment performance.(4) The personalized design endows the nerve scaffold with more clinical applicability.Considering that the formation of traumatic neuroma is due to the disorder accumulation of scar tissue, and the irregularity and immaturity of axon regeneration. The nerve tissue is a complex structure composed of multiple interacting cells. Due to the highly complex structure, it is difficult for researchers to assess the degree of nerve damage. According to different nerve injuries of patients, exploring new methods and strategies to develop more personalized treatment methods that are more suitable for clinical application is necessary. In this way, the formation of traumatic neuroma, especially to prevent the irregular axon the regeneration of neuroma and the disorder accumulation of scar tissue, could be thoroughly and effectively prevented .in vitro. Stem cells are original undifferentiated cells with multipotent differentiation and self-replication ability, which are the original cells forming various tissues and organs  spheres to maintain and promote the stemness of stem cells, which can play a paracrine effect in three-dimensional space due to hypoxia . Fu. Fuin vi hypoxia  (47). Otin vitro and in vivo artificial sensory nerves could communicate with cells through optical methods, they have not yet reached the link with a single neuron. Based on the concept of electronic skin sensing  to confirm or reveal the effects, adverse reactions and/or absorption, distribution, metabolism, and excretion of the test drugs . The purTo sum up, many research results have sound effects on the prevention and treatment of neuromas, such as reducing the incidence rate and the pain of patients. In the future, it should be easier to meet the needs of treating traumatic neuroma based on the advantages of existing treatment methods and combined with existing science and technology. This review focuses on preventing and treating neuroma with biomaterials, stem cells, and human-computer interfaces. Although these scientific researches are only at the research stage, they are also a big step toward clinical application. From the perspective of medical materials, the effectiveness and safety of all materials are the core issues in the treatment and prevention of neuroma. An effective design will better solve the complex problems in the treatment and prevention of neuroma, for example, how the existing human-computer interface metal materials deal with the humid environment of biology. Regarding safety, how to effectively avoid adverse reactions, such as inflammation, metabolism, toxicity, and antigen reaction in tissues. Furthermore, expensive materials will also bring financial pressure on patients. In future clinical work, the treatment and prevention of neuroma is still a scientific problem. Interdisciplinary methods such as biomaterials, 3D printing technology, stem cells, and human-computer interface can assist, intervene, prevent, and treat neuromas. Therefore, the interdisciplinary combination of medicine and biomaterials must be an essential way to treat neuroma and nerve repair in the future.LZ: writing and editing the manuscript. TH and WZ: investigation and visualization. NH: supervision and writing-review and editing. YW and PZ: supervision, conceptualization, writing-review and editing, and funding acquisition. All authors contributed to the article and approved the submitted version.


Nowadays, technology has changed the way individuals interact with the actual world around. Since 2021, Metaverse has received a lot of attention globally and has been the hot topic of the technology world . In theFuturists and technologists have assessed how healthcare services may be changed and promoted by the Metaverse in future. Within the recent pandemic, augmented reality has been used by the World Health Organization (WHO) to train COVID-19 respondents and mental health experts how to utilize the virtual reality for treating people with mental illnesses and emotional difficulties such as post-traumatic stress, phobias, anxiety disorders, hallucinations, and delusions. It has also been used in medical schools for educational purposes. Thus, the Metaverse seems to be beneficial in helping medical professionals in many aspects of their work involving the use of these technologies.Currently, surgeons working in leading hospitals and universities use technologies such as augmented reality, virtual reality, and artificial intelligence. Although these technologies provide a 3D view of a patient's body and help surgeons plan and perform surgeries more efficiently, they have several disadvantages such as creating realistic surgical objects within a computer-generated space, providing pocket size immersion with a limited resolution, and restriction to specific clinical settings. Metaverse can overcome this challenges via providing realistic interaction amongst doctors, patients, and objects. Other benefits of Metaverse include personalized health data monitoring, analysis of patients' clinical data, and complete elimination of physical and paper-based patients' records. On the other hand, there are some challenges associated with the application of Metaverse in healthcare services including the possibility of users' privacy loss, high cost of this technology, disagreement between various health-related organizations and institutions for launching this technology, possibility of violating ethical issues in the use of the technology, possibility of threatening human health, high rate of depression, violence, and self-harm, possibility of having negative effects on the cultural security of countries and consequently affecting the health status, deepening gaps and inequalities between developed and developing countries, and possibility of going beyond the dark web and its inappropriate applications such as human trafficking for the removal of organs and body parts.Given that health is one of the most important issues globally, governments and technology giants should fully clarify various aspects and potentials of Metaverse before its widespread use. In this context, it is necessary to make the most of its capabilities and minimize its associated concerns.The authors have no conflict of interest to declare.


The human gut microbiota and its associated perturbations are implicated in a variety of cardiovascular diseases (CVDs). There is evidence that the structure and metabolic composition of the gut microbiome and some of its metabolites have mechanistic associations with several CVDs. Nevertheless, there is a need to unravel metabolic behavior and underlying mechanisms of microbiome-host interactions. This need is even more highlighted when considering that microbiome-secreted metabolites contributing to CVDs are the subject of intensive research to develop new prevention and therapeutic techniques. In addition to the application of high-throughput data used in microbiome-related studies, advanced computational tools enable us to integrate omics into different mathematical models, including constraint-based models, dynamic models, agent-based models, and machine learning tools, to build a holistic picture of metabolic pathological mechanisms. In this article, we aim to review and introduce state-of-the-art mathematical models and computational approaches addressing the link between the microbiome and CVDs. Dwelling in the human gut is a complex microbial community made up of various cell types spanning a wide range of taxa . This diThe essential role of microbiota entails the digestion of food and drugs in the intestine before they enter the bloodstream and reach the target tissue –16, whervia specific genes  in the form of notorious diseases like liver fibrosis and cirrhosis . Once thic genes , can be ic genes    –32. TMAOs (CVDs) , plateles (CVDs) , 35, blos (CVDs) , the riss (CVDs) , 38, as s (CVDs)   . Some sts (CVDs)  [for mors (CVDs) ]. The mis (CVDs) . The syns (CVDs) .Despite the significance of CVDs and their emerging etiological link to the microbiome , many quOmics methods provide a more in-depth metabolic signature of diseases, yet they are inadequate to draw concrete mechanistic conclusions. Comprehensive systematic views, which involve systems-oriented techniques and computational modeling, complement experimentation to unveil the microbiome causality of CVDs. Herein, we aim to review the state-of-the-art computational approaches proposed to determine microbiome-CVDs interplay. Given the importance of data-driven omics approaches, we briefly review the recent advances in this topic, followed by an elaborate discussion of common approaches that can build on these technologies to model microbiome-based pathologies.Advances in omics technologies have offered great insights into the biochemical processes interacting with the microbiome and CVDs by proving useful information on the regulatory role of different components, underpinning the equilibrium between human organs and the gut microbiota. Studies, for instance, have indicated that a variety of biological processes are regulated by microRNAs (miRNAs). miRNAs serve a key role in the host immunological response to counteract infections caused by bacterial pathogens , 48. CorRecent bioinformatics methodologies have boosted the capabilities of integrating data and identifying biomarkers and drug targets, presenting a new picture of treating gastrointestinal disorders including dietary interventions and their consequences on CVDs. The improvement of high-throughput technologies and culture-independent genomic methods over the past few years made it particularly possible to characterize the microbial ecology in great detail , 53. TheMicrobiome composition and function have been determined with high-throughput omics technologies, such as metagenomics , metaproTo more specifically profile the bacterial composition, novel approaches like shotgun metagenomics sequencing have been employed. Metagenomics has revealed constructive information on the impacts of the microbiome on the health and disease status of hosts . MetatraGenome-scale metabolic models , provide bases that can be used by stoichiometric methods. Constraint-based models (CBMs) have been shown as pragmatic tools to investigate genome-scale metabolic networks. CBMs in metabolic networks regularly come in a steady-state form with relevant constraints imposed on multiple reactions. This results in a bounded convex cone, which includes optimal solutions. Each point within this feasible solution space represents a single flux distribution, which contains fluxes of every reaction throughout the network. Flux balance analysis (FBA) is a common linear programming optimization problem that assumes metabolite accumulation is zero during the growth phase:cj determine the weights of the reaction j. Also, vj and Sij are the reaction j's flux and the stoichiometric coefficient of metabolite i in reaction j. Also, vj is constrained to where ion, see ]. In mosBesides the automated and semi-automated approaches, machine learning techniques have evolved to improve GEM prediction by determining principal features from large-scale datasets. BoostGAPFILL, using a standard matrix factorization, obtains the metabolite adjacency matrix to predict possible candidate reactions from a reaction network . The resCandida albicans with some improvement  models and human metabolic reaction (HMR), recognized as the two most comprehensive generic GEMs for humans . Once coLPL and FADS2 on CVDs  , have beThe sole application of one type of data, e.g., transcriptomic data, might not lead to explicit results. The integration of multi-omics data is necessary to better understand how phenotypic behavior of metabolic pathways changes in different environmental and even genetic conditions. The variation can be captured by machine learning tools like the support vector method and used as references to regulate metabolic model constraints for a narrower feasible solution space see .Considering disturbances existing within high-throughput data, machine learning approaches have boosted the quality of the integration process. To distinguish hidden features of metabolomic data, FIngerID  and BioTHuman gut microbiota exhibits a great deal of spatial and temporal heterogeneity. Microbial populations in the intestine significantly vary in both the cross-section and length of the gut. Spatiotemporal features play a fundamental role in a comprehensive understanding of the human-microbiome interaction since the microbiome fluctuates based on transient environmental factors. Since a bacterial imbalance at one position in the gut could precipitate a local inflammatory response , developPseudomonas aeruginosa  drew attention for simulating the behavior of consortiums where time was considered as the independent variable. Initial dynamic models applied a quasi-steady-state  assumptiruginosa , Bauer eruginosa  presenteruginosa  and d-Opruginosa , μbialSiruginosa , which aThe main challenge in the investigation of the gut-heart axis is to identify the interactions between the individual gut species and CVD progression, important pieces of information that can introduce potential new paths for drug discovery. Since it is unfeasible to investigate all microbiome dynamics experimentally, multiscale models are promising approaches. To this end, the selection of appropriate multiscale models is crucial see . To predBox 4The microbiome is a complex network interacting between different temporal and spatial scales. Multiscale models are used when answering a scientific question needs information from different resolutions. There are gaps between different measurable scales and multiscale models are intended to bridge them. Clostridium, Desulfovibrio, and Bifidobacterium as well as their metabolic functions. In terms of availability, MESA and AgentPy are recent open-source Python frameworks for implementing and analyzing ABMs and can be integrated with a wide range of Python libraries  prove to be particularly useful. This framework allows researchers to encode the intricacies of a multi-bacterial system into a series of relatively simple rules that can be tuned more precisely to determine the underlying functions . In ABMsibraries , 137.via logic-based models (The application of ABMs to cardiac fibrosis or platelet aggregation has been previously studied , 139. Cain-vitro and in-vivo platforms. GEMs integrated with other computational models at different scales can be used to investigate the role of individual species at the community level and their metabolic interactions with cardiometabolic diseases. Interventions hampered by experimental limitations can be identified to define clinical scenarios and elucidate underlying disease mechanisms.Using computational approaches highlighting biochemical processes involved in CVDs, different types of genotypic and phenotypic information are encoded into mathematical models. The tool can be used to mitigate CVDs at different stages, simulate cellular growth under different environmental conditions, and give hypotheses to be investigated by Although the widespread use of metabolic modeling is promising, several shortcomings limit their applications in that they are limited to biochemical interactions, while the roles of signaling and gene regulatory components are disregarded. It is also crucial to find new methodologies, based on personalized prediction, to alleviate uncertainties that emerge as the result of mapping GPR associations. Future efforts should be emphasized on establishing universal GEM reconstruction protocols with the aim of minimizing uncertainties arising in metabolic modeling of microbiome-CVDs crosstalk.In the healthcare industry, it is essential to find ways to provide personalized medicine, which maximizes the efficiency of treatments and reduces side effects while keeping costs down . The ultTo enable personalized prevention, diagnosis, and treatment of diseases such as CVDs new systems-oriented approaches have been used to study the structural characteristics of the microbiome to elucidate the causal mechanisms. Given the importance of the gut microbiome in human health, researchers have performed different types of studies to further reveal the behavior and structure of the gut microbial communities as well as their unknown interactions with the host. Advancements in high-throughput data equipment make the availability of different omics easier. However, even with access to this wealth of information, predicting the behavior of microbiome-host interplay is often still burdensome. Accordingly, mathematical tools and computational approaches have been deployed to better grasp these heterologous data.The emergence and integration of different meta-omics data, e.g., integration of time-series data, has made it more sensible how microbial communities interact with the human host and respond to disturbance. On the other hand, GEMs, particularly when integrated with omics, provide us with a great understanding of underlying mechanisms associated with CVDs. Several regulatory methods to define more accurate constraints and bi-level optimization algorithms to model the growth and interactions of the gut microbiota have been proposed; some of these can also be applied to study microbiome-host interactions. Combining the essential assumptions and theories from different types of models yields even deeper insight into communities. Mounting evidence from microbiome studies confirms the possible role of metabolites produced by bacterial communities in treating cardiometabolic diseases. In order to prevent CVDs and prevent early intervention, microbiome and host-diet interplay can promote personalized nutrition.via a multidisciplinary perspective featuring the collaboration between researchers with clinical and engineering backgrounds to render effective personalized treatment.The future focus should be on systems-oriented studies of microbial metabolites to modulate host physiology more effectively. Systems biology-type studies should be conducted All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.