This cutting-edge technique has the potential to revolutionize disease diagnosis, therapy assessment, and patient outcomes. In this ImmunoPET imaging editorial, we will delve into recent research to provide an overview of how ImmunoPET is shaping the future of medicine and explore its applications in various diseases  to visualize and quantify biomarkers diseases , 2.ImmunoPET imaging combines the high specificity and selectivity of monoclonal antibodies with the sensitivity and quantitative capabilities of PET imaging. This innovative approach offers a non-invasive, real-time assessment of disease processes at a molecular level, providing valuable information that can guide diagnosis, monitor disease progression, and evaluate the efficacy of various therapies. ImmunoPET imaging has been extensively studied in the context of oncology, but its potential applications extend to other areas, such as neurology and immunology , 3.in vivo. By combining these two technologies, ImmunoPET imaging offers a powerful tool for disease diagnosis and therapy assessment .In a recent review published in Frontiers in Medicine as part of the Research Topic The authors explore the design options and clinical proof-of-concept studies of ImmunoPET tracers. They highlight the importance of optimizing the design of ImmunoPET probes for improved imaging performance and clinical translation. They also discuss the clinical utility of ImmunoPET in various diseases, including cancer, infectious diseases, and autoimmune disorders.One of the most promising areas of ImmunoPET imaging application is in oncology, where it has shown potential in tumor detection, monitoring, and treatment response assessment. Recent studies have explored the use of ImmunoPET imaging in various cancer types, including lung cancer, breast cancer, and hematological malignancies.Mulero et al.).As part of same Research Topic published in frontiers in Medicine a group published promising results in the diagnosis of Triple-Negative Breast Cancer (This article explores the use of ImmunoPET imaging in detecting triple-negative breast cancer (TNBC), a particularly aggressive subtype with limited targeted therapies. In this study, researchers developed a nanobody-based PET imaging strategy targeting membrane type 1-matrix metalloproteinase (MT1-MMP), a protein associated with tumor malignancy, progression, and metastasis. Their results demonstrated the precise tumor-targeting capacity of the radiolabeled nanobodies in a TNBC mouse model, highlighting the potential of ImmunoPET imaging as a diagnostic tool based in nanobodies new approach able to access more easily than full standard antibodies.Manafi-Farid et al.) the authors delve into the application of ImmunoPET in solid tumor imaging. They discuss the challenges associated with antibody-based PET imaging and provide insights into the development of novel imaging agents. This comprehensive review emphasizes the potential of ImmunoPET as a non-invasive imaging modality for precise tumor characterization and treatment response evaluation.In the same collection we could find an overview of the Oncological application of ImmunoPET , researchers evaluated the pharmacokinetics, biodistribution, and dosimetry of a murine anti-PD-L1 antibody radiolabeled with zirconium-89 in healthy mice and immunocompetent mice with lung cancer. Their findings demonstrated that tumor uptake occurred within 24 h post-injection, with the best imaging time at 48 h. This study highlights the potential of ImmunoPET imaging in assessing tumor PD-L1 expression in lung cancer, which could improve patient selection for immunotherapy treatments.In a recent study performed in lung cancer and published in the same special collection number  T-cell therapies have emerged as a breakthrough treatment for hematological malignancies, but challenges such as relapse and unique toxicities remain.Mulgaonkar et al.). By leveraging ImmunoPET imaging, clinicians may be able to identify resistance mechanisms and toxic events early, enabling more effective therapeutic interventions and improved patient outcomes.This article included in the Research Topic discusses the potential of ImmunoPET imaging to address these challenges by providing a non-invasive platform for longitudinal monitoring of target antigen expression and CAR T-cell pharmacokinetics (Despite the significant progress made in the field of ImmunoPET imaging, several challenges remain to be addressed. One of the primary limitations is the relatively slow pharmacokinetics and prolonged circulation half-life of full-length antibodies, which can lead to high background signals and reduced image quality. Novel strategies, such as the use of nanobodies or engineered antibody fragments, are being explored to overcome these limitations and further enhance the performance of ImmunoPET imaging.Moreover, the development of novel targeting agents, such as immune checkpoint inhibitors and CAR T-cell therapies, has opened new avenues for ImmunoPET imaging applications. By combining these innovative treatments with ImmunoPET imaging, researchers and clinicians can obtain a wealth of information on disease processes and treatment response, ultimately leading to more effective and personalized therapeutic strategies for patients.ImmunoPET imaging in disease diagnosis and therapy assessment. They highlight the potential of ImmunoPET as a versatile imaging tool for characterizing diseases at a molecular level, monitoring treatment responses, and guiding personalized therapies. However, challenges such as tracer design, radiochemistry, and clinical translation remain, emphasizing the need for further research and collaboration among scientists, clinicians, and industry partners.In this editorial the articles reviewed collectively, demonstrate the growing importance of The articles published in this special collection of Frontiers in Medicine contribute significantly to our understanding of ImmunoPET imaging and provide a solid foundation for future advancements in this field. As ImmunoPET continues to evolve, its integration into clinical practice holds great promise for improving patient outcomes, enabling early detection, and facilitating targeted therapies. Continued research and investment in ImmunoPET imaging are crucial to unlock its full potential and bring this technology closer to routine clinical use.in vivo. By harnessing the specificity of antibodies and the sensitivity of PET imaging, ImmunoPET has the potential to revolutionize patient care and outcomes in various fields, such as oncology, neurology, and immunology. As researchers continue to explore and refine ImmunoPET imaging techniques, we can expect to see even greater advancements in our understanding of disease processes and the development of targeted therapies in the years to come.ImmunoPET imaging represents a groundbreaking approach in disease diagnosis and therapy assessment, offering a non-invasive, real-time assessment of molecular processes FM have made significant contributions to the review of the five papers published in Frontiers in Medicine on the topic of ImmunoPET imaging. FM played a pivotal role in conceptualizing the editorial and outlining the structure and scope of the review. Their expertise in molecular imaging and precision medicine provided a solid foundation for the analysis of the ImmunoPET imaging technique and its clinical application.


Efflux pumps function as an advanced defense system against antimicrobials by reducing the concentration of drugs inside the bacteria and extruding the substances outside. Various extraneous substances, including antimicrobials, toxic heavy metals, dyes, and detergents, have been removed by this protective barrier composed of diverse transporter proteins found in between the cell membrane and the periplasm within the bacterial cell. In this review, multiple efflux pump families have been analytically and widely outlined, and their potential applications have been discussed in detail. Additionally, this review also discusses a variety of biological functions of efflux pumps, including their role in the formation of biofilms, quorum sensing, their survivability, and the virulence in bacteria, and the genes/proteins associated with efflux pumps have also been explored for their potential relevance to antimicrobial resistance and antibiotic residue detection. A final discussion centers around efflux pump inhibitors, particularly those derived from plants. Currently, antimicrobial resistance, the most complicated health concern across the world, which is primarily associated with an extended hospital stay, expensive treatment, and high mortality and morbidity rates, needs undeniable attention and multiple operative approaches involving the “One Health” concept. As the concept specifies, the interrelatedness among food, animals, and human health with the environment and the intentional collaboration between different sectors' efforts to confront the standing challenge  combine to form a composite known as a tripartite complex, which ultimately works together for the extrusion of noxious agents  superfamily, multidrug and toxic compound extrusion (MATE) superfamily, major facilitator superfamily (MFS), resistance nodulation and cell division (RND) superfamily, small multidrug resistance (SMR) superfamily, and proteobacterial antimicrobial compound efflux (PACE)  secretion in Escherichia coli  C-terminal cytoplasmic tail  resulted in increased susceptibility to polymixins and aminoglycosides, with a significant decrease in swimming motility and biofilm formation ability, and even caused impairment in defense capability to combat superoxide stress ] resistant}, MacAB efflux pump confers resistance against a variety of macrolide and penicillin-like antibiotics along with arsenite [As (III)].The MacAB-TolC efflux pump system is a tripartite complex belonging to the ABC and is the most comprehensively studied EP system among gram negative bacteria which is actively associated with the extrusion of macrolides and polypeptides virulence factors driven Enterococcus faecalis, Msr protein in Streptococcus, LmrA in Lactococcus lactis ], was found to be responsible for conferring resistance against macrolides and to collaborate with the Mef transport family  family are broadly disseminated among the three domains, namely, archaea, bacteria, and eukarya  to the inside and the other disclosures the pocket toward the outside of the cell. However, the structure and catalytic reactions mediated desired conformational changes are still not properly understood and one of the main reason behind this is the evidence indicating two crystal structures of the MATE transporter protein having an outward fronting conformation. Additionally, transporter proteins belonging to the MATE family were primarily well-known for mediating drugs or ions antiport via utilizing Na+ or H+ energy sources. The difference in the utilization of different energy sources such as H+ or Na+ gradient in different family members within the MATE superfamily has been suggested according to previous x-ray crystallographic studies concerning the NorM subfamily depending upon Na+ coupling in the C-lobe   was coined  present in Acinetobacter baumannii, loss of the MFS transporter protein AbaQ resulted in a significant decrease in bacterial virulence and motility capability  superfamily members are the most well-known efflux pump systems because of their astonishing capability of extruding a wide range of substrates, which includes various classes of antibiotics, such as tetracyclines, chloramphenicol, different β-lactam antibiotics, and besides antibiotics, several other compounds such as dyes, detergents, metals, bacterial metabolites are also utilized as a substrate by this pump  were targeted and amplified  in antimicrobials is not an infrequent event, for example, in disinfectants, and as a result, the RND efflux pump superfamily has developed the ability to resist these compounds for their survivability. Further, these RND superfamily is divided into two main categories: (i) hydrophobic and amphiphilic (HAE)-RND family, for example, AcrB, AcrD, AcrF, MdtC, MdtD, and YhiV, (ii) HME-RND family, for example, CusA which utilizes Cu(I) and Ag(I) as the most important substrate  family members utilize proton gradient to export a wide range of antibiotics, hence contributing toward MDR development. On the basis of the sequence, the SMR family can be divided into two main physiological subtypes  found to be responsible for developing resistance toward different compounds and additionally, numerous homologs of AceI conferring resistance against various biocides and mediating transportation of fluorescent dyes, such as proflavine and acriflavine, has been observed which differentiates this family from other families of efflux pump  revealed the role of Acinetobacter chlorhexidine efflux protein (AceI) system in A. baumannii  family  conducted first by Grinius and Goldberg in 1994 . Additionally, as a result of the movement of substrates via AcrB in the direction of the distal binding pocket (DBP), which is situated deep in the carrier domain, a conformational alteration toward the T state assisting the transfer of the substrate from the central pore of AcrB toward TolC entrance has been observed. Subsequently, the ejection of the substrate from AcrB into TolC occurs via the rotating functional mechanism, which involves the protein transitional step, i.e., from state T to state O  and then toward the distal binding pocket (DBP), plays an important role in defining the poly-specificity feature of the transporter.Further, it has been reported that a second access site for substrate was found to be located in a cleft that formed in between PC1 and PC2 domains. The binding of AcrA and TolC is facilitated by the docking domains (DN and DC), which are located on the top of the porter domain. Additionally, tight binding of the top of AcrB with the TolC base is very essential for preventing the substrate leakage into periplasm aided by β-strands, which are placed antiparallel to generate a funnel-like construction. The crystal structure initially reported by Murakami et al.  revealedvia another site placed within the porter domains PC1 and PC2, ~15 Å on top of the membrane plane, leads toward tunnel 2, which further elongates in the direction of the protein center  is a huge chamber surrounded by hydrophobic phenylalanine (Phe) residues and polar residues , is recognized for its ability to bind with the hydrophobic pocket located within AcrB, further inhibiting the drug extrusion activity  encourages the binding of EPI with tetracycline; additionally, the response of the combination of tobramycin plus EPI along with rifampicin, fluoroquinolone, and fosfomycin was also analyzed, which revealed that they exert a robust effect cooperatively upon the bacteria, which resulted into reduction in the MIC80 level against these antibiotics   have a potential impact in preventing antimicrobial resistance globally. A significant challenge in the discovery of EPI has been its highly hydrophobic nature and the substrate-binding poly-specific site for the target. However, the primary studies on the x-ray crystal structures of different compounds such as pyranopyridine (Sjuts et al., P. aeruginosa.However, incidences of another resistance mechanism associated with membrane-embedded MDR efflux pumps which can extrude a wide range of noxious compounds such as antibiotics, dyes, and biocides have been reported (Mitchell et al., In this review study, we have discussed the important role played by efflux pump family members in developing resistance against single or multiple antibiotics as well as against various compounds other than the antimicrobial agents including heavy metals, preservatives, and toxins. Apart from different classes of antibiotics, efflux pumps also provide resistance against disinfectants and virulence factors and even develop cross-resistance against other different noxious compounds, which further leads to the development of a multidrug-resistant phenotype. The working mechanism along with the regulation of an efflux pump system is an intricate process that actively participates in different biological processes in bacteria such as biofilm formation, quorum sensing, and adhesion of bacteria to host, and their progressive multiplication have been highlighted in this review. This review further highlights the importance of the discovery of novel EPIs, which should be plant-based, safe, and non-toxic, and many efflux pump inhibitors that are under clinical trial as well. Efflux pump inhibitors derived from plants are of great importance and are studied widely presently. However, the variations in function and regulatory mechanisms of the efflux pump systems along with the progress and utilization of a variety of efflux pump inhibitors still need further exploration. According to the progressive research work, it has been suggested that TetR family members can be studied further for the discovery of antibiotic residues associated with multidrug resistance. In addition to the role of the aforementioned active regulatory proteins, some other proteins with an ability to identify single or multiple substrates and specific substrate-binding domains that can be utilized to identify antibiotic residues involved in substrate binding have been reported earlier. Therefore, other than the TetR regulatory protein, the detection of residues of antibiotics and transcriptional regulatory protein requires the utilization of efflux pump concomitant genes. Additionally, the proteins with a high substrate binding specificity toward diverse antimicrobials with more appropriate features are very demanding. Moreover, this review discussed the association of the expressional levels of efflux pump systems with various other defense mechanisms such as biofilm formation and quorum sensing, which provides novel insights for expanding the extent of fundamental research. In this article, we provided an overview of efflux genes and significant transporters indicating an area which requires persistent exploration to provide supervision for clinical practices.SC was involved in the literature review, writing of the original draft, figure illustrations, conceptualization, preparing the draft of the manuscript, reviewing, editing, revising the manuscript, has contributed to the article, and approved the submitted version.


As one of the most important components of the innate immune system, neutrophils are always at the forefront of the response to diseases. The immune functions of neutrophils include phagocytosis, degranulation, production of reactive oxygen species, and the production of neutrophil extracellular traps (NETs). NETs are composed of deconcentrated chromatin DNA, histones, myeloperoxidase (MPO) and neutrophil elastase (NE), playing an important role in the resistance to some pathogenic microbial invasions. Until recent years, when NETs were found to play a critical role in cancer. NETs play bidirectional regulation both positive and negative roles in the development and progression of cancer. Targeted NETs may provide new therapeutic strategies for the treatment of cancer. However, the molecular and cellular regulatory mechanisms underlying the formation and role of NET in cancer remain unclear. This review just summarizes the recent progress in regulatory mechanisms about the formation of NETs and their role in cancers. Pseudomonas aeruginosa show a decrease in antibacterial activity when NE was bound to the antibacterial DNA-histone complexes [The immune system is a defense network covering the whole body, with the ability to identify “self” and “non-self”, which is the key for hosts to defend against pathogen invasions and eliminate pathogens ,2. Neutromplexes . These rBack in 1996, researchers used phorbol 12-myristate 13-acetate (PMA) to maximally activate neutrophils and found the rupture of the cell membrane, a phenomenon markedly different from necrosis and apoptosis, and this stimulation was a new way of activating neutrophils. It was until 2004, when the formation of NETs was discovered, that the process was first named. Studies had found that when neutrophils were stimulated by interleukin-8 (IL-8), PMA or lipopolysaccharide (LPS), neutrophils were activated to form membrane protuberance and released NETs , and thiOnly activated neutrophils produce NETs, while naïve neutrophils do not. NETs are released primarily through a cell death process called NETosis, in which the cell membrane ruptures and the cell dies. Now, of course, studies have shown that there is another way to make NETs without damaging the cell membrane, and the neutrophils retain their formal functions after this process is finished. The release of NETs and its component extracellular DNA are double-edged swords for the immune system. On the one hand, as one of the innate immune components, neutrophils release NETs in response to the invading pathogens, which helps to capture and kill pathogenic microorganisms to achieve immune protection. On the other hand, during the generation of NETs, the exposed chemical components are harmful to the hosts, because it will cause a certain degree of damage to the endothelial cells and tissues of the hosts . One of Studies have shown that NETs can help neutrophils fix and trap bacteria, fungi and viruses, thereby clearing pathogens, while mice lacking the capacity of NETs production such as deletion of genes for related proteins are more susceptible to infections, which demonstrates the important role of NETs in infectious diseases . During Neutrophils can kill bacteria through phagocytosis and the production of ROS, and they can use the network of NETs to capture bacteria and kill them. Different from bacteria and viruses, fungi are larger and contain hyphae or spores . There is no complete understanding of how neutrophils perceive microbial size, but it is clear that the release of NETs in the events of infections is dependent on microbial size. A study of human fungal infections has shown that NETs may exert antifungal effects by controlling mycelial growth, and in patients with chronic granulomatous (CGD) disease, the presence of NETs restricts mycelial growth at a moderate rate, thereby providing a degree of antifungal effect . In addiAt the end of 2019, the Novel Coronavirus called SARS-CoV-2 pandemic swept across the world, seriously affecting our daily life and our health. Analysis of clinical data from COVID-19 patients showed that the proportion of neutrophils and lymphocytes showed an increasing trend, and the increased level of NETs, one of the markers of neutrophil activation, could also be significantly detected in patients ,26. WhatNeutrophils can be activated in response to stimulation, and partially activated neutrophils can produce NETs. According to the production of oxidants in the process, the generation of NETs can be divided into oxidant-dependent and oxidant-independent. Similarly, according to the time sequence of neutrophil response to stimulation, it can be divided into early non-lytic and late lytic NET formation. The difference between the two is whether the neutrophil cell membrane is broken. The production of NETs in both ways is the result of activation of neutrophils, which receive infection or stimulation and recognize through various receptors, including toll-like receptors (TLR), antibody crystallizable fragment (Fc) receptors or other complement receptors, to complete activation and produce NETs . It shouThe classic late lytic NETs generation includes a dominant ROS dependent form and a few ROS independent forms . ChemicaInterestingly, in some studies, when neutrophils are stimulated by ionomycin and other substances, neutrophils will respond in time to produce NETs, even though NADPH oxidase is not involved in this process, but the production of mitochondrial ROS is involved, so the production of NETs is regulated by the mitochondria in these processes. It was found that under the stimulation of ionomycin, intracellular calcium ion production would activate the calcium-activated small conductance potassium (SK) channel member SK3, which was the main component of intracellular NOX-independent pathway , and theROS is an important indicator of NETs formation or NETosis, but how ROS induces this process is not fully understood. The chromatin untangling ability of DNA repair mechanisms was found to be a key driver of NETosis. In NOX-dependent NETosis processes, ROS first activates various MAPKs pathway cascades leading to activation of transcription factors and subsequent transcriptional excitation. At the same time, ROS oxidizes guanine. At this point, DNA damage begins to repair, and chromatin is deconcentrated . In addiIn 2016, it was found that the inhibitory receptor on leukocyte 1 (SIRL1) is involved in a unique signaling pathway in the induction of NETs production, that is, the process does not involve oxidant production . StudiesNETs production in this process occurs late and is accompanied by cell membrane rupture. As a normal physiological process in vivo, it is not clear whether this process has a certain relationship with other cell death processes in vivo, and whether the formation of lytic NETs production is regulated by other cell death mechanisms. In patients with sickle cell disease (SCD), intracellular polymerization of mutated hemoglobin can lead to the development sterile inflammation, in vivo microscopic observations of SCD mice and invitro studies of the blood of SCD patients have shown that the sterile inflammatory environment promotes the activation of neutrophil-gasdermin D (GSDMD), which triggers the release of NETs, thus resulting the development of acute lung and neutrophil-platelet aggregation . We callCompared to the late lytic NETs production, the non-lytic NETs generation occurs earlier . SecondlThe similarity between them lies in that the stimulation of some pathogenic microorganisms, both of them need the relevant complement system of neutrophils and/or TLR receptors to receive the external stimulus signal, thus inducing the formation of NETs. Staphylococcus aureus can activate neutrophils via TLR2 and complement receptors, which directly activate intracellular PAD4 and stimulate the production of non-lytic rapid NETs production . In addiPrevious studies have described the important regulatory role of mitochondrial ROS in the late lytic NETs production, and some studies have found that the release of mitochondrial DNA also plays an important role in the early non-lytic NETs production. Firstly, neutrophils treated with granulocyte-macrophage colony-stimulating factors (GM-CSF), a hematopoietic growth factor and then treated with TLR4 agonist showed the release of mitochondrial DNA, which is regulated by mitochondrial ROS, showing another form of non-lytic NETs formation to some extent ,53.How neutrophils release NETs and still maintain the integrity of the membrane has not been fully determined. Whether vesicles play a mediating role in this process, or whether the membrane spontaneously restores its integrity after the release of substances, the current study cannot fully explain. Do the way NETs are generated at different times reflect the state of the cell and its normal functions to some extent? Therefore, the study of how the cell membrane maintains its integrity during the generation of non-lytic NETs is helpful to link the late lytic NETs generation to the early non-lytic NETs production and to understand the cell states.All physiological and biochemical processes are strictly regulated, and NETosis is no exception. Studies have shown that when the invading pathogens are small, neutrophils can clear them by phagocytosis, but when the pathogenic microorganisms are too large to phagocytosis, neutrophils play an immune clearance role by producing NETs. The key factor determining the competition between NETosis and phagocytosis is the NE, when a pathogenic microorganism is small, the phagosome fuse with azurophilic granules, which insulate NE away from the nucleus, so as to prevent the chromatin from becoming deconcentrated . In thisAlthough the formation of NETs is strictly regulated and NETs play an important role in fighting against invading pathogens, pathogenic microorganisms can still escape the effects of NETs through a few pathways . First oNETs have a facilitating and inhibitory role in cancers . On the More and more experimental results show that the inflammatory response in the tumor microenvironment can bridge the host and cancer cells, thus affecting the metabolic cascade of cancer cells . The tumIn tumors, neutrophils have two phenotypes, namely N1 and N2. In the occurrence and development of cancer, the two phenotypes of neutrophils play completely opposite roles, N1 functions to anti-tumor, and N2 plays a pro-tumor role . It has In the tumor microenvironment, in addition to NETs, more tumor-infiltrating immune cells play an important role, so the role of NETs and related immune cells is also extremely important in tumor progression. T cells play a major functional role in tumor-related diseases, and the role of NETs prompts us to consider a question: whether T cells and NETs play a synergistic anti-tumor role in tumors. In the tumor microenvironment, T cells are functionally depleted by chronic antigen stimulation. These depleted T cells show overexpression of inhibitory receptors and reduced production of effector cytokines, thus failing to clear tumor cells . It founTumor-secreted protease cathepsin C (CTSC) also acts on neutrophils by activating neutrophil membrane binding proteinase 3 (PR3), promoting the production of NETs and thus promoting lung metastasis of breast cancer cells . On the Additionally, NETs can promote tumor cell growth by affecting mitochondrial function. As we all know, mitochondria are the energy source of the body, and tumor cells are no exception. The energy generated by mitochondria can be provided to tumor cells, thus promoting the occurrence and progression of cells. A study found that in mice with PAD4 deficiency or mice treated with DNase or NE inhibitors, through the evaluation index of the mitochondrial function and density as the mitochondrial outer membrane on the expression of mitochondrial protein transposition enzymes as well as a sign of cell proliferation, all can be found in these cases, the tumor cells are characterized by low cell proliferation, and mitochondrial function was lower than normal conditions . In hepaIn addition to the role played by related proteins, DNA in NETs also plays an important role. It has been found that NETs are abundant in liver metabolism and serum in many cancer patients, and NETs-DNA acts as a chemokine to attract cancer cells, which can be found as well as in mouse models. NETs-DNA activates the downstream ILK-β-parvin pathway by binding to CCDC25 transmembrane proteins on cancer cells, thereby enhancing cancer cell mobility .+ T cells as cytotoxic effect cells, and it can be found by using time-lapse confocal microscopy. The presence of NETs around tumor cells can significantly reduce the connection between CD8+ T cells and NK cells and thus play a protective role in tumor cells [In addition to the direct promotion of the growth and development of tumor cells by NETs, NETs can also protect tumor cells by influencing the cytotoxic effects of other killer cells, such as cytotoxic lymphocytes and NK cells. CXCR1 and CXCR2 receptors are expressed on the surface of neutrophils , and tumor cells . This deIn summary, the web-like structure of NETs can enclose tumor cells, thereby protecting them from the scavenging and killing effects of other host cells such as macrophages and related cytokines.The double-edged effect of NETs still holds true in cancer diagnosis and prognosis. NETs scores of 19 NETs-related genes were analyzed by LASSO Cox model, and NETs were found to be significantly associated with multiple malignant biological processes, and MPO was also associated with adverse clinical outcomes. These biomarkers represent the ability of NETs formation to predict patients’ progression . IL-17 cCurrent research on NETs and cancer progression is mainly focused on the positive feedback regulation between the two, that is, NETs directly affect the growth, development, and proliferation of tumor cells, while tumor cells and other immune cells in the tumor microenvironment can also directly promote the formation and regulation of tumor related neutrophil NET, which forms positive feedback promoting tumor action loop, which is very important for tumor formation and progression, so targeting NETs may become a new idea for tumor therapy. Unfortunately, in current clinical studies, no studies have shown how to target NETs to treat cancer . GonzaleAdditionally, in the process of some cancers, such as gastric cancer, pancreatic cancer and lung cancer, the formation of cancer thrombosis is the second leading cause of death in cancer patients, with a very high incidence of 15.8% in gastric cancer, 19.2% in pancreatic cancer and 13.9% in lung cancer ,81, and As we have known, in addition to phagocytosis, degranulation and ROS generation, NETs, as one of the important strategies of neutrophils against large invasive pathogenic microbes, have always been a hot spot and focus of research on the way and the effects of its action. From the initial discovery of NETs to the subsequent studies, the bactericidal effect of NETs has been widely recognized by researchers, but recent studies have found that NETs do not always play a “good” role in the process of disease, NETs have also been confirmed to accelerate the process of diseases in many cases. In different cancer models, NETs play different roles. However, in the same disease such as cancer, there are both positive and negative roles of NETs in different types of cancers. On the one hand, this is related to the microenvironment in the host, and on the other hand, it is related to the characteristics of the cancer itself. There are many substances that stimulate neutrophils to produce NETs. These stimulation conditions can cause an early or late response of neutrophils. The intracellular processes involved in the formation of NETs are different at different times. In infectious diseases, NETs generally play an important role in antimicrobial killing, helping neutrophils capture pathogens and kill pathogenic microorganisms. In cancer, the role of NETs also exists in both positive and negative aspects, and NETs themselves can also cause certain damage to host cells. Therefore, studying the specific effect and mechanisms of NETs in cancer is of great significance for the occurrence and development of cancer. The research of NETs as a therapeutic target of cancer has attracted extensive attention. In view of the double-edged role of NETs in cancer, targeting NETs will provide new strategies for cancer treatment.


Christoph Nikendei, Till Johannes Bugaj, Anna Cranz, Alina Herrmann, Julia TabatabaiHeidelberger Standards der Klimamedizin – Wissen und Handlungsstrategien für den klinischen Alltag und die medizinische Lehre im KlimawandelPublisher: Heidelberger Klinische StandardsYear of publication: 2023, 352 pages, price: € 34,99ISBN: 978-3-00-074681-9The climate crisis threatens our natural livelihoods and civilization in many ways. With the steady increase in mean global temperature, the crossing of irreversible climate tipping points is becoming increasingly likely. There is a threat of a massive acceleration of biodiversity loss, acidification of the oceans, more frequent food shortages, an increase in extreme weather events, and climate-related refugee movements.Heidelberg standards of climate medicine provides broad knowledge, as well as practice-oriented recommendations for action on the scientific basics, the  treatment of physical and psychological effects of the climate crisis, and the necessary transformation processes towards a more ecologically sustainable health sector. In 12 chapters with a total of 45 articles, the participating authors summarize the current state of research and information from their  practice and provide useful tips and advice for the everyday professional life of all participants in the health sector.As a compact “pocket book”, the Heidelberg standards of climate medicine provide a brief and concise overview of the scientific basics of the climate crisis (chapter 1) and their impact on natural and social systems (chapter 2). The knowledge of these basics will, on the one hand, help the reader with regard to the following book chapters, and, on the other hand, it should serve as a practical tool in (scientific) discourse.First, the physical impacts of the climate crisis, it becomes evident how closely environmental changes  are linked to human health: The occurrence of many diseases, such as heat stroke, COPD, allergies, diabetes, or kidney failure, are influenced by the climate crisis. In addition to explaining this relationship, the chapter presents definitions relevant to clinicians, pathophysiological processes, key recommendations for clinical care, and helpful therapeutic strategies. The psychological effects of climate change are reflected upon in more detail in chapter 4, ranging from trauma in the context of natural disasters, to connections between climate, weather, and suicidality. Additionally, chapter 5 is dedicated to general cognitive processes and biases in psychological perceptions and processing of climate change. The discrepancy between knowledge and action regarding the climate crisis is also impressively illustrated.Two comprehensive chapters then highlight the numerous direct and indirect impacts of the climate crisis on human health. In the third chapter on the Heidelberg standards of climate medicine reveals concrete fields of action in the health sector  in order to decisively counter the health crisis stemming from the climate crisis (chapter 6). Afterwards, various health co-benefits of climate protection measures are explained using plausible examples (chapter 7), framed by practical tips for climate-sensitive health counseling and patient-oriented climate communication (chapter 8). Furthermore, it is presented in an understandable and precise way, how a sustainable transformation of the health sector can succeed concretely (chapter 9). Moreover, it is explained how findings on the climate crisis can be integrated into research and teaching in a targeted manner (chapters 10 and 11). Finally, considerations on the medical ethos in times of climate crisis are presented and various initiatives in the health sector are introduced (chapter 12). In this respect, the contentual focus of the book illustrates both the complex effects of the climate crisis, as well as the remaining scope of action, both on an individual and structural level. Numerous tables and illustrations provide a quick overview of key aspects of the chapters. A more in-depth discussion of the topics is made possible by the main text and a large number of (in part further) source references.Subsequently, the Heidelberg standards of climate medicine is recommended in particular for interested stakeholders in the health sector, who want to engage with the basics and consequences of the climate crisis for their everyday professional life, implement gained knowledge in their  practice, research and teaching, and also want to understand and help shape transformation processes.Reading the The author declares that she has no competing interests.


Trauma-induced coagulopathy (TIC) is a major cause of morbidity and mortality in patients with traumatic injury. It describes the spectrum of coagulation abnormalities that occur because of the trauma itself and the body’s response to the trauma. These coagulation abnormalities range from hypocoagulability and hyperfibrinolysis, resulting in potentially fatal bleeding, in the early stages of trauma to hypercoagulability, leading to widespread clot formation, in the later stages. Pathological changes in the vascular endothelium and its regulation of haemostasis, a phenomenon known as the endotheliopathy of trauma (EoT), are thought to underlie TIC. Our understanding of EoT and its contribution to TIC remains in its infancy largely due to the scarcity of experimental research. This review discusses the mechanisms employed by the vascular endothelium to regulate haemostasis and their dysregulation following traumatic injury before providing an overview of the available experimental in vitro and in vivo models of trauma and their applicability for the study of the EoT and its contribution to TIC. Globally, traumatic injury remains one of the leading causes of death in persons under 44 years of age, accounting for over 4 million deaths every year . This exImpaired coagulation and fibrinolysis following traumatic injury, a clinical phenomenon termed trauma-induced coagulopathy (TIC), have been observed for decades, with temporal changes in coagulation following severe trauma first clinically documented and reported in the 1960s ,12,13. TTraumatic injury is associated with complex pathophysiological and immunological responses, as illustrated in The endothelium is among the first cellular barriers to respond to traumatic injury . It is aConsequently, there is a growing need for the development of experimental models, both in vitro and in vivo, to aid in furthering our understanding of the pathological mechanisms that underlie the EoT and its ability to drive TIC. Traumatic injuries are highly heterogeneous, varying in aetiology, severity, anatomical location, and the pathophysiological responses they trigger. Therefore, experimentally modelling the endotheliopathy that occurs following traumatic injuries remains highly challenging. This review seeks to provide an overview of the endothelial regulation of haemostasis and thrombosis in health and following injury before summarising the in vitro and in vivo models currently employed to study the EoT and its contribution to TIC, particularly following extracranial or peripheral traumatic injuries.Vascular endothelial cells (ECs) constitute the innermost layer of blood vessels and regulate various processes, including the trafficking of leukocytes into tissues, maintenance of selective vascular permeability, inflammation, vascular tone, haemostasis, and thrombosis ,33. In iPhysical barrier. Through intercellular adherens and tight junctions, ECs form a barrier that separates the underlying vascular layers and the surrounding tissue from the blood that flows in the vessel lumen . ThroughGlycocalyx. The endothelial glycocalyx is a negatively charged, carbohydrate-rich layer that covers the luminal surface of the vascular endothelium ,41. It iAmong the EC-membrane-spanning proteoglycans is syndecan-1, for which heparan sulphate (HS) side chains inhibit coagulation by interacting with anti-thrombin (AT), which, as its name implies, inactivates thrombin as well as the coagulation factor Xa, and tissue factor pathway inhibitor (TFPI), which inactivates factor VIIa upstream of thrombin generation in the extrinsic pathway of coagulation . IncreasThe glycoprotein thrombomodulin (TM) is also a major constituent of the endothelial glycocalyx. TM spans the EC membrane, and its luminal portion can be shed into the bloodstream as soluble TM (sTM), which retains biological activity . TM has Elevated levels of sTM have consistently been reported in patients with traumatic injuries and are suggestive of increased TM cleavage and shedding on the endothelial surface . AccompaFibrinolytic factors. ECs produce, store, and release tissue plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA) . Followi2) and the soluble gas nitric oxide (NO) [2 passively diffuses across the endothelial membrane into the blood, where it inhibits platelet activation by ligating the Gs-coupled IP prostanoid receptor, resulting in the cytosolic generation of inhibitory cAMP [2 can be augmented by a plethora of agonists, including histamine, bradykinin, and thrombin [2, which renders platelets hyporesponsive to agonist stimulation.Antiplatelet factors. In addition to discouraging fibrin formation, the endothelium potently inhibits platelet activation and subsequent aggregation by the release of anti-platelet factors, namely, the arachidonic acid metabolite prostacyclin (PGIide (NO) ,75. PGI2ory cAMP . The endthrombin ,77. Alth2, diffuses across the endothelial membrane to inhibit platelet activation via the stimulation of soluble guanylate cyclase and the generation of inhibitory cGMP within platelets [NO is generated from the amino acid L-arginine by endothelial NO synthase (eNOS) and, similarly to PGIlatelets . Endothelatelets . ECs alslatelets . E-NTPDalatelets . WhetherAltered platelet–EC interactions have been proposed to occur after trauma and to contribute to the development of TIC. For example, rapid and sustained increases in the plasma levels of vWF, particularly that of the ultra-large, multimeric form (UL-vWF), together with decreases in plasma levels of the UL-vWF-degrading metalloproteinase ADAMTS13 have been demonstrated in trauma patients, suggesting an augmented release of vWF multimers from the Weibel–Palade bodies of activated ECs immediately following traumatic injury and impaired clearance by ADAMTS13 ,82. IncrIn vitro models of trauma are helping to dissect the cellular and molecular mechanisms of the EoT and its contribution to TIC. They provide an invaluable platform for performing well-controlled, reproducible experiments and are particularly useful for identifying the stimuli cascades that trigger the induction of the EoT following injury. They can be used to identify therapeutic targets for normalising the traumatised endothelium and its regulation of coagulation and fibrinolysis with their utility determined by their fidelity to in vivo trauma pathobiology. This section discusses the various approaches that have been used to model aspects of the complex pathophysiology of trauma and induce the EoT in vitro. Due to the paucity of in vitro models of the EoT, this section also discusses the applicability of established in vitro models of bleeding for the study of the EoT and its influence on haemostatic processes.2O2 [2O2 [2O2. These data suggest that this in vitro model could be used to study endothelial changes induced solely by haemorrhagic shock under static conditions. This model, however, fails to consider the effects of the flowing blood and the shear stress that it exerts on the luminal endothelial surface, which is known to be a key determinant of the composition of the glycocalyx.Endothelial models of isolated haemorrhagic shock. Haemorrhagic shock has been simulated in vitro to study its effects on the endothelium. Human umbilical vein ECs (HUVECs), for example, have been subjected to clinically relevant concentrations of epinephrine and norepinephrine, hypoxia followed by reoxygenation, and sublethal concentrations of H2O2 . Individ2O2 . This sy2O2 [2O2 . NorepinEndothelialised microfluidic models of isolated haemorrhagic shock. Endothelialised microfluidic channels have been used to assess the endothelial dysfunction induced by haemorrhagic shock under blood-flow-mimicking conditions . HUVECs In vitro models utilising patient-derived or traumatised ECs. Currently, there is a lack of in vitro models that fully and accurately recapitulate the complex interplay between the pathophysiological  and immunological (innate immune responses and surges in pro-inflammatory cytokines) processes that are thought to induce the EoT in injured patients. It is possible that using ECs derived from patients, particularly from their injured or damaged tissues, may circumvent this issue but only if the traumatised phenotype of patient ECs persists in culture or the memory of trauma is reinforced by in vitro stimulation with trauma-related factors, such as catecholamines, hypoxia, pro-inflammatory cytokines, or DAMPs. Obtaining ECs from injured tissues may prove difficult. Alternatively, circulating ECs, which are dislodged from the vessel wall by vascular injury, such as that which occurs in trauma, or endothelial progenitor cells, which are mobilised from the bone marrow by eNOS activation in response to injury and give rise to mature ECs, can be readily obtained from patient blood samples ,87,88,89Endothelialised microfluidic models of bleeding. Thus far, two endothelialised microfluidic models of mechanical injury haemorrhage have been described that could potentially be modified and used to model EoT. The device, developed by Sakurai et al., is composed of two channels: an endothelialised microchannel (recapitulating the microvasculature) that opens into a separate “bleeding” microchannel (serving as a bleeding wound) . A pneum−1 while fluid is pulled through the extravascular microchannel at a reduced shear of 0.5 s−1 to create a transmural pressure gradient across the vessel wall chamber [Another microfluidic model mimicking penetrating vascular injury and the bleeding that ensues was developed by Poventud-Fuentes et al.  They int chamber . This pr chamber . The rea chamber .Vascularised organ-on-a-chip. ECs within the vasculature communicate with other cell types, including circulating immune cells within the vessel lumen and stromal  and parenchymal cells resident within the surrounding tissue, the behaviour of which is also likely to be influenced by traumatic injuries . In vitrNumerous attempts have been made to develop animal models of trauma that reflect the clinical scenario in traumatically injured patients ,94. ThesModels of isolated trauma. Noble and Collip were the first to develop an in vivo model of isolated blunt trauma, which mimics lethal traumatic injury by causing extensive tissue injury in the absence of gross haemorrhage. To induce blunt trauma, a rotating plastic wheel with internal shelves (the Noble-Collip drum) was used to repeatedly strike down the animal. “Noble-Collip” trauma in rats rapidly induced fibrinolysis activation and subsequent suppression. This was implied by the upregulation of tPA and PAI-1 in various organs, including the kidneys, lungs, and liver, and the increase in plasma levels of inactive tPA-PAI-1 complexes . These fModels of isolated haemorrhage. Haemorrhagic shock has been experimentally produced in animals by either fixed-volume, pressure-controlled, or uncontrolled haemorrhage . In modeModels of pressure-controlled haemorrhage involve bleeding the animal until the mean arterial pressure (MAP) drops to a defined level (varying between 29 and 55 mmHg), which is maintained for a set period by repeated haemorrhaging or fluid infusion . It has Animal models of uncontrolled haemorrhages are preferred to models of fixed-volume and pressure-controlled haemorrhage as they more closely resemble the clinical situation of trauma patients with uncontrolled bleeding and allow haemostatic processes to influence the progression of the haemorrhage. Uncontrolled haemorrhage is induced by vascular trauma, including solid organ injury  and levels of aPC, mimicking clinical laboratory observations in trauma patients and demonstrating aPC-driven acute coagulopathy . HoweverModels of combined haemorrhage and polytrauma. Animal models of combined haemorrhage and polytrauma have been shown to better recapitulate severe human trauma, defined by an anatomical injury severity score >15, and to consistently show signs of coagulopathy and endotheliopathy. For example, Wallen et al. used a murine model of polytrauma, in which mice were subjected, in sequence, to weight-drop-induced traumatic brain injury, pressure-controlled haemorrhage with resuscitation, and laparotomy with bilateral abdominal rectus muscle crush injury to induce the EoT . AlthougSimilarly, in rat models of combined haemorrhage and polytrauma, coagulation changes, including the prolongation of PT and aPTT, decreased fibrinogen levels, and impaired clot stability , were alDespite many models being described, there appears to be a significant lack of in vitro and in vivo models of peripheral trauma that can be used to further our understanding of the contribution of the EoT to TIC. With respect to modelling trauma in vitro, studies have thus far only assessed the effect of haemorrhagic shock, which constitutes one aspect of trauma pathology and may not be sufficient to alter the haemostatic function of ECs in patients to give rise to TIC. Using ECs or their surrogates, such as circulating ECs or bone-marrow-derived endothelial progenitor cells, obtained from patients with traumatic injuries may prove superior as they would possess the traumatised phenotype of the patients or memory of it, which can be reinforced by in vitro stimulation with trauma-related factors. Moreover, in vitro models have yet to examine the interaction of ECs with the coagulation and fibrinolysis systems and the impact of haemorrhagic shock and other aspects of trauma pathology, which can be performed using established haemostatic assays, including fluorometric thrombin generation and turbidimetric clot lysis assays, in the presence of cultured ECs. Better yet, the endotheliopathy induced by trauma could be modelled using in vitro microfluidic systems that more closely resemble the physiological environment that ECs are subjected to in vivo and enable the integration of the biologically active, deformable 3D extravascular tissue and its components, the effects of which are often neglected. In such dynamic in vitro systems, faithful to the complexity of the vasculature, haemostatic plug formation, structure, stability, and lysis could be visualised and monitored using fluorescent staining and imaging of platelets and fibrin(ogen) within whole blood following the simulation of mechanical vascular injury. Future in vitro studies must also consider the heterogeneity of the endothelium and its implications, as, with the advent of single-cell omics, ECs within different vascular beds have been shown to exhibit distinct differences in phenotype and function and may, therefore, respond differently to trauma ,127.With regard to in vivo models, although a plethora of models have been developed and described, they have not been very well characterised in terms of the coagulopathic and associated endothelial changes. This is likely attributable to our poor understanding of the endotheliopathy and coagulopathy that occur in traumatised patients. Overall, in vivo evidence suggests that haemorrhage alone, whether controlled or uncontrolled, might not be sufficient to induce coagulopathy and the associated endotheliopathy. However, when compounded by trauma, including bone fractures, solid organ damage, and soft tissue injury, haemorrhage is more likely to result in coagulopathic and endothelial changes comparable to those observed in trauma patients. Furthermore, to date, in vivo investigations have been limited to understanding the acute or early phase of TIC, in which the processes of hypocoagulability and hyperfibrinolysis tend to predominate. Long-term trauma models that simulate the clinical trajectory of trauma and, therefore, can be used to assess the temporal changes in the phenotype of ECs and their regulation of coagulation and fibrinolysis are missing. There are also no in vivo models that recapitulate the clinical scenario in which patients survive the trauma and haemorrhage but go on to develop late TIC, which is characterised by hypercoagulability and multiple organ failure.


While age-related auditory deficits and cochlear alterations are well described, those affecting the vestibular sensory organs and more broadly the central vestibular pathways are much less documented. Although there is inter-individual heterogeneity in the phenomenon of vestibular ageing, common tissue alterations, such as losses of sensory hair cells or primary and secondary neurons during the ageing process, can be noted. In this review, we document the cellular and molecular processes that occur during ageing in the peripheral and central vestibular system and relate them to the impact of age-related vestibular deficits based on current knowledge. Ageing is often seen as a pathophysiological process, when in fact, it is a normal process that affects all the body’s tissues and organs. It particularly affects sensory organs and systems, leading to sensory deficits that are perceived in different ways by different individuals. It also modifies a whole range of biological networks and functions, which can affect our balance, our posture and our ability to interact with our environment. Age-related damages to musculoskeletal and tendon networks, visual integration pathways and adaptation mechanisms, as well as metabolic functions and cognitive processes, all contribute to the development of age-related postural-locomotor deficits. In this review, we have chosen to highlight more specifically the age-related alterations that affect the vestibular sensors  and the central vestibular pathways (with a particular focus on the vestibular nuclei of the brainstem). The data available on this subject in the literature are displayed in the two following sections.Recently, a massive age-related loss of synaptic contacts between vestibular hair cells and primary vestibular neurons has been observed using new technological approaches. These observations challenge the established dogmas on the ageing of the vestibular organ by highlighting a major point of fragility within our peripheral sensory organs. Situations in which tissue ageing and its functional correlates can be accelerated must be added to our understanding of the structural degradation of the vestibular system under normal ageing conditions. This is the case, for example, with the acceleration of age-related hearing loss, supported by a drastic decrease in synaptic contacts between inner hair cells and auditory fibres, following auditory over-stimulations demonstrated in young mice. It is possible, although not yet described, that such situations of accelerated sensory ageing may also occur in the vestibule. The morpho-functional observations made in humans post mortem and in animal models of ageing enable us to better understand the natural and pathological ageing of the vestibular organ and to better understand the tissue support of age-related vestibular deficits A.Until a few decades ago, the question of the existence of age-related cellular degeneration in the human vestibular system and more widely in mammals was the subject of debate. To date, the question has clearly still not been fully resolved. Almost 50 years ago, Rosenhall was the first to mention the lack of a clear correlation between vestibular deficits and tissue and cellular alterations . In the Using Nomarski interference contrast microscopy, Merchant and colleagues determined the total number of vestibular hair cells in each of the five vestibular organs   Figure B. From aIn summary, the loss of hair cells and primary vestibular neurons occurs in men from the age of 40 years, becoming significant in the period 70–90 years. During this period, tissue damage is more significant in the ampullae than in the maculae sensory epithelia. In his review on the ageing of the human vestibular system, Zalewski indicated that cell loss affects the centre of the sensory epithelia more than the periphery and that type 1 hair cells  are more fragile than type 2 cells . Within Recently, using a novel histological approach combining an immunocytochemical analysis and quantification of synaptic proteins, the team of Prof. Corfas from the Kresge Hearing Research Institute at the University of Michigan in Ann Arbor (USA) has made a major step forward in our understanding of the cellular mechanisms impacted by vestibular ageing . The teaA significant acceleration of age-related auditory primary neuron loss was previously demonstrated in mice, secondary to auditory over-stimulation early in the animals’ lives . In thisThe spontaneous reafferentation of inner ear hair cells is one of the hypotheses to explain the functional restoration following acute peripheral vestibulopathies, such as vestibular neuritis or labyrinthitis . In ordeOther components of vestibular sensors may be affected by aging. However, even though several studies have identified the genes and molecular processes involved in the birth and formation of otoconia ,27, therIt is still challenging to establish a precise correlation between the age-related cellular and molecular changes mentioned above, affecting the different components of vestibular sensors, and age-related balance disorders. Several excellent recently published reviews, combining observations in humans and animal models of ageing, have reported the current evidence for age-related changes in the vestibular system and their importance to clinicians treating balance disorders ,37.Like the peripheral vestibular system, the central vestibular system displays a remarkable capacity for self-repair. Vestibular compensation, a model of post-injury plasticity in the central nervous system, refers to a set of endogenous mechanisms of neuroplasticity, which are well described in the vestibular nuclei, in response to damage to the peripheral vestibular system and underlying functional restoration. In the course of ageing, this ‘homeostatic’ plasticity, although still present, diminishes and is accompanied by sensorimotor and cognitive disturbances. Independently of age, vestibular compensation can be improved by pharmacological therapy and by physical rehabilitation based on the strengthening of other sensory modalities, such as vision or proprioception, and of cognitive and motor components. In the following paragraphs, we first describe the neurobiological mechanisms of vestibular compensation and then discuss the impact of ageing on this adaptive plasticity.Following its encoding in the inner ear vestibular sensory organs, the vestibular sensory information travels along the vestibular nerve  to a first central integration relay, the brainstem complex of the four vestibular nuclei , which transforms it into pre-motor, vegetative, perceptual and cognitive information . NeuronsUnilateral damage to the vestibular sensors induces a characteristic acute vestibular syndrome in various species, including humans. This syndrome is the result of the alteration in the vestibulo-spinal, vestibulo-oculomotor and vestibulo-vegetative reflexes, as well as the alteration in vestibulo-cortical signals ,43. It cIn most species, post-injury vestibular syndrome includes static deficits (present when the body is not moving) and dynamic deficits (present during displacements). Static deficits include oculomotor (spontaneous nystagmus) and postural  alterations, which are compensated for within a few days or weeks. Dynamic deficits , on the other hand, are compensated much less completely and over a longer period of time ,48.The vestibular compensation process involves neurochemical, hormonal, structural, metabolic and electrophysiological reorganizations within the vestibular nuclei disconnected from their peripheral sensors. During vestibular compensation, the loss of information from the vestibular sensory organs leads to a reweighting (or sensory substitution) of the different sensory channels  in order to maintain the balance function ,50.Brain ageing is characterized by several neurochemical changes involving structural proteins, energy metabolism, neurotransmitters, and neuropeptides and their receptors . Age-relLike sensory modalities, the motor component, represented by the musculoskeletal system, plays a key role in the maintenance of balance in both young and older adults. However, this system is also altered by ageing. The age-related loss of muscle function involves quantitative and qualitative changes in skeletal muscle structure and function. This process is generally slow, and the loss of function varies considerably from one individual to another, but it occurs in all individuals, even those who are healthy, well-nourished and physically active. The decrease in muscle mass and the accompanying loss of function is referred to as sarcopenia. It is one of the most apparent changes in the aging process . Given tThe data regarding neuronal density in the vestibular nuclei during ageing are rather controversial. Neuronal losses have been observed in the vestibular nuclei complex in humans ,55,56,57Johnson and Miquel  analysedThe apparent discrepancies between the results of different functional and structural studies in aged animals and humans suggest considerable variability in the effects of ageing on the vestibular system. In addition to a probable interspecies difference, it is likely that much of the variability within a species is due to genetic and epigenetic differences influencing the adaptive plasticity of the ageing vestibular system.It is reasonable to assume that age-related alterations in vestibular function result in part from neurochemical changes in the neural circuitry involved. To date, most studies in aged animals have been limited to the brainstem vestibular nuclei. The vestibular nuclei are connected in a network of several nerve structures, allowing them to receive and integrate information from different sensory modalities for transmission to other structures. These axons, which converge on the vestibular nuclei, release a wide variety of neurotransmitters. The main afferents to the vestibular nuclei come from the vestibular primary neurons, whose neurotransmitter is glutamate. Neurons in the vestibular nuclei also receive glutamatergic afferents from the spinal cord, GABAergic afferents from the cerebellum and contralateral vestibular nuclei via the commissural system, dopaminergic afferents from the midbrain nuclei, serotoninergic afferents from the raphe nuclei, and histaminergic afferents exclusively from the tuberomammillary nuclei of the hypothalamus. Glutamate and GABA are neurotransmitters associated with the excitation and inhibition of neurons in the central nervous system, respectively. They function in synchrony to maintain an excitation/inhibition balance . Vestibular neuronal networks function predominantly with these two neurotransmitters. The electrophysiological responses of medial vestibular nucleus neurons to NMDA (N-methyl-D-aspartate), AMPA (aminomethylphosphonic acid) and kainate (agonists of the three types of ionotropic glutamate receptors), recorded in vitro on brainstem slices, are similar in young (3 months) and old (24 months) rats, suggesting that there is no change in the sensitivity of the three ionotropic glutamate receptor subtypes to their selective agonists during ageing . A compaHim et al. studied neurons in the medial vestibular nucleus of 24-month-old rats and found an increased sensitivity to the GABAa receptor agonist muscimol. They concluded that this was a compensatory response to the age-related loss of neurons in the medial vestibular nucleus . GiardinUsing brain tissue samples and the HPLC technique to measure the concentrations of norepinephrine (NA), serotonin (5-HT) and dopamine (DA), as well as their metabolites in the medial vestibular nucleus of rats aged 4, 21 and 24 months, Cransac et al. observed that NA concentrations decreased with age, while those of 5-HT and its metabolite, 5-hydroxyindoleacetic acid (5-HIAA), increased. In contrast, the levels of DA and its metabolite, 3,4-dihydroxyphenylacetic acid (DOPAC), remained unchanged . Di MaurNeurogenesis, the level of neuronal excitability, BDNF (brain-derived neurotrophic factor), inflammation players (astrocytes and microglia), stress hormones and neurochemical systems , all of which are elements of the deafferented vestibular environment important for vestibular compensation , also unOld age is characterized by increased expression levels of pro-inflammatory cytokines and decreased expression of genes whose products are anti-inflammatory, resulting in a chronic low-grade inflammatory state in the brain. In the aged brain, microglia are more active. Faced with a pro-inflammatory stimulus (such as bacteria), these cells are hyper-reactive and produce greater quantities of cytokines and over a longer period of time. This could explain the sometimes-prolonged behavioural disturbances in older adults, which may be accompanied by cognitive impairment, in the event of infection or other acute illnesses, and could also contribute to the development of age-related neurodegenerative diseases . Ageing Brain-derived neurotrophic factor (BDNF) is associated with neuronal maintenance, neuronal survival, plasticity and neurotransmitter regulation. Although its expression in the brain does not appear to be altered with age, some studies have shown a reduced ability of the older adult brain to produce this factor in response to stress . PatientThe plasticity of intrinsic neuronal excitability facilitates learning and memory processes. Reductions in intrinsic excitability, as well as aberrant plasticity and, in some cases, pathological hyperexcitability, have been associated with cognitive deficits in animal models of cognitive ageing or Alzheimer’s disease. Targeting molecular mediators that control intrinsic neuronal excitability, which would promote learning-related intrinsic neuronal plasticity, is a promising therapeutic strategy for maintaining cognitive function during ageing or in response to neurodegenerative disease .It therefore seems clear that aging alters the neurobiological plasticity mechanisms essential for restoring and maintaining vestibular function in the event of damage. Aging of vestibular function, with its consequences on the elderly’s postural instability and frequency of falls, is likely to result from an alteration in these same plasticity mechanisms within peripheral and central vestibular structures. Specifically targeting these different endogenous plasticity mechanisms through pharmacology and/or rehabilitation could thus be a promising therapeutic strategy for maintaining vestibular function during aging.This is a very poorly documented area. There are few data on the different vestibular symptoms and their evolution with age. In our laboratory, we have developed a mouse model of unilateral vestibular injury induced by excitotoxicity in order to compare the ability of young (3 months) and old (22 months) adult mice to restore their balance and posture . In thisThe mechanisms of neuroplasticity in vestibular nuclei disconnected from their peripheral afferents occur within a time window, between 3 and 30 days after unilateral vestibular nerve transection in different species. The first four weeks after unilateral peripheral vestibular injury probably represent a critical period, during which these adaptive neuroplasticity mechanisms, including vestibular neurogenesis, are activated to promote vestibular functional recovery. In support of this notion, a sensorimotor restriction applied during the first week after a unilateral vestibular nerve transection in an adult cat or monkey prevents postural recovery, whereas when applied later, this restriction no longer has an effect on their recovery ,84. The Interestingly, the molecular ingredients used by the mature deafferented vestibular environment ) for the compensation process are similar to those used in the hippocampus for the induction of the electrophysiological phenomenon of long-term potentiation, which probably represents the neurobiological substrate of learning and memory . This poThe correlation between age-related cellular and molecular damage and the posture and balance deficits observed in older adult patients, as well as in animal models of ageing, leads us to think that we have identified the mechanisms that support vestibular ageing. However, we are still far from understanding how age impacts the plasticity properties that make the vestibular system unique, such as the repair of peripheral vestibular synapses or central compensation. However, this is a challenge that must be met if we are to understand how vestibular damage in young adults governs the subsequent evolution of vestibular sensory networks. The spread and simplification of biotechnology approaches suggests that there is scope for interventions in the vestibular sphere to protect or repair sensory cells, their contacts with the fibres that form the vestibular nerve, or the central networks involved in the integration of vestibular sensory information. It is true that approaches involving neurotrophins, for example, may hold out the hope of being able to slow down the action of time on our tissues. However, any interventional action must first be based on a real understanding of the critical periods present during the development of the vestibular sensory networks, but which are also found throughout life in the repair or compensation processes in situations of vestibular damage. Methods of the clinical exploration of vestibular function will also have to evolve to allow for more precise and specific monitoring of the changes in the sensory organs and vestibular networks during ageing. These data will allow for the better targeting of preventive and therapeutic approaches.Throughout this review, we mentioned divergences between studies in animals and in humans; however, we must remember that the human body in relation to balance requires more coordination and motor control compared to animals, due to the bipedal position adopted by humans. This leads to a smaller base of support and consequently a greater intensity of muscle co-contractions to maintain a desired posture or maintain one’s posture without causing changes, pain or damage to the individual. This needs to be considered in the weighting between animal and human studies.In this review, we have chosen to shed light specifically on age-dependent alterations which affect both the vestibular sensors and central vestibular pathways. It is obvious that these age-dependent tissue damages, together with the loss of neural plasticity processes, are one of the major causes of balance and posturo-locomotor deficits. We know, however, that the efficacy and reactivity of the gate and balance processes also result from the integration of inputs from vision and proprioception and that the functional state of the vestibulo-ocular reflex and vestibulo-spinal pathways is critical for good coordination of one’s equilibrium both at rest and during displacements. The processes of body self-perception and the orientation of our body in space are also essential parameters to our interaction with our environment  and for


Evidence suggests that, during pandemics such as COVID-19, people with low incomes within developing countries suffered disproportionately. Households across countries differentially experienced the socio-economic impact of the pandemic. In sub-Saharan Africa, the extended family and the community have provided valuable support in crises, given that state-administered backing may not be sufficient or may differ from the family's expectations. Many studies have been conducted on community safety nets, yet little description and understanding of community safety nets has been provided. The components of the non-formal safety nets are yet to be adequately defined or evaluated for effectiveness. Traditional family and community safety nets have been under stress due to the impact of COVID-19. Many countries, including Kenya, have associated COVID-19 with an increased number of households facing social and economic crises. Families and communities got fatigued due to the extended period and the further strain the pandemic had on individuals and societies. Utilizing existing literature on the socio-economic impact of COVID-19 in Kenya and the roles and perceptions of community safety nets, this paper seeks to explain the roles and perceptions of social relationships and kinship networks as safety nets in Africa, specifically in the Kenyan context. This paper employs the concept of culture of relatedness to understand the informal safety nets in Kenya better. During the COVID-19 pandemic, individuals strengthened the previously weakened kinship structures. They addressed some of the challenges experienced within the networks through the involvement of neighbors and friends embracing the culture of relatedness. Therefore, government strategies for social support during pandemics need to design programs to strengthen the community safety nets that remained resilient throughout the health crisis. A policy brief by the Strategic Policy Advisory Unit  noted that the COVID-19 pandemic had had direct and indirect effects on the socio-economic levels of households. This policy brief further states that the impact of COVID-19 varies from an income earner in the family falling ill, which leads to a drop in the ratio of active members to dependents to when it is the dependents of the income earner who fall sick . DespiteThe Organization for Economic Co-operation and Development (OECD) noted that countries across the globe introduced stringent confinement measures during the pandemic . The corIn the Kenyan context, the speed and severity of the pandemic shock have been met with unprecedented levels of support, both in-depth and scope . Like otDuring the COVID-19 pandemic, the Government of Kenya helped support families through specific initiatives geared toward alleviating or reducing the shocks and stresses of the pandemic  and expressive  support . SituatiThe Kenyan community is majorly patriarchal. In the patriarchal societies in Kenya, payment of bridewealth provided space and suitable resources for children and their mothers within the kin group . The husHIV/AIDS as a pandemic prompted the need to review kinship structures and roles during that time. During the COVID-19 pandemic, individuals in Kenya suffered economically, socially, and even psychologically , who revThe policy brief by the Strategic Policy Advisory Unit   indicateOxfam  further The patriarchal society in Kenya has its kinship mainly based on blood ties. Traditionally, the Kenyan family is tasked with the provision of moral, ethical, spiritual, and cultural content to individuals . The famThe concept of the cultures of relatedness (2000) proposed by Janet Carsten examines relatedness as a broader concept of kinship, enlarging the analytical territory. It has opened the door to a general social contextualization of kinship . The conIn the book Chapter Choosing kin: Sharing and subsistence in a Greenlandic hunting community, Nuttal argues that kinship is the foundation of social relatedness and social organization . Nuttal,The kinship networks have always been helpful during pandemics such as COVID-19. The confinement measures and the hard-economic times resulting from the loss of income for most of the population meant that the family had to come in and support their kin. Though not well-described, families and kin structures could care for the sick at home when their fellow kin could not afford hospital care. Kinship structures supported family members to sustain their livelihoods by contributing to buying necessities for each other. Kin relations, neighborhood, and community structures were further strengthened and provided support and care for its members despite the negative impact of the pandemic. However, the long duration of the COVID-19 pandemic caused emotional, social, physical, and financial fatigue in families forcing individuals to forge new relations outside the family and the kin structure. Individuals reach out to friends and neighbors who are not related to them by blood but through social relations to get social support, given the insufficiency of the government's social support. Therefore, the shift occurred from kinship networks to cultures of relatedness and eventually social relatedness toward supporting each other during the COVID-19 pandemic.As a result of COVID-19, its long duration had significant social and economic stresses and strain in the Kenyan context. The Government alone could, however, not addresses these challenges. The kinship networks comprising family and close family friends helped to relieve individuals of the socio-economic challenges caused by COVID-19. There is a saying in Kenya that kinship relationships due to marriage are always complimented through friendship. There is a need to contextualize the various social support networks provided by family and kin relationships. During the pandemic, the support networks extended to neighbors and all social networks created by individuals apart from their families. The aspect of context is vital, given the dynamism experienced within the family and kinship system today. The changes in family and kin relations structure, coupled with the long duration of the pandemic, affected the levels of support. Therefore, further studies can be conducted within different contexts, especially where there have been drastic changes in the family structure and how these changes have affected social support during a pandemic.This paper can indeed help advise policy on social protection systems in Kenya. However, it is limited in its methodological approach, given that the current study did not engage in fieldwork to describe the kinship structure, its roles, and kin perception. However, given the socio-economic challenges families experienced during the pandemic, it was necessary to note that the kin structures were strengthened and further expanded outside the biological kin.It would be interesting for researchers to conduct a field study exploring the change of structures within the kinship networks in the wake of COVID-19 within the Kenyan context, given that kinship is socio-culturally constructed and maintained rather than based on genealogy.There is a need to examine the structural dynamics within kinship networks significantly and how they have impacted the provision of safety nets among the different members of society.The disruption and weakening of the non-formal intergenerational transfers have had a different picture during the COVID-19 pandemic. Kin relations, neighborliness, and community structures were strengthened further during COVID-19. This was evident through providing support and care for family members independently despite the pandemic's negative impact on individuals' lives. Therefore, in designing social protection programs to mitigate the socio-economic consequences of pandemics such as COVID-19, policymakers need to create programs that consider building socio-economic resources of households and strengthening community safety nets.During a crisis, Governments help individuals through monetary transfers, material support, and services other community members offer . These kAN conceptualized and designed the final manuscript. This paper is part of the author's work at the African Research Universities Alliance conference in 2021.