Abnormal activation of human endogenous retroviruses (HERVs) has been associated with several diseases such as cancer, autoimmunity, and neurological disorders. In particular, in cancer HERV activity and expression have been specifically associated with tumor aggressiveness and patient outcomes. Cancer cell aggressiveness is intimately linked to the acquisition of peculiar plasticity and heterogeneity based on cell stemness features, as well as on the crosstalk between cancer cells and the microenvironment. The latter is a driving factor in the acquisition of aggressive phenotypes, associated with metastasis and resistance to conventional cancer therapies. Remarkably, in different cell types and stages of development, HERV expression is mainly regulated by epigenetic mechanisms and is subjected to a very precise temporal and spatial regulation according to the surrounding microenvironment. Focusing on our research experience with HERV-K involvement in the aggressiveness and plasticity of melanoma cells, this perspective aims to highlight the role of HERV-K in the crosstalk between cancer cells and the tumor microenvironment. The implications for a combination therapy targeted at HERVs with standard approaches are discussed. Human endogenous retroviruses are replication-defective proviruses comprising a portion of human genome (∼8%). HERVs are recognized as having a role in health maintenance  and compIn the last few decades, many studies have highlighted the involvement of HERVs in complex diseases, such as cancer, autoimmunity and neurological disorders . AlthougThe ability of tumors to adapt to microenvironmental changes is embedded in their plasticity. Moreover, on the basis of the genetic predisposition, both differentiated and stem cells are driven toward transformation by the epigenetic pressure of the tumor niche and the microenvironmental changes .An overview of the knowledge on HERVs related to tumors, in light of our experience in melanoma, is provided in order to achieve new insights into the contribution of HERV-K to the crosstalk between cancer cells and the tumor microenvironment. In addition, we suggest future perspectives on their potential therapeutic uses.Several mechanisms by which HERVs could produce pathological effects have been proposed, including generation of new variants of HERVs, insertional mutagenesis, and protein toxicity . In thisSeveral studies suggested that the aberrant activation of HERVs promotes tumorigenesis through oncogenic mechanisms, such as: (1) insertional mutagenesis with inactivation of tumor suppressor genes ; (2) actpol and env boundary, HML-2 produces the protein Env (single spliced) and accessory proteins Np9 and Rec (double spliced)  . Their ispliced) . HERV-K spliced) . Interesspliced) . Accordispliced) .Stem cells have self-renewal capacity and give rise to progeny capable of differentiating into diverse cell types. The transcription factors OCT4, SOX2, and NANOG have fundamental roles in maintaining the pluripotency and stemness features of hESCs and contribute to the reprogramming of adult somatic cells into iPSCs . Recent Possessing stemness features is crucial for cancer progression and metastasis. The generation of subpopulations with stemness features determines cancer self-renewal, proliferation and differentiation, allowing immune evasion and acquisition of resistance to therapy. These subpopulations, called CSCs, give rise to heterogeneous cell populations and maintain an undifferentiated state that equips them with the plasticity required to survive environmental stress .The role of HERVs in stemness and the acquisition of cancer stemness are linked by a complex crosstalk of cellular signals, in which microenvironmental changes play a significant role .Several studies suggest that the tumorigenesis is determined by genetic alterations, which contribute to transformation, as well as by external factors present in the cancer microenvironment. The microenvironment is therefore considered a part of the tumor that constantly changes in parallel with cancer progression, as a result of bidirectional interactions between tumor cells and cellular and molecular components of their “niche” . These iCellular plasticity is fundamental for tumor progression and metastasis, to adapt to changes in the microenvironment . AggressSeveral studies from our and other groups demonstrated that HERV-K (HML-2), has a potential aggravating role in malignant melanoma and in immune escape during metastasis . Since HFigure 1). This has supplied a model to study the crosstalk between HERVs and cancer cells in a changing microenvironment. The TVM-A12 cellular monolayer is characterized by the presence of cells with different morphologies including small ovoid, spindle polygonal and large dendritic forms. Notably, the multiple morphology with melanin production persisted after years of continued passage in culture. When grown in different media, despite changing the morphology and functional characteristics, TVM-A12 retain the ability to restore the original phenotype if standard conditions are re-established. Peculiarly, when cultured in specific media that promote differentiation, TVM-A12 cells show specific phenotypes of melanogenic, adipogenic, and osteogenic lineages (unpublished data) . This morphological transition correlated with the change of culture media, without committing to terminal differentiation, has been previously described and is considered a hallmark of stemness in melanoma cells . A major event for the generation of metastatic tumor cells is the inhibition of anoikis, the programmed cell death pathway induced by loss of integrin-mediated cell matrix interactions, revealed in vitro by the ability of cells to grow in an anchorage-independent manner , a recognized protocol for inducing microenvironmental stress conditions t manner . In the Figure 1). Grapes are characterized by increased expression of CSCs markers (CD133 and nestin), loss of expression of immune recognition molecules  and an increase in melanoma progression and metastasis associated markers (CD10 and CXCR4). This phenotype switch is accompanied by an increased expression of HERV-K, and the link to microenvironmental changes is confirmed by a strong down-regulation of HERV-K expression when cells are returned to media containing serum . Once again confirming its important role, the silencing of HERV-K in TVM-A12 leads to a reduction in Grapes formation and an induction of cell death.When switching to a serum free medium, such as X-VIVO , TVM-A12 generated non-adherent dark cellular aggregates called Grapes, with a low growth rate . Cancer progression is accompanied by metabolic alterations and epigenetic reprogramming. The tumor microenvironment, poor in nutrients and oxygen, is responsible for the metabolic switch observed in cancer cells. The accumulation of glycolysis metabolic products, such as lactate, induces local immune suppression, which facilitates tumor progression and metastasis . The enhancement of patient’s immune response plays a key role in the treatment of cancer. Indeed, in the field of cancer immunotherapy, progress has been made in the development of new technologies aimed at boosting the immune system, such as monoclonal antibodies and engineered CAR-T against tumor antigens (in vitro and in vivo mouse models (The eradication of tumors and prevention of recurrences are current challenges in cancer therapy. Thus, starting from conventional cancer treatments, including chemotherapy, radiotherapy and surgery, new combination approaches are needed. In this view, we consider HERV-K targeting as a strategy to improve response to therapy (antigens . Actuallantigens . Targetee models . Moreovee models , studiese models .Another approach is the identification of the microenvironmental factors and the corresponding signal transduction pathways that are responsible for transdifferentiation of cancer cells. These could be potential targets for a new therapeutic approach for cancer reprogramming into a differentiated state, with a decrease or even loss of cancer stemness features and malignancy . One proHistone deacetylate inhibitors are currently used in the clinical setting as anticancer agents that alter the regulation of histone proteins. HDACi can modify the acetylation status of histones, resulting in the induction of cell cycle arrest, apoptosis or differentiation . HDACi pIn a broader context, our group and other authors had already suggested intervening on the activity of retroelements with antiretroviral drugs , which nIn this scenario, the responsiveness to external stimuli of HERVs attributes to these genetic elements a high relevance in the crosstalk between tumor and microenvironment. Based on our experience we have demonstrated that HERV-K is fundamental in the acquisition of stemness features and aggressiveness under the pressure of the microenvironment. Following the path indicated by our results on melanoma cells, we aim to widen the scope and depth of our knowledge of HERV-K in cancer plasticity, by exploring other cancer types and by deciphering the molecular pathways underlying the responsiveness of HERV-K to the microenvironment. We believe that future combination therapies able to target HERV-K and other retroelements will become indispensable weapons in a wider arsenal for fighting cancers. Therefore, we propose that expanding the range of therapeutic options will allow defining personalized combination therapies in the future.All authors listed have made substantial, direct and intellectual contributions to this perspective, revised and approved the final version of the manuscript 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.


That progress has resulted in the development of an integrated,multidisciplinary approach to patients and the advancement of many medical specialties,radiology in particular. Imaging examinations have revolutionized the diagnosis andfollow-up of cancer, facilitating its detection, staging, monitoring, andtreatment. However, inappropriate and unplanned excisions ofmalignant bone tumors are due to insufficient imaging or incorrect diagnosticinterpretations. Therefore, in the initial evaluation of such tumors, the radiologistshould communicate any suspicion of malignant potential or local aggressiveness, inorder to inform the therapeutic decision-making process(3).The ability of a radiologist to make an immediate distinction between benign andmalignant bone tumors, through imaging, can guarantee an appropriate approach byqualified specialists at referral centers, ensuring excellence in the treatment of theaffected patients(4).Among the malignant bone tumors with the highest incidence in individuals ≤ 20years of age, the most notable are osteosarcoma and Ewing’s sarcoma, the manifestationsof which vary depending on the geographic origin and ethnicity of the individual inquestion. The initial challenge for the radiologist is to make an accurate diagnosis ofsuch tumors, which has a direct impact on the treatment and survival of the affectedpatients. The first step in the imaging investigation is conventional X-ray, which canbe followed by examinations of greater complexity, such as computed tomography andmagnetic resonance imaging, which have the capacity to evaluate different tissues and toobtain multiplanar images(5).The development of a cognitive map for the detection of solitary bone tumors in childhoodwould become an essential part of clinical practice, as a complement to diagnosticimaging, allowing the correct strategic interpretation of the diagnoses made, withlittle error variance. It would be possible to create an application to supportprofessionals in the area, globally, reducing iatrogenic errors and minimizing thenumber of inaccurate diagnoses, as well as the negative consequencesthereofThe development of cognitive maps and the corresponding applications has been growing.That has been achieved through the use of artificial intelligence (AI), which employscomputing power in the attempt to reproduce human abilities and skills in the realm ofthinking and problem solving, combining scientific, mathematical, and probabilisticdata.Recent, application-mediated, digital solutions developed by AI research groups, such asBabylon Health in the United Kingdom, are widely accessible and are being usedefficiently. Those systems promote quality health care by providing features such asspeech recognition in the form of chat bots, aiding in the prevention and diagnosis ofdiseases.Various research centers specializing in AI have developed training algorithms forspecific demands adapted to the reality of each diagnostic area, as well as decisiontrees, such as those for skin cancer detection (mainly melanoma) and the evaluation ofdiabetic retinopathy-both of which have had a high level of success in comparison withthat of trained physicians. In addition, the development of facial recognition softwarehas the potential to facilitate the diagnosis of rare genetic diseases, which often gounderdiagnosed due to a lack of knowledge on the part of physicians.(6).The diagnostic ability developed by state-of-the-art computers from a specific database,together with logical human reasoning, brings enormous efficiency to medical practiceand has a major financial impact. The optimistic view of the applicability of AI in themedical field is that it will enhance, rather than replace, human performance, combiningthe benefit of creative innovation with the replication of an appropriate formula. Incontrast, fear and insecurity about AI replacing physicians in several areas remains anunknown factor in the evaluation of this new paradigmTechnological advances, at the organizational or individual level, are virtuallyguaranteed in the near future. However, it should be borne in mind that face-to-facephysician-patient interaction will continue to be essential in the diagnostic andtherapeutic approach, as will the involvement of multidisciplinary teams includingpsychologists and physiotherapists, in order to ensure the well-being and maintain thehealth status of patients and their families in different areas of medicine. Therefore,it is necessary to prioritize a model of affective and emotional care based primarily onhuman relationships.


The current review summarizes recent development in the pathogenesis of preeclampsia with special focus on novel diagnostic biomarkers and their relevance to potential therapeutic options for this disease state. Specifically, the review highlights the renal manifestations of the disease with emphasis on the involvement of angiogenic factors in vascular injury and on how restoration of the angiogenic balance affects renal and cardiovascular outcome of Preeclamptic women.Preeclampsia is a serious complication of pregnancy where it affects 5–8% of all pregnancies. It increases the morbidity and mortality of both the fetus and pregnant woman, especially in developing countries. It deleteriously affects several vital organs, including the kidneys, liver, brain, and lung. Although, the pathogenesis of preeclampsia has not yet been fully understood, growing evidence suggests that aberrations in the angiogenic factors levels and coagulopathy are responsible for the clinical manifestations of the disease. The common nominator of tissue damage of all these target organs is endothelial injury, which impedes their normal function. At the renal level, glomerular endothelial injury leads to the development of maternal proteinuria. Actually, peripheral vasoconstriction secondary to maternal systemic inflammation and endothelial cell activation is sufficient for the development of preeclampsia-induced hypertension. Similarly, preeclampsia can cause hepatic and neurologic dysfunction due to vascular damage and/or hypertension. Obviously, preeclampsia adversely affects various organs, however it is not yet clear whether pre-eclampsia  Table 1). Concerning the latter, preeclampsia may cause intra-uterine fetal growth restriction (IUGR), placental abruption, preterm delivery and associated complications including, neonatal respiratory distress syndrome, cerebral palsy, necrotizing enterocolitis retinopathy of prematurity and even perinatal death  is a profound complication of pregnancy, where it affects 3–8% of all pregnancies and dramatically increases the risk of all-cause mortality, especially in women who experienced early, severe, preterm episode . PreeclaTable 1; . Besidesde novo hypertension, new onset of proteinuria and liver dysfunction after mid pregnancy, motivated by the discovery of additional biomarkers of preeclampsia . In order to achieve spiral remodeling during normal pregnancy, many molecules including vasoactive substances, growth factors, adhesion molecules and proteases are secreted by the placenta and the vasculature    and VEGFR-2 coupled to endothelial nitric oxide synthase (eNOS) required for angiogenesis ( (HIF-1) . Support (HIF-1) . At the  (HIF-1) .In clinical setting, sFlt-1 levels were found to be elevated as early as 5 weeks before the diagnosis of preeclampsia and directly correlate with disease severity . FurtherFigure 3; Endoglin (ENG) is a type I membrane glycoprotein localized to the cell membrane where it constitutes the transmembrane co-receptor for TGF beta receptor complex (TGF-β1 and TGF-β3) . ENG is One of the major features of preeclampsia is generalized vasoconstriction and reduced plasma volume, assumedly due to endothelial activation even weeks before clear evidence of the disease . EndotheFinally, HO-1 plays an anti-inflammatory and inhibitory role on sFlt-1 and sEng release via its metabolite carbon monoxide (CO) . In linede novo hypertension and new onset of proteinuria after mid pregnancy  as early as the first 4 weeks of pregnancy . The colFigure 4; Figure 4). In this context podocyturia (loss of podocytes in the urine), along shedding of slit diaphragm proteins such as nephrin, podocin, synaptopodin and podocalyxin were noticed in preeclampsia, and even precede the typical clinical features of preeclampsia by several weeks  accompanied by new onset proteinuria (>300 mg/d) or worsening proteinuria diagnosed after 20 weeks of pregnancy and generalized edema. The latter is mainly due to primary renal retention of salt and water despite the suppression of RAAS during preeclampsia due to vasoconstriction, in contrast to its upregulation in normal pregnancy, which is characterized by vasodilation . Thus, t+ diet, diuretics, Ca++ supplementation, Vitamin C and E were ineffective in most cases  . Since 3Although, experimental studies in animal models of preeclampsia have shown that endothelin receptor blockers prevent the development of the disease , clinicaPreeclampsia is a multifactorial clinical state that adversely affects almost all vital organs of pregnant women. After a half century of stumbling in understanding the molecular basis of the disease, the last decade has witnessed great advancement in the research of preeclampsia as evident by the discovery of wide battery of novel biomarkers that allow early diagnosis of the disease and prediction of the outcome.In early-onset, pre-eclampsia there is clear evidence of reduced maternal spiral artery conversion in early pregnancy due to deficient trophoblast invasion and arterial remodeling, resulting in aberrant maternal–fetal interactions during early pregnancy and placental malperfusion. Oxidative stress of the placenta causes the increased secretion of sFLT-1 and reduced PlGF, and so explains the biomarker patterns. The abnormal angiogenic ratios are subsequent to the impaired placentation, and not the cause of it, as there is no evidence that sFLT affects trophoblast invasion. In contrast, in late-onset pre-eclampsia there is slight reduction in arterial conversion and the placental perfusion is maintained or even increased. Therefore, there is only minimal placental stress and sFLT and PLGF secretion by the placenta are close to normal range. These cases, which represent the overwhelming majority of pre-eclampsia, are now thought to be due to a genetic maternal pre-disposition to cardiovascular disease, which manifests as pre-eclampsia in response to pregnancy-induced stress.Thus, sFlt-1 and sEng do not serve solely as biomarkers, rather they are responsible for the angiogenic imbalance and generalized endothelial dysfunction characterizing preeclampsia. The new insights into the pathogenesis of this clinical condition will provide great opportunity to improve the care of preeclamptic women before delivery and undoubtedly will lead 1 day to the development of novel strategies for prevention and treatment of the disease. Pipeline clinical trials based on elimination of serum sFlt-1 by means of apheresis yielded promising results indicating that the remedy for this prevalent dangerous entity is within reach .ZA writing the section that deals with the renal aspect of preeclampsia and organizing all sections. JJ writing the introduction and organizing the MS. AJ writing the biochemical biomarkers of preeclampsia. ZAA writing the vascular aspects of preeclampsia and the molecular base underlying the pathogenesis of the diseases, editing the whole MS.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.


AGER, the gene encoding RAGE, expression and on alternative splicing of AGER. To this end, we conducted RNA-Seq on bronchial biopsies for asymptomatic smokers (n = 36) and never smokers (n = 40). Total AGER gene expression was accessed using DESeq2, while alternative splicing was investigated by measuring the number of specific split reads spanning exon-exon junctions and the total split reads. One of the major isoforms of RAGE is endogenous soluble (es) RAGE, an anti-inflammatory decoy receptor, making up for approximately 10% of the total amount of soluble (s)RAGE. We found that smokers show decreased total gene expression of AGER in bronchial biopsies, while the relative abundance of the esRAGE isoform is increased. Furthermore, no difference in the serum levels of total sRAGE were observed between smokers and non-smokers. Our data indicates that smoking initiates a protective anti-inflammatory mechanism with decreased expression of the pro-inflammatory gene AGER and increased relative abundance of the anti-inflammatory isoform esRAGE.Cigarette smoking is one of the major risk factors for the development of chronic obstructive pulmonary disease (COPD). Evidence is accumulating that Receptor for Advanced Glycation-End products (RAGE)-signaling is a key pathway in the pathophysiology of COPD. To date, it is unknown how smoking affects RAGE expression. In the current study, we investigated the effect of smoking on  AGER, is spliced out, resulting in the endogenous soluble form of RAGE (esRAGE), which passes the cell membrane and is released into the extracellular space upon translation.To date, cigarette smoking is one of the biggest public health threats worldwide, being causative for the dead of approximately 7 million people every year, according to the World Health Organization (WHO). Smoking can lead to multiple diseases, including cardiovascular diseases, lung cancer and chronic obstructive pulmonary disease (COPD). The underlying mechanisms of these diseases are still largely unknown. However, there seems to be one molecular pathway which connects the three diseases, the receptor for advanced glycation end-products (RAGE) signaling pathway. RAGE is a pro-inflammatory pattern recognition receptor, which is mainly expressed by type I alveolar cells. The freely circulating soluble form of RAGE (sRAGE), inhibits RAGE signaling by binding RAGE ligands and preventing homo-dimerization of RAGE, necessary for activation. sRAGE can be formed by proteolytic cleavage or by alternative splicing. In the latter case the transmembrane domain, encoded by exon 10 of the gene encoding RAGE, AGER in lung tissue of smokers and never smokers and subsequently evaluated the level of alternative splicing in these individuals. Alternative splicing was measured using a novel, in house developed technique, based on comparing the number of specific split reads spanning exon-exon junctions to the total split reads per gene.In cardiovascular diseases it has been shown that RAGE signaling triggers and maintains the inflammatory state, and sRAGE can be used as a biomarker for the development of cardiovascular diseases , while iClinicalTrials.gov Identifier: NCT00848406) [AGER and analyzed using the R-package DESeq2. Feature counts were set as the dependent variable, smoking status was investigated correcting for age and gender. The splice site usage was quantified by counting split reads mapping across exon-exon junctions using a custom perl script (available upon request). We processed BAM alignment files and skipped reads marked as PCR duplicates. For each intron in the alignment  we recorded the chromosome and first and last intron base. Afterwards, we quantified the number of reads for all observed intron positions across alignment files from all samples.Here, we used bronchial biopsies from 37 active smokers and 40 never smokers without airway obstruction, which were matched based on age, sex, body mass index and lung function (0848406) . ClinicaAGER expression in smokers compared to never smokers . To investigate whether smoking affects the expression of endogenous soluble RAGE (esRAGE), all splicing events within the AGER gene were measured. We were able to detect all annotated intron splicing sites, an extension of exon 4 and the splicing of exon 10 which leads to the production of esRAGE . Thus, the total expression of AGER is decreased in bronchial tissue of smokers, whereas the fraction of RAGE which leads to esRAGE is increased.Here, we showed a significant decrease of total AGER were detected on mRNA level in in vitro cultured human cells [AGER in human bronchial biopsies. Here, we were able to detect two alternative splice variants of RAGE, an elongation of the fourth exon and the splicing out of exon 10. Our study is the first to show differences in alternative splicing of AGER in smokers and never smokers. Here, it was shown that the expression of the pro-inflammatory RAGE receptor decreases and the relative portion of AGER expression which leads to the production of the anti-inflammatory decoy receptor esRAGE, increases. This suggests an anti-inflammatory mechanism to protect against an exaggerated immune reaction upon smoke exposure. Dysregulation of these anti-inflammatory mechanisms may trigger smoke-related diseases, including cardiovascular diseases, lung cancer and COPD. However, in the current population we also found that CD8+ T-cells were increased in current smokers compared to never-smokers (data not shown), as low levels of AGER expression have been observed in CD8+ T-cells before, we cannot exclude the possibility of enhanced splicing of the transcript that leads to esRAGE in CD8+ T-cells, influencing our results.While studies on the effect of smoking on RAGE expression are limited, in vitro and murine studies have shown that exposure of lung epithelial cells to cigarette smoke extract or mice to cigarette smoke increased the expression of RAGE . Moreovean cells . In the AGER gene in relation to the total AGER gene expression. Here, we showed that although smokers have lowered total AGER expression, the portion of AGER, which leads to the production of the anti-inflammatory esRAGE protein is increased. Our study provides new insight in the molecular mechanisms of the human body to protect against the harmful effects of cigarette smoking. Upon dysregulation of these processes the susceptibility for smoke-induced diseases may increase and restoring the balance in the RAGE pathway may be utilized as potential therapeutic target in several smoke-related pathologies.In summary, this is the first study investigating the expression of all splice sites within the


The stressotope may constitute a blueprint of embedded interactions between stress-related variations in cell states, molecular mediators and systemic networks, a map of circuits that reflect the inherited and acquired stress responses in an ever-changing, microorganismal-loaded medium. Several features of the proposed model are discussed as a starting point to pin down the maximum common stress responses across immune-neuroendocrine relevant physiological levels and scenarios, including the characterization of behavioral responses, in fish.In the last decade, the concept of animal stress has been stressed thin to accommodate the effects of short-term changes in cell and tissue physiology, major behavioral syndromes in individuals and ecological disturbances in populations. Seyle's definition of stress as “the nonspecific (common) result of any demand upon the body” now encompasses homeostasis in a broader sense, including all the hierarchical levels in a networked biological system. The heterogeneity of stress responses thus varies within individuals, and stressors become multimodal in terms of typology, source and effects, as well as the responses that each individual elicits to cope with the disturbance. In fish, the time course of changes after stress strongly depends on several factors, including the stressful experiences in early life, the vertical transmission of stressful-prone phenotypes, the degree of individual phenotypic plasticity, the robustness and variety of the epigenetic network related to environmentally induced changes, and the intrinsic behavioral responses  of each individual. The hierarchical heterogeneity of stress responses demands a code that may decrypt and simplify the analysis of both proximate and evolutionary causes of a particular stress phenotype. We propose an analytical framework, the  This diversity impedes a unified and common description of stress-related effects of environmental insults in fish, and, in consequence, is understandably overlooked in comparative interspecies analyses of stress physiology. Often, the physiological effects of stressors are treated as species-specific features of the chosen animal, but not always expressly acknowledged as such. Therefore, in the literature, the uncovered stress-related feature of a single or few species becomes, misleadingly, a prominent characteristic of content-rich interactions between stress-related gene expression and phenotype turnover across the life stories of each species. Consequently, the high diversity of teleost lifestyles enriches the physiological analysis of stress effects in fish, but also flaws a unified description of common responses to stress. To overcome this dilemma, the analysis of pan-specific common predictors of stress-related responses should be entrusted to the accurate selection of more explanatory variables. For example, when analyzing the effects of high or low temperatures on physiological performance in ectothermic species, choosing species-specific optimal temperature limits (thermopreferundum) as baseline values allows for comparing the effects of common stressors  vs. maladaptive (distressed) pathways of stress responses. The same applies for the comparative inter-species analysis of immune responses to stressors in adult fish, where we should consider specifically the maturation of primary and secondary immune organs rather than the relative size of fishes. The microorganism load may substantially differ between marine and freshwater realms, but both environments share the deleterious effects of the communities of resilient low-abundance pathogens . This approach would reduce the complexity of species-specific stress analysis to a set of common descriptors, endogenous and exogenous, of such responses. Here, we define a teleost “stressotope” as an adaptive scenario dominated by common environmental selective pressures that elicit common multilevel severe stress-induced responses and produce a measurable allostatic load in the organism.Considering the complex influences between environmental stressors and pathogen communities, in this short review we propose a modified biotope concept  for analDefining the components and dynamics of a stressotope may help to reframe the variability of interspecific stress responses in teleosts in terms of the cross-linked interactions between niche characteristics, diverse genomic scaffoldings and phenotypic specificities that define a set of common, multilevel stress responses in fish. Several endogenous and exogenous features that may be relevant to modeling stressotopes are presented below as a starting point, by no means exhaustive, to discuss the value of this ecophysiological approach to analyze the commonalities to stress responses.homeostasis) of the organism. A myriad of mechanisms available to face the impact of stressors will be selected or modulated depending on many factors: the species itself, the environmental conditions, and chiefly, the intensity, duration and predictability of the stressor. Therefore, an important part of the machinery behind the stress response is the same that is engaged after other stimuli that are not considered stressors, such as reproductive changes, exercise, immune stimulants, feeding, light-dark transitions or the presence of conspecifics or enrichment objects. That is why it is also difficult to make a definition of the stress concept with precision.Although some definitions and general considerations on the stress concept involve the idea of an altered status and physiological exceptionality, it is also true that coping with stressors, the stress course, and the response of the organism are not only a common mechanism but also a very sound and conserved response among living species. Hence, the stress responses should be considered as one of the basic and important mechanisms that are key to maintain the physiological, cellular and molecular stability (eustress and distress (Hormesis has been defined as any process in which a cell or an organism exhibits a biphasic response to exposure to increasing amounts of a specific condition (distress). Likewise, the term allostasis  axis and the hypothalamic-pituitary-interrenal (HPI) axis (The PI) axis . The SC PI) axis .By binding to glucocorticoid (GR) or mineralocorticoid (MR) receptors, cortisol regulates neuroimmunoendocrine circuitries elicits stress-induced immunosuppression and contributes to allostatic imbalances. That is why is particularly suited for stress-related surveys in natural and artificial environments and the focus of the search for common global markers of stress states in fish. However, the levels of cortisol in distressed fish and, consequently, the individual perception and physiological effects of the intensity of the stressors, are usually strongly biased for neuroendocrine and immune systems in a highly species-specific manner, which makes the prognosis of stress recovery both apparently simple and dauntingly complex . MoreoveCortisol implants may fail to act as a proxy of behavioral patterns in teleosts , 16, andBesides cortisol, other mediators of stress responses, namely major regulatory axis components , opioids and a myriad of immune cytokines have been extensively used to define commonalities in altered stress states, but the species bias remain. In the last decade the quest for commonalities of stress responses in fish has focused in peripheral structures such as the mucosae, that sense and distribute alarm signals from pathogens, parasites, bacteria, injuries, sudden changes of salinity or oxygen or the presence of chemicals in the water , 21. SkiNotwithstanding the intensity of the stressor, in fish as in other vertebrates, the onset of short-term stress mechanisms usually correlates with genome-fixed and protective adaptive responses to seasonal and predictable environmental perturbations and health insults, whereas long-term responses to stressors tend to be considered as harmful expressions of allostatic imbalances in an unpredictable or pathogen-ridden environment . This brAncient and extant biotic and abiotic dynamics of aquatic environments shaped the adaptive/essential stress responses of fish in a species-specific fashion and should be considered when defining a stressotope. Here we discuss the effects of environmental stressors from a dual perspective, including the physical heterogeneity  and the reeducation of genomic landscapes in populations placed under explicitly perceived predation risk.The term “fishes” continue to be a phylogenetic trap that encompass a loosely grouping of more than 28,600 species of ray-finned fish (Actinopterygii) and elasmobranchs, unequally distributed in freshwater  and marine  environments . The disAnoxia and osmotic changes affect teleost performance, but, being fish ectothermic and oxygen levels and saline content strongly dependent of temperature, thermal conditions largely define the boundaries of stressotopes. In fish, a sudden drop in temperature diminishes the production of immune cellular and molecular resources, impairs T cell-dependent immune responses and may led to cellular inactivation or anergy –42. HighFundulus heteroclitus) in polluted estuaries (ahr) signaling pathways, cytochrome P450 1A (cyp1a), heat shock proteins (hsp70), multidrug resistance transport proteins (mrp) and estrogen receptors (esr2b). In this model of distress modulation, the environmental trade-offs defined a pattern of gene expression and the emergence of low-responders stress-tolerant populations, but the fitness costs depended on specific particularities of newly adapted phenotypes. This suggests that the physiological costs of evolving tolerances to specific stressors strongly depend on the population and individual fitness in a particular niche. In other words, in diversified population assemblages, well-characterized and common stress phenotypes expressed from stress-related genetic markers may quickly reverse in a population-specific manner, hindering the definition of a set of common stress genes. Moreover, the expression of gene regulatory networks observed in different populations of killifish was complex enough to preclude a one-to-one relationship between clusters of expressed genes and adaptive features of observed fish phenotypes  in each environment. Several model species, such as trout, zebrafish or carps inhabit freshwater niches and may endure unexpected selective pressures due to the limitations of toxic drainages, xenobiotic clearance or dissolved oxygen-consuming autotrophic blooms, common to lentic environments. Under these conditions a high turnover of species richness, together with accelerated evolution of stress-related homeostatic mechanisms is to be expected. For example, in fast-growing short-lived killifish species, the exposome, defined as an adding-up response to a lifetime expositions to environmental insults  correlatstuaries . In thisenotypes , 52, shaperceived anticipatory stress, acute or not, resulting from continuous predation risk. Laundré's “Landscape of Fear” (LoF) defines this perceived stress considering the risks of foraging in unsafety habitats (Oncorhynchus. mykiss) and its prey, (Daphnia pulex) in a salinized environment coupled with alarm kairomones, osmotic stress diminished the predatory pressure and favored prey abundance, whereas alarm cues reduced trout aggression  influenced by stress. In the quest for rationalize and simplify stress responses across species, an even more applied definition of stress may help : perceivhabitats . Predatihabitats , 56. Howhabitats –59 and jhabitats . In a higression . The effO. kisutch) prefer spawning habitats that greatly reduce their survival (Pomacentrus amboinensis) reducing their antipredator responses  environmental anoxia stress during development and diapausa stages (Gadus morhua) also has a surprisingly high number of major histocompatibility complex (MHC) I genes that supply the absence of MHC II components, thus maintaining functional antigen trapping and processing pathways during the onset of immune responses , xenobiotic exposure modified methylation patterns during embryogenesis (Gasterosteus aculeatus) offspring of stressed mothers has been ascribed also to epigenetic changes , a marine species, and rainbow trout (Oncorhynchus mykiss), a freshwater teleost, being the former more responsive to stressors. The stress- and immune-related transcripts tested , together with the analysis of mucosal- and plasmatic-derived cortisol levels constitute a typical set of markers of distressed states that may help to define a minimum common set of gene-driven responses to stressors in teleosts.Teleost inhabit a stress-prone scenario that favors the evolution of highly reactive immunological surfaces, such as fish mucosal skin, gills, or gut, infiltrated by mucosa-associated lymphoid tissues (MALT), exquisitely sensitive to pathogenic or xenobiotic insults , and thaNested in the archaic roman pantheon, a two-headed figure, Janus, represent, among other things, the transition from one state to another, or from the past to the future. In both vertebrates and invertebrates, behavioral phenotypes may change during the lifetime of an individual, following a reaction norm defined by environmental changes that enhance or suppress the expression of key behavioral mediators, and constrained by the adaptability of the genome . A stresThe majority of fish follow the usual vertebrate gonochorism, with both sexes being determined genetically or environmentally . SeveralPoecilia reticulata) parasitized by Gyrodactylus spp., showed an increased responsiveness to infection in females that lead to differential evolution of resistance phenotypes  treated with cortisol showed lower responsiveness to stress and exhibit less exploratory behavior and aggression than those of non-treated females  and the cestode parasite Schistocephalus solidus  populations, the few large fertile females surrounded by many smaller males skew the sex ratio and have greater fitness measured by the number of offspring . Unexpected temperature changes may influence epigenetic regulation of breeding strategies in teleosts with ESD as described for mangrove killifishes . Similarffspring . In thisffspring , probablAnguilla anguilla), defining a limited stressotope to modulate the causes and consequences of the stepped decline in eel populations (In diadromous species, the still poorly understood and complex influence of glucocorticoids as mediators of stress responses modulates stressome structure and function. In teleosts, crossing continental and oceanic aquatic environments stresses the physiology of osmoregulation and metabolism in a complex combination of enhancing and suppressive expression of HPI, growth and thyroidal axes. A recent study embraced the joint analysis of ontogenetic stages, sexual, and parasitic effects in hypoxia-stressed European eels (ulations . Parasitulations . In thisAs discussed above, fish stressotopes harbor several opportunistic and obligate parasitic, fungal, viral, and bacterial pathogens that may transmit stress-prone phenotypes vertically, by parasite colonization of gonadal tissues, and direct cortisol effects into eggs , 132 andOverall, these and other studies imply that to accurately define a stressotope, the range of abnormal values in distress physiological adjustments, the scope of stressome components to be included in the analysis of allostatic load and the intersex differential responses to severe stressors, should necessarily be taken into account. Considering that in teleosts, as in the rest of vertebrates, steroids regulate reproductive outcomes but also metabolism, stress responses, behavior and immune function, usually in a seasonal way , 134, thWe have outlined some of the key processes and influences required to properly define a stressotope, ranging from the molecular to the ecological ones. Stress is a foreground concept defined against a background of interactions between network genome expression and phenome consolidation in a particular ecological niche. A stressotope approach that could help to elucidate common responses to diverse stressful scenarios is not only informative but also necessary to reduce the diversity of fish lifestyles to a minimum common set of telltales and indicators of allostatic loads originating from multiple and recurrent stressors. There is a growing shift in the literature of stress responses in fish toward a more integrate view of allostatic description. However, this approach is still hampered by the lack of analytical tools, peculiarities of fish genomes and the fuzzy definition of common inter-specific endpoints of distress-related physiological changes across behavioral phenotypes. Moreover, fish are considered more labile and diverse in their physiology than other vertebrates. We can describe teleosts as animals that indulge in sex changes, inhabit environments hostile to ectothermic metabolisms, grow indefinitely, modify their coping styles, or individualities in response to environmental and parasitic insults , 136, haJB and LT conceived and wrote the review and JB crafted the figures. Both authors contributed to manuscript revision, read, and approved the submitted version.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.


With a newly World Health Organization (WHO)–prequalified typhoid conjugate vaccine (TCV), Gavi funding for eligible countries, and a WHO policy recommendation for TCV use, now is the time for countries to introduce TCVs as part of an integrated typhoid control program, particularly in light of the increasing burden of antimicrobial resistance. Continued vaccine development efforts will lead to secure supply of low-cost vaccines, and ongoing vaccine studies will provide critical vaccine performance data and inform optimal deployment strategies, in both routine use and in outbreak settings. TCV programs should include thoughtful communication planning and community engagement to counter vaccine hesitancy. This is a historic moment for typhoid control. Despite continuing gaps, we now have a more refined understanding of the burden of typhoid fever, as well as improved tools available to reduce the burden dramatically. Recent multicenter surveillance studies in Africa and Asia have also improved understanding of the age and geographic distribution of typhoid, demonstrating that it is an illness that affects young children as well as school age children living in both urban and rural settings . These aSalmonella Typhi; these children would not have been protected by either the Vi-PS or Ty21a vaccine. A single intramuscular dose of TCV is recommended for primary vaccination of infants and children from 6 months of age and adults up to 45 years of age, with an option for catch-up campaigns in children up to 15 years of age [Since the first WHO recommendation in 2000 for the unconjugated Vi polysaccharide (Vi-PS) and live-attenuated Ty21a vaccines, considerable progress in vaccination as a typhoid control strategy has been realized. The updated 2018 WHO policy on typhoid vaccination includes a first-time recommendation for the routine use of TCVs, including in children <2 years of age in countries with a high burden of disease and/or high rate of antimicrobial-resistant S. Typhi [Historical precedents in many industrialized countries teach us that typhoid control is feasible through establishment and continued maintenance of water and sewage systems that ensure that food and drinking water are separated from human fecal contamination , 10. HowS. Typhi .Reducing the global burden of typhoid is a focus of both international health organizations and major global health funders. A central tenet of this focus is optimal deployment of vaccines in endemic regions, and critical to its success is sustainable, secure vaccine supply , 14, 15.While the recent prequalification of the Bharat Biotech TCV and the pipeline of TCV candidates augur well for a healthy vaccine market, there continues to be a need to understand the impact and operational feasibility of large-scale TCV deployment strategies. The TCV studies being conducted under the leadership of TyVAC will provide field efficacy data, outcomes that are made more critical by the fact that national licensure of the vaccine was based on immunogenicity data . As withS. Typhi and other invasive salmonelloses [To improve monitoring of the disease burden, the WHO recently released surveillance standards for nelloses  and reconelloses , there inelloses , and sernelloses . Once vaS. Typhi is a major factor contributing to the need for vaccine introduction and increased surveillance [Salmonella species in its list of antibiotic-resistant “priority pathogens” to guide and promote research and development of new antibiotics to address the global growth of AMR [S. Typhi isolates with resistance against chloramphenicol, ampicillin, trimethoprim-sulfamethoxazole, fluoroquinolones, and third-generation cephalosporins enhances the threat of infections with limited treatment options [S. Typhi and reduce the overall incidence of febrile illnesses, thereby reducing the need for and exposure to antibiotics.The ongoing rise of antimicrobial resistance (AMR) in eillance . The US eillance . In 2017h of AMR . The eme options . The widIncreasing global interconnectedness and the resultant growing risk of infectious disease spread across wide geographies make it imperative that new vaccines and improved surveillance are accompanied by a better understanding of local perceptions about specific vaccines and the diseases that they aim to prevent.In 2019, the WHO named “vaccine hesitancy,” as one of 10 global health threats, alongside Ebola, AMR, and climate change . Global Similar to many vaccine-preventable diseases, typhoid thrives in conditions of sociopolitical breakdown. Past conflicts have exposed refugees in multiple locations to the catastrophic impact of infected food and water sources. For example, crowding and degraded living conditions, including poor sanitation and hygiene, have contributed to typhoid outbreaks in Bosnia-Herzegovina Ivory Coast, Rwanda, Tanzania, South Sudan, North Darfur, and Syria . In mostWith the availability of improved typhoid disease burden data and low-cost TCVs, countries have a unique opportunity to implement TCVs as part of an integrated typhoid control program. Given the increasing threat of AMR, and the longer time horizon of improving water and sanitation infrastructure, TCVs are a critical tool in both immediate and long-term typhoid control efforts. Routine use of TCVs in endemic countries has considerable potential to reduce the burden of disease, and TCVs have a vital role to play in outbreak control, particularly in vulnerable populations. It is important to implement lessons learned from other vaccine introductions and to represent the full societal value of TCV programs through thoughtful advocacy and communications planning to counter vaccine hesitancy.


This article aims to demonstrate the importance of the TMJ (Temporomandibular Joint) decompression in the treatment of degenerative processes and disc displacements, reporting two clinical cases treated with orthopedic and decompressive correction of TMJ.The studies reported in this article show patients with muscle and joint pain who were evaluated pre and post-treatment through MRI (Magnetic Resonance Irradiation) to follow-up bone marrow regeneration and TMJ disc placement. Transcutaneous electrical stimulation (TENS), measurement equipment and IO  were used to evaluate and treat the patients. A critical review of literature has also been conducted to confront clinical outcomes.Marrow bone regeneration and disc placement were observed in both patients.The use of measurement equipment associated with TENS to find the correct rest position of the Jaw an the use of IO to decompress the TMJ was an effective way to promote bone marrow regeneration and disc placement, consequently improving function and quality of life. Key words:Descompression, surgical, orthotic devices, temporomandibular joint disorders, temporomandibular joint disc, occlusal splints. Changes in joint space may also be related to TMJ arthropathies, especially with disc displacements ,2. FailuThis article aims to connect the importance of decompression of the temporomandibular joint in the treatment of degenerative processes and disc displacements, reporting two clinical cases treated with orthopedic and decompressive correction of TMJ.Case 1A 67-year-old woman with complaints of facial pain and tiredness in the masseter muscles for 7 years which got worse in the last year. She reported throbbing pains, previous TMJ clicks that evolved into crepitations. The pain got worse with chewing and during crises, it expanded to bilateral temporal region and nape. The patient was edentulous and used total dentures, removable upper and implant supported lower. She underwent numerous professional interventions such as myorelaxant splints, antidepressant medications, analgesics and anti-inflammatories without significant improvement.Magnetic resonance imaging of the TMJ’s suggested bilaterally degenerative process, such as accentuated sclerosis of the right subchondral bone, osteophytes, displacement and sharpening of the articular disc and condylar repositioning. Fig. A. The joCase 2A 30-year-old woman complaining of joint pain and bilaterally clicking of both TMJ for 5 years, which got worse in the last two years. She also reported face pain when she woke up and left masseter tiredness. Chewing and speaking usually aggravated pain in the left TMJ and had louder clicks in the right TMJ. After numerous interventions such as functional orthopedics, myorelaxant splints, manual therapies, laser, acupuncture, antidepressants and various analgesics for about 2 years, the patient had not experienced any significant improvement of the condition. She also had a history of hypertension controlled with medications.The same treatment protocol was used for joint decompression orthopedic neurophysiological alignment of the mandible. Follow up showed improvements in muscle recruitment based on Learreta´s EMG test ,8. The oTransient improvements in joint symptomatology of temporomandibular disorders with the use of splint / stabilizing plaques have been well known, but little is known about the real reason for efficacy in terms of resolution of symptoms. Instead, symptomatic improvement is observed for some two to three months and then, gradual return of symptoms.It has been shown that the key treatment for the pains that involve the various joints of the body, including TMJ, is to reduce the overload and allow joint movement as soon as possible -3,9,10. Necessarily the neurophysiological response generated by the occlusal orthotic need to be evaluated. For this purpose, electromyography readings were performed as proposed by Learreta  and deteBoth cases started with neuromuscular deprogramming with orthotic devices, but the patient with medullar sclerosis and reactive arthritis was treated with antibio-tic, low dose nauxetron to improve immunity (Younger) and supplementation.All the interventions in this proposed model follow the recommendations of the literature regarding the less invasive and reversible treatment. It is up to the dentist who conducts the case, planning in a second phase after orthopedic correction of the mandible, reprograming the dental occlusion according to the established vertical dimension, without modifying the condylar positioning, so that it will be possible to perform the three-dimensional volumetric orthodontics , prostheThe decompression of the temporomandibular joint through the deprogramming of the musculature and neurophysiological orthopedic correction of the mandible presents great potential in the treatment of the degenerative processes and disc displacement of the TMJ. Clinical research controlled and evaluated by magnetic resonance imaging should be performed to confirm these findings.


To investigate the role of body mass index (BMI), systolic blood pressure, and smoking behaviour in explaining the effect of education on the risk of cardiovascular disease outcomes.Mendelian randomisation study.UK Biobank and international genome-wide association study data.Predominantly participants of European ancestry.Educational attainment, BMI, systolic blood pressure, and smoking behaviour in observational analysis, and randomly allocated genetic variants to instrument these traits in mendelian randomisation.The risk of coronary heart disease, stroke, myocardial infarction, and cardiovascular disease , and the degree to which this is mediated through BMI, systolic blood pressure, and smoking behaviour respectively.Each additional standard deviation of education (3.6 years) was associated with a 13% lower risk of coronary heart disease  in observational analysis and a 37% lower risk  in mendelian randomisation analysis. As a proportion of the total risk reduction, BMI was estimated to mediate 15%  and 18% (14% to 23%) in the observational and mendelian randomisation estimates, respectively. Corresponding estimates were 11% (9% to 13%) and 21% (15% to 27%) for systolic blood pressure and 19% (15% to 22%) and 34% (17% to 50%) for smoking behaviour. All three risk factors combined were estimated to mediate 42% (36% to 48%) and 36% (5% to 68%) of the effect of education on coronary heart disease in observational and mendelian randomisation analyses, respectively. Similar results were obtained when investigating the risk of stroke, myocardial infarction, and cardiovascular disease.BMI, systolic blood pressure, and smoking behaviour mediate a substantial proportion of the protective effect of education on the risk of cardiovascular outcomes and intervening on these would lead to reductions in cases of cardiovascular disease attributable to lower levels of education. However, more than half of the protective effect of education remains unexplained and requires further investigation. Cardiovascular disease is the leading cause of mortality worldwide, accounting for over 17 million deaths annually.blood pressure measured at one time point will suffer from measurement error due to day-to-day fluctuations and will not capture changes across the life course. This measurement error can lead to an underestimation of mediation.Existing studies suggest that body mass index (BMI), systolic blood pressure, and smoking behaviour partly explain differences in the risk of cardiovascular disease related to educational attainment.Mendelian randomisation uses genetic variants as instruments to estimate the effect of an exposure on an outcome of interest,Mendelian randomisation has previously been used to show the causal effects of education on BMI, systolic blood pressure, and smoking behaviour and also the effects of BMI and smoking behaviour on cardiovascular disease.This study used multivariable regression of observational data, one-sample mendelian randomisation of individual level genetic data, and two-sample mendelian randomisation of summary level genetic data to investigate whether BMI, systolic blood pressure, and lifetime smoking behaviour explain the protective effect of education on the risk of coronary heart disease, stroke, myocardial infarction, and cardiovascular disease .The UK Biobank recruited 503 317 British adults between 2006 and 2010. Participants attended assessment centres involving questionnaires, interviews, anthropometric, physical, and genetic measurements.The supplementary methods show the data on educational attainment , BMI, systolic blood pressure, smoking behaviour, and all covariates. A continuous lifetime measure of smoking behaviour, incorporating smoking initiation, duration, heaviness, and cessation is used in this analysis. Full details are presented elsewhere.2<0.1) genome-wide-wide significant single nucleotide polymorphisms after analysing data from the full sample.2<0.001 and distance >10 000 kb, by using a 1000 genomes European reference panel through the TwoSampleMR package (default settings of the ‘clump_data’ command) in the statistical software R.In the two-sample mendelian randomisation analysis, we obtained summary genetic associations from genome-wide association study data for each respective phenotype. For education, this was the Social Science Genetic Association Consortium genome-wide association study meta-analysis of years of schooling in 1 131 881 participants of European ancestry,In observational analysis of UK Biobank data, we used multivariable logistic regression to estimate the association of education with cardiovascular disease and its subtypes. We adjusted all analyses using UK Biobank data for potential confounders: age, sex, place of birth, birth distance from London, and Townsend Deprivation Index at birth. These confounders were determined a priori, with place of birth and birth distance from London included to control for population structure in the UK Biobank.In two-sample mendelian randomisation analysis, the effects of education on cardiovascular subtypes were investigated using ratio method mendelian randomisation with standard errors derived using the delta method.In multivariable observational and one-sample mendelian randomisation analyses, when investigating the degree to which the effects of education on cardiovascular disease and its subtypes are mediated through each risk factor  individually, we used the product of coefficients method to estimate the indirect effect .We used multivariable linear regression in the observational analysis to estimate the association of education with each risk factor after adjusting for confounders . We then estimated the effect of each risk factor on the individual cardiovascular disease subtypes with additional adjustment for self-reported educational attainment.We used the inverse-variance weighted mendelian randomisation approach for the two-sample mendelian randomisation to estimate the effect of education on each risk factor. We used regression-based multivariable mendelian randomisation to estimate the effect of each risk factor on the risk of the considered cardiovascular disease subtypes, adjusting for genetic effect of the instruments on education.Methods for investigating the role of all three risk factors together are presented in the supplementary methods.One-sample mendelian randomisation analysis was carried out in the UK Biobank. Full details of the genetic variants used are in the supplementary methods and supplementary tables 19 to 21. In brief, a weighted allele score was created based on genome-wide significant single nucleotide polymorphisms identified in recent genome-wide association study meta-analyses for the considered exposures .We performed the analysis by using Stata version 14 (StataCorp LP) and R version 3.4.3 . We used the mrrobust package for Stata and the TwoSample MR package for R to facilitate MR analyses.No patients or participants were involved in setting the research question or the outcome measures, nor were they involved in developing plans for design or implementation of the study. No patients were asked to advise on interpretation or writing up of results. There are no plans to disseminate the results of the research to study participants or the relevant patient community.The UK Biobank sample used in the observational and one-sample mendelian randomisation analysis was comparable to the participants in UK Biobank as a whole, although the UK Biobank is not representative of the wider UK population .All three approaches also provided consistent evidence for a protective effect of education with risk of cardiovascular disease and its subtypes (supplementary figures 6 and 7).Similar results were found for other cardiovascular disease subtypes in multivariable observational analyses. Smoking behaviour consistently mediated around 20% of the association. BMI explained between 10% and 17% of the association between education and cardiovascular disease and its subtypes; systolic blood pressure explained between 8% and 18% of the association. In two-sample mendelian randomisation analyses, smoking behaviour explained up to 34% of the association between education and cardiovascular disease subtypes; BMI estimated up to 18% and systolic blood pressure up to 28% of the association. One-sample mendelian randomisation analyses estimated similar amounts of the association explained by systolic blood pressure and smoking behaviour but was less consistent for BMI (supplementary figure 13).Our observational and genetic analyses support that the effect of education on the risk of cardiovascular disease is mediated by approximately up to one third through any of BMI, systolic blood pressure, or smoking behaviour. When investigating all three risk factors together, it was estimated that around 40% of the association between education and cardiovascular disease is explained by the three risk factors combined, both in observational and mendelian randomisation analyses. Note that over half of the effects of education remain unexplained in these analyses. Our main analysis did not consider the contributions of exercise, diet, health system factors, lipid profile, and glycaemic traits.We have triangulated evidence across three distinct approaches. Although the point estimates vary, along with the mediation results, all three approaches indicate the same conclusions. Our mendelian randomisation estimates are much larger in magnitude than the observational results. In mendelian randomisation, the genetic instruments used to proxy the exposure and mediators estimate their lifetime effect, rather than one snapshot, which could explain the larger estimates in mendelian randomisation. Additionally, this could be owing to bias from negative confounding or measurement error in multivariable analyses. Cases recruited to the case-control studies included in two-sample analyses might represent a more extreme phenotype than in cohort studies such as the UK Biobank. The two-sample mendelian randomisation estimates are more precise than the one-sample mendelian randomisation results from the UK Biobank, likely related to the larger sample sizes and the number of cases.Mendelian randomisation studies have previously investigated the causal effects of education on coronary heart disease, BMI, systolic blood pressure, and smoking behaviour,Several studies have used observational multivariable regression methods to support mediating roles of BMI, systolic blood pressure, and smoking behaviour in the pathway between education and the risk of cardiovascular disease,The major strength of our work is that it allowed for assessment of the causal role of mediators by using mendelian randomisation, an approach that is robust to non-differential measurement error in the mediator. We have used multiple data sources and approaches, each with different potential sources of biases, to thus improve the reliability of our findings through triangulation.For all cardiovascular disease subtypes and individual risk factors considered, the largest effects of education were consistently seen with the mendelian randomisation approaches, with smaller effects seen in the analysis of observational data. Measurement error in a mediator leads to an underestimation of the proportion mediated, so the discrepancy between our observational and mendelian randomisation analyses could be attributable to mendelian randomisation analyses suffering less bias from measurement error.Estimates from mendelian randomisation analyses are robust to reverse causation bias, owing to the random allocation of genetic instruments at conception (and thus before development of the outcome under consideration). Although Tyrrell and colleagues have previously used mendelian randomisation to suggest an effect of BMI on education,Another limitation of the mendelian randomisation approach is that estimates can be biased by pleiotropic pathways where the instrument is associated with the outcome through a phenotype independent of the exposure under consideration. To investigate this possibility, we additionally performed mendelian randomisation-Egger and weighted median sensitivity analyses that are more robust to such pleiotropy,Analyses in the UK Biobank were carried out on white, British participants, potentially limiting the generalisability of our results to other populations and ethnicities. However, two-sample mendelian randomisation analyses were not exclusive to white European participants  and produced consistent results to one-sample mendelian randomisation analyses. The UK Biobank is not representative of the UK population as a whole and is subject to healthy volunteer bias.When estimating the indirect effects of a mediator on a binary outcome, the product of the coefficients method results in the least amount of bias,Past policies that increase the duration of compulsory education have improved health and such endeavours must continue.By using distinct analytical methods, including genetic approaches that can draw causal inference, our results suggest that interventions aimed at reducing BMI, systolic blood pressure, and smoking behaviour in European populations would lead to reductions in cases of cardiovascular disease attributable to lower levels of education. Importantly, over half of the effect of education on the risk of cardiovascular disease is not mediated through these risk factors and further work is required towards investigating this.Lower levels of education are causally related to a higher risk of cardiovascular diseaseBody mass index, systolic blood pressure, and smoking behaviour mediate the effect of educationCardiovascular disease attributable to lower levels of education can be reduced by intervening on these risk factors


Epilepsy is a serious neurological disorder which affects every aspect of patients’ life, including added socio-economic burden. Unfortunately, only a few suppressive medicines are available, and a complete cure for the disease has not been found yet. Excluding the effectiveness of available therapies, the timely detection and monitoring of epilepsy are of utmost priority for early remediation and prevention. Inability to detect underlying epileptic signatures at early stage causes serious damage to the central nervous system (CNS) and irreversible detrimental variations in the organ system. Therefore, development of a multi-task solving novel smart biosensing systems is urgently required. The present review highlights advancements in state-of-art biosensing technology investigated for epilepsy diseases diagnostics and progression monitoring or both together. State of art epilepsy biosensors are composed of nano-enabled smart sensing platform integrated with micro/electronics and display. These diagnostics systems provide bio-information needed to understand disease progression and therapy optimization timely. The associated challenges related to the development of an efficient epilepsy biosensor and vision considering future prospects are also discussed in this report. This review will serve as a guide platform to scholars for understanding and planning of future research aiming to develop a smart bio-sensing system to detect and monitor epilepsy for point-of-care (PoC) applications. Globally, among the serious neurological disorders, epilepsy is the most common disorder and has been ranked fourth in the United States of America (USA) just after migraine, strokes and Alzheimer’s disease. Presently, despite medical advancements and progress in new therapies, the heterogeneity and complexity of the disease affect more than sixty-five million people worldwide ), one-third of which have uncontrolled seizures ,2. Epile2+, Ca2+, and few others in the extracellular space or release of such ions  from erythrocytes) after an injury or trauma can enhance the neuronal damage through production of hydroxyl free radicals, deoxyribose, and deoxyribonucleic acid (DNA) degradation (Fenton reaction). The reactive oxygen species (ROS) generated, in turn, inflict the healthy neurons to become epileptic which promotes the disorder  as one of the prominent reasons in most cases of epileptic seizures, either caused by some accident or neuronal dysfunctions . Furtherdisorder  13,14].,14.2+, CMethodological problems, inclusion criteria, diagnostic uncertainty and heterogeneous nature  of distribution are few other causes of unsuccessful therapeutic solutions for epilepsy. An uncertain and dynamic classification of epilepsy is also one of the obstacles in the way for its improved theranostic cure. Based on findings, the updated classification of epilepsy which is reported by International League Against Epilepsy (ILAE) in 2017 can be helpful in identifying the diverse treatment modalities and a better understanding of epilepsy, as it has been observed that the most effective therapeutics are based on the etiological classes of the disease, which include genetics, infectious, metabolic, immune, and other factors. However, still many types of seizures are kept in the unclassified section for further research investigation .An epilepsy incident is considered treatable, pertaining to its timely diagnosis, clinical proficiency, and level of seriousness. The predictability of seizures, co-ordinates of epileptic focus, and proper monitoring could prevent the sufferings, casualties, and improve the morbidity in patient’s life ,16,17. TIn general, epilepsy biomarkers can be categorized as electrophysiological signatures, neuroimaging, and molecular biomarkers . ElectroOverall, diagnostics of epilepsy type or seizures occurring, and identification of active region during illness, through advanced technology has been the most prominent and active area of research which is pivotal for therapeutic remediation and prevention of diseases . As firsKeeping advancements and challenges in view, the understanding of the state-of-art analytical devices which can be used for the detection is very important for epilepsy management and is the focus of this review. The nanotechnology assisted advanced sensing systems, research outputs existing in the market, and other systems capable in detecting and monitoring epilepsy are focussed. In order to understand the actual neurological condition and to avoid garbage in–garbage out (GIGO) process, therapeutics have to be amalgamated with the real-time sensing platforms . CognitiMRI is another remarkable technique which views the anatomical structures, using hydrogen nuclei of the water molecule inside brain tissue. An MRI does structural imaging to differentiate between tissue types, providing high, spatial resolution images. However, the inability of MRI to register metabolic functions leads to the generation of functional MRI (fMRI). The fMRI technique uses oxygen levels to study the changes over the hydrogen nuclei of water molecules in MRI and can differentiate between tissues with respect to time. The superior long-distance temporal resolution of fMRI offers an advantage over MRI. Since its inception in 1992, fMRI use has amplified like an outburst to become one of the most trusted neuroscience tools. Diverse animal brain regions can be imaged for transformed electrical activity of neurons. Above all in fMRI the functional brain image can be obtained using cerebral arterial blood flow changes with spin labeling ,29,30, oTechniques like PET, ictal single-photon emission computed tomography (SPECT), MRI, and optical coherence tomography (OCT) have further revolutionized investigations of epilepsy ,38. In PThe correlations among various vital organ behaviors with epilepsy are also significant to detect minute processes in motion. A major drawback of present epilepsy control scenario involves improper follow-up on the number of seizures, the efficacy of anti-epileptic drugs (AEDs), supportive medicines, real-time analysis of changes in the physiology, behavior, and chemicals in the system . The advDifferent types of seizure are detected using a specific type of sensors. Finding the main legitimate component character of the seizure is the most elementary and beginning step towards choosing an appropriate seizure detection sensor device. Two such components used to evaluate the seizure are physiological signatures and movement patterns. Physiological signatures include temperature, heart rate, sweating, respiratory rate, and other physiological parameters. Wherein the temperature change could be detected using wristband, heart rate change by electrocardiogram, sweating by electrodermal activity (EDA), and respiratory rate change by the use of thoracic bands. Movement patterns of various body parts like the eye, head, limbs, can be detected using the accelerometer, EMG, seizure alert dogs, video-mattress monitoring sensors, and electrooculogram. Ideally, the best seizure sensor would possess the ability to detect both physiological as well as movement cues rendered by the patient. Nanotechnology-enabled biosensors emerged as potential analytical devices for early-stage diseases diagnostics, therapy optimization, and customization of personalized therapeutics ,70. PoolIt is expected that nano-intervention into EEG and ECoG, will make the most reliable methods of seizures detection, even more, improved for clinical use. The use of conventional electrodes for recording is accompanied by problems like the discomfort of displacement and irritation by their mere presence ,76. ReceThis led to the construction and integration of a sophisticated technique like EEG into a simple headgear and made the detection of epilepsy in chronically ill patients effortlessly uncomplicated . For furA method to measure the kinetics of omnipresent calcium ions, which play diverse intracellular and extracellular roles in the body, was developed using magnetic calcium responsive nanoparticles, which can be detected using MRI. These nanoparticles are proven to respond to the slightest variations in calcium concentration, which can detect brain activation and thus help us map brain dynamism for nanoparticle-based sensors for molecular imaging with MRI . The res+, K+, Cl−, Ca2+ ions and others for identification of brain disorders are prevalent . Fu. Fu22]. Advancements in the technology of the future, i.e., nanobiotechnology and device miniaturization, will help in the development of such desirable implantable biosensor for in vivo applications. They continuously correlate the EEG activities or spikes and can trigger medication towards the epilepsy outburst region by infusion pump only on demand, thus, eradicating the further deterioration of CNS by overdose or inaccurate drug delivery. The inclusion of nanobots, which can carry neurotransmitters or growth factors such as engineered cells to express and release GABA, progenitor cells, and neural stem cells which can potentially replace and restore damaged neural tissue have revolutionized the theranostic arena for epilepsy. New generation AEDs have been developed with improved efficiency in the past decade but the control over repercussions of the drug, their appropriate concentration, the ability of the drug to traverse through the BBB and higher drug resident time inside the brain are a few other matters for concern. Insights into the recurrence of epileptic seizures and classification based on their initiation will be a challenge for new generation sensors during the management of epilepsy.N-methyl-D-aspartate (NMDA), kainate types, metabotropic glutamate receptors), nicotinic acetylcholine receptors, potassium channels, neuro-peptide receptors, adenosine receptors, and metabolic enzymes. However, all such drugs are associated with side effects, affecting the normal functioning of the brain and have failed to tackle the recurrence of seizures in many cases, so sensors based on the identification of new molecular targets for treatment and genetic modification may be path-breaking in this arena. As treatments should be directed towards the actual mechanisms of epileptogenesis or epidemiology, rather than working on unaltered channels or receptors. This may decrease the side effects drastically and could be used as surrogate endpoints for expedited testing of AED. Such target specific drugs would not interfere with normal brain functioning, neurodevelopment, and regeneration in the patients. Presently, drug development is based upon unaltered ion channels which affects the fast synaptic transmission in CNS such as ionotropic glutamate receptors (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA), Based on bioinformatic algorithms, sensors based on genomics and subsequent drug release can be another significant advanced approach. These bioinformatic sensors can be very helpful in the management and classification of epilepsy through screening the particular targets with available drug compounds outside the body (in vitro or cell-based) using gene targets and functional assays. Another important aspect is the promotion of pharmacogenomics, which can produce drugs customized for specific patients with a particular genome type. Thus, gene chips sensor technology can be more effective in patients affected by genetic polymorphism , where, generalized medication would not work. The aspects of early-stage epilepsy diagnostics at PoC application are illustrated in A methodological treatment through early detection, live monitoring, and data analysis, followed by drug delivery, have magnificently improved the theranostic approach towards neurodegenerative diseases. These PoC clinical treatments can improve and prolong the life for epileptic patients, and also greatly reduces the medical care costs, especially for chronically ill patients . HoweverTM  is another remote physiological telemonitoring system with the capability of respiration, HRV, and fitness measurement with the 3D accelerometer.®  is a non-invasive monitoring technique specifically developed for the detection of GTCS, which is placed over the belly of the biceps. It is currently in phase III clinical trials as a specific sensor for seizure type and is one of the fastest GTCS sensing systems to date. The inbuilt portable surface EMG (sEMG) in SPEAC® showed equivalence (100%) in the detection of GTCS compared with the gold standard video EEG system with an average time for alarm is 5.53 seconds and average false alarm of 1.4 per 24 h. It is the first FDA-approved non-EEG- based seizure monitoring system. The mechanism of detection involves the activation of motor cortices which is precisely detected by sEMG and reducing the stigma involving complex sensing techniques for a longer detection period. Quantification of the signals from different epileptic seizures is the next step in progress for the broad application of this smart tech.The creation of an algorithm which can analyze specific epileptic behaviors based on the recorded biomarkers is of prime importance. However, because of the similarity in the consequences or symptoms of epileptic seizures makes it difficult to happen. In this regards, Brain Sentinel’s SPEACWearable sensors like Embrace and Embrace 2 watches developed by the Massachusetts Institute of Technology  are of great value due to their ability to detect epilepsy seizure with accuracy. The sensor platform detects the convulsive seizures which involve rapid involuntary rhythmic movement in a period of few seconds, overall body balance, and have USB as well as Bluetooth connectivity. It is specific in the measurement of GTCS and tracks the overall activity of the patient. The loss in consciousness and misbalancing activity of the person is recognized by the smartwatch, followed by intimation to the caregiver as an alarm system ,132. TheOverall, in order to manage epilepsy, the state-of-art detection systems have remarkable scope for improvement via adopting a systematic approach . Data anIn the future, the advancements in wearable gadgets, by the use of nanotechnology to detect and diagnose epilepsy for real-time analysis, can also be used as a timely reminder for drug influx, making drug intake timing stress less for proper management of epilepsy. All these concepts may exceptionally enhance the treatment and research scenario, which can ultimately lead us to cure just not epilepsy, but also other diseases rooted in the human body, ahead.Hence, the need of the hour is a multimodal device which can synergistically detect various biomarkers at a given time. The device should be wireless, mobile, hassle-free, light, and can be carried by the patient themselves. It must be easily wearable like a watch or an anklet, to be worn always. Miniaturization of the various biosensing techniques and integrating it into one small device can only take place with the wizardry of nanotechnology. It is the field of nano-technology only which can provide us an integrated solution to epilepsy cure, remediation, and theranostic developments. Basically, the collaboration among technological giants , research institutions  and various discussion platforms like epilepsytalk, is needed in this active period, such as a combination of Garmin wearable’s data capture and the ActiGraph analytical platform that provides a strong monitoring system. Smart nanosensor- enabled apparels, headsets, bracelets, and other daily wearables remove the stigma and pain associated with complex monitoring techniques. The development of newer devices and APPs which collaborated the already patented products, software, data analysis platforms could only help the caregivers, doctors, and patients a feeling of relief. As we have established through literature and discussions that timely detection along with precaution is the key to cure or check the epileptic epidemic. The sensors or techniques enabled with recent technological advancements, nano-biotechnology, ultra-fast, low power consuming tech., and compiled data analysis is the key to success for now in neurodegenerative disorders, such as epilepsy. The clinical validations of the results and FDA approval of devices are increasing, but still not enough to say that we have conquered this disorder. Such epi-care devices reduce the frequency of visits to hospitals and long term remote monitoring modality. Thus, the miniaturization followed by hybridization of sensing techniques can result in the measurement of specific epileptic seizures based on observing and charting of affected biological markers.


As a polymer matrix containing a large amount of water, hydrogels have been widely used in many fields such as biology and medicine due to its similarity to extracellular matrix components, and its contact with blood, body fluids, and human tissue does not affect the metabolic processes of living organisms. However, due to the lack of unique physical properties of traditional polymer hydrogels, its further application in the high-end field is limited. With the progress of study, a series of hydrogels with special structures, such as double network hydrogel, composite hydrogel, Tetra-PEG gel, and topological gel, have improved the situation to a large extent. At the same time, the progress of research on the biocompatibility and biodegradability of hydrogels, which are expected to be used in biomedical fields, is also worthy of attention. This review introduces four such types of high-strength polymeric hydrogels and the mechanisms for improving their mechanical strength. Moreover, a discussion will be made around specific methods for imparting special physical properties to hydrogels and applications in the field of biomedicine such as cell culture, medical surgery, tissue engineering, and biosensing. At the end of the review, the main reasons and contradictions for the limits of the current applications are explained. An outlook on the future research in related fields and the importance of carrying out research in this area to promote medical progress are emphasized. Hydrogels are polymer network systems containing a large amount of water in the matrix  with watIn recent years, with the development of hydrogels with excellent physical properties , new appDouble network (DN) hydrogels were proposed by Professor Gong and her collaborators at Hokkaido University in 2003 . The DN The organic/inorganic nanocomposite hydrogel is the nanocomposite material formed by dispersing an inorganic phase on nanometer scale into an organic polymer matrix. Nanocomposite (NC) gels have the strength and thermal stability of inorganic materials as well as the functionality of organic polymers ,20. The The organic/organic composite hydrogel is represented by the macromolecular microsphere composite (MMC) gel , which uIn 2008, Sakai  developeThe topological gel is also called the Slide-Ring Gel, which was synthesized by Okumura and Ito in 2001 . TopologBiocompatibility refers to the property of living tissue to react with inactive materials ,53. HydrIn 1948, Rosen first reported the use of murine fibroblast cultures to screen for polymers, and began the research and application of cytotoxicity experiments to evaluate the biocompatibility of materials . The earBiodegradable polymer materials refer to materials that can be degraded or metabolized by a living organism under certain conditions. Such materials may be involved in human metabolism and eventually pass out of the body . Given tFurthermore, when these hydrogels undergo partial degradation by the tissue, it is possible to produce inherent toxic monomers or oligomers. Even if the polymer may not be toxic, its monomers or shorter oligomers, including dimers , trimersResearch on cellular biomaterials in the last decade has turned toward three-dimensional approaches . HydrogeMore interestingly, Wilkinson designed a hematopoietic stem cell culture system that uses PVA in culture fluids to culture hematopoietic stem cells using high levels of thrombopoietin and low levels of stem cell factors, and the hematopoietic stem cells of the experimental mice proliferated extensively . PVA is Uncontrolled bleeding results in more than 30% of traumatic deaths, more than half of which occur before emergency care arrives. For deep wounds in particular, it is difficult to stop bleeding by pressure or a tourniquet due to the irregular shape of the wound, and currently, the hemostasis commonly employed in surgery does not show satisfactory effects on deep wounds. Zhao used chitosan derivatives and carbon nanotube materials to prepare injectable shape memory nanocomposite porous colloidal hemostatic materials, shown in Furthermore, rapid hemostasis and the realization of wet side hemostasis are also huge clinical needs. At present, there is no effective rapid hemostasis for arterial and major organ bleeding. As shown in On the other hand, the methacrylic acid (MA) graft substitution conversion rate is the core parameter used to measure the properties of GelMA. When the substitution rate is higher than 15%, it can be photo-cured with crosslinking, and the substitution rate reaches up to about 90%. When the substitution rate is low, GelMA exhibits superior biocompatibility. However, in this process, if the grafting is incomplete or not subjected to dialysis, the toxic small molecule MA may remain , and con2 nanofiber membrane by utilizing a sol-gel electro-spinning method and further prepared a super-elastic SiO2 nanofiber-shell polymer by homogenous dispersion freeze-drying of the flexible SiO2 nanofiber composite chitosan solution [2 nanofiber-chitosan (NF-CS) scaffold can be implanted into the rabbit mandibular defect area of different shapes under compression; it quickly recovers the initial shape after absorbing body fluids, and it closely fits to the bone. The preparation method of the stent is simple and flexible. By adjusting the injection ratio of SiO2 nanofibers and chitosan, a scaffold with a morphological structure and a mechanical property gradient distribution is prepared, and the biomineralization and mesenchymal stem cell differentiation gradient distribution is realized in soft tissue. It has broad application prospects in bone defect repair at the interface.Irregular bone defects, or bone defects such as cartilage, tendons, and ligaments, are a clinical problem in the treatment of bone defects. Autologous bone grafting is still the first choice for bone repair, but the limited source of autologous bone and the tendency of lesion formation in the donor site severely limit its application. Therefore, tissue engineering scaffolds that facilitate minimally invasive surgery and adaptive irregular bone defects and promote bone regeneration are expected to be ideal bone repair materials. As illustrated in solution . The steSurprisingly, PVA hydrogels exhibit properties comparable to cartilage in many respects ,83,84, aMeanwhile, although the above hydrogel has very low cytotoxicity, the process of degradation in the body does not rule out the production of toxic molecules and further damage to the body caused by entering the blood circulation system. The specific mechanism and solution still need further research.− attacking the B atom, leading to a conformation transition of phenylboronic molecule into a tetrahedral anion; (3) the formed tetrahedral anion of phenylboronic molecules combining with carbohydrate molecules to form five-membered or six-membered cyclic complexes, which can be hydrolyzed in acidic solutions to recover boronic acid compounds and carbohydrate molecules. Therefore, the response of the whole sensing process is reversible [Lenses, usually used for vision correction as a portable and accessible device, with its favorable biocompatibility with decades of clinical use, have now caught much attention in drug delivery and the tear analyte detection field ,88. Chenversible .In the field of electrochemistry, Jing has prepared a series of flexible sensors with good biocompatibility, super-long stretchability, self-adherence, and self-repairing performance . DopaminNanodrugs have great potential and application prospects in the clinical treatment of cancer. Nanomedicine is generally composed of carriers and chemotherapeutic drugs. Drugs play a therapeutic role, and carriers play an embedding and transporting role. Polymer micelles have attracted much attention in recent years because of their good biocompatibility, easy structure modification, and “core-shell” structure. Li constructed cisplatin-crosslinked polymer prodrug micelle nanodrugs with a dual stabilization effect by coordination complexation and synergistic stabilization of polymer prodrugs . Figure Wei prepared a novel pH-responsive molecularly imprinted polymer hydrogel that can effectively control the release of dexamethasone sodium phosphate (DXP) . As showThe high water content and void structure of the hydrogels has resulted in their limited application. By increasing the polymer concentration, the mechanical strength can be increased with poor biocompatibility and lower degradability, and this is the main contradiction in the application of mechanical properties of hydrogels in the biomedical field.Research progress in the past two years has demonstrated that the introduction of non-chemical bonds into the system has become an effective method of improving the strength of hydrogels, but the synergistic effect between non-chemical bonds and chemical bonds still need further research and development. The development of hydrogels with special physical properties, which are based on the premise of ensuring good biocompatibility and biodegradability, should be more similar to bio-gels in terms of onlooker structure and biological function.High-end medicine is one of the potential applications for high-intensity hydrogels, such as human tissue repair, organ culture in vitro, and targeted cancer treatment. With further intersection of polymer and biomedical science, attempts to give hydrogels unique physical properties through different methods are expected to be more widely used in the biomedical field and to achieve medical advancement.