Although the safety performance of the Australian commercial fishing industry has been the subject of multiple investigations, it has ultimately remained undefined. While most Australian industries notify industry regulators of significant workplace incidents and injuries in their operations, the majority of persons in the commercial fishing industry are contractors who are paid piecework and in some jurisdictions specifically excluded from the worker compensation legislation, meaning that most occupational injuries, including fatalities, are not captured in the centralized worker compensation data sets. This study presents the analysis of a systematic review of industry databases, published academic, and, Australian coroners reports to assist improve the definition of the nation's commercial fishing industry safety performance. The analysis shows occupational fatality rates are significantly higher than currently reported, and recurring factors contributing to deaths at sea remain unaddressed. The study is significant as it demonstrates how workplace injuries and deaths can be hidden within data sets applying broad industry classification and provides a foundation for future research in Australian fishing and other industries. The Australian Commercial Fishing Industry (ACFI) directly employs approximately 6,000 persons. On average, the industry produces 174,000 tons of product per year, with an economic value of $5.3 bn, representing a strong contribution to the Australian economy . EmploymAlthough the detail of Australian occupational health and safety legislation varies between its States and Territories, henceforth referred to as States, the general principles are based on the United Kingdom's Robens-style legislation . The occHowever, the commercial fishing industry regulation is not consistent and comprises a complex mix of Federal and State agencies, with legislation specific to geographic regions, the species being fished, licensing and operation of vessels, and the prevention of illegal fishing in Australian waters. While fishing vessels are considered a workplace consistently across all jurisdictions legislation, the people who work on them may not be deemed to be workers or employees. The classification of workers is dependent upon the applicable occupational health and safety, and worker's compensation legislation –18.For example, The Western Australian Workers' Compensation and Injury Management Act 1981  defines any person who has entered into or works under a contract of service or apprenticeship with an employer, whether by way of manual labor, clerical work, or otherwise and whether the contract is expressed or implied, is oral or in writing”.“However, this Western Australian Act specifically excludes crews of fishing vessels as these workers:in respect to injuries occurring to such members of a fishing vessel as contribute to the cost of working that vessel, and are remunerated by shares in the profits or the gross earnings of the working of that vessel”.“Similarly elsewhere, such as in Queensland, which has the largest fishing fleet, crews of fishing vessels do not receive salary or wages, instead their income is a share of the profits, or loss, of the vessel, after running costs and other liabilities are deducted. In effect, this “share catch” income arrangement results in the workers being self-employed contractors in their workplace, and they personally are responsible for paying their tax, superannuation , and frequently medical and other insurances , 20.In effect, the exclusion of fishing crew being classified as a worker removes most obligations on the employer to report workplace incidents and injuries to the workers/crew. Crew may of course report workplace injuries to their insurer; however, this may have an impact on the cost of the insurances. These circumstances have created systemic under-reporting of incidents and injuries in the commercial fishing industry.Safe Work Australia categorizes the worker compensation data and information using the Australian and New Zealand Industrial Classification (ANZSIC). As ANZSIC coding groups “business units carrying out similar productive activities” together , commercSafe Work Australia  reports In 2004, agriculture, forestry, and fishing recorded 77 fatalities, the highest number observed from the data reviewed. In 2019, the lowest number, 30 fatalities, was recorded. Agriculture, forestry, and fishing recorded the highest fatality rate per 100,000 workers for 15 of the 16 years, peaking at 21.6 fatalities per 100,000 workers in 2004 and recording the lowest in 2019 of 9.1 fatalities per 100,000 workers. As Safe Work Australia reports the fishing industry data combined with agriculture and forestry, analysis of fishing-specific data is not possible.the true state of safety performance within the Australian commercial wild catch fishing industry remains unknown”.Safe Work Australia reports rates of injury and fatality per 100,000 workers regardless of injury or size of industry. Noting that the ACFI only has a workforce of approximately 6,000 people  published research focussed on the ACFI and (2) coronial investigations and other safety investigations and reports relevant to the ACFI with results presented according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist. The results are then distilled to identify the number of fatalities within the industry with greater accuracy, while thematic analysis is completed to identify the recurring contributing factors.The motivation for, and significance of, the study is 2-fold. First, the results of the study may assist the development of targeted safety interventions within the ACFI and the reduction of avoidable fatalities within the industry. Second, the findings with regards to the suitability of current data classification and analysis may have broader-reaching impacts across Australian workplaces wherever broad industry data classifications have the potential to disguise or dilute actual injury and fatality rates.The study is subsequently presented as follows. First, we present the methodology of the study and detail the search terms, inclusion criteria, and limitations of the systematic literature reviews. Next, we present the results of each review before discussing their implications and recommending potential industry improvements. Finally, we provide our conclusion and recommendations for future research.In the first phase of the study, a systematic review of contemporary studies on occupational health and safety within the ACFI was completed. This systematic review enabled the identification, examination, and synthesis of relevant academia, government, and industry reports. The second phase of the study involved a systematic review and thematic analysis of Australian coronial findings and safety investigations related to ACFI incidents. This narrative approach was selected due to both the anticipated heterogeneous and limited research available, as well as enabling a review of the ‘state of knowledge’ of the field .For Phase 1, studies meeting the following criteria were included in the analysis: peer-reviewed studies or reports, as well as post-incident reviews, inquiries, and inquests after incidents, published by government and non-government organizations . Two review authors independently tested the search criteria and completed the initial search before reviewing the titles and abstracts, and selecting final articles for detailed full-text analysis. Any disagreement was resolved by discussion and majority decision between all article authors. Following the removal of duplications, the titles and abstracts were screened. The results are presented according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist.The search strategy included only terms relating to the occupational health and safety of crew on fishing vessels in the Australian wild catch fishing industry . A seconFor Phase 2, as the databases reviewed were specific to Australian incidents within the relevant jurisdictions, all available reports related to commercial fishing were screened. Databases included Australian Coroners Courts in each State  including all coronial published inquiries, findings, and reports into deaths, as well as safety investigations and reports by the Australian Transport Safety Bureau (ATSB) and Australian Maritime Safety Administration (AMSA). The search was completed in September 2020. Two review authors independently tested the search criteria and completed the initial search before reviewing the titles and abstracts and then selecting final articles for detailed full-text analysis. Any disagreement was resolved by discussion and majority decision between all authors. Following the removal of duplications, the titles and abstracts were screened. The results are presented according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist.Fc), that is the fatality rate within each industry per 10,000 Australian workers as opposed to fatality rate per 100,000 Australian workers, will be calculated using equation (1):Contextualized fatality rates ;Assess the pros and cons of reporting occupational fatality and injury rates per 10,000 workers in an industry, as opposed to diluting the rates using the 100,000 workers; andInformed by the above, review the Safe Work Australia priority industries league table, and associated performance improvement initiatives.The aims of this research were to determine the contextualized rate of fatality and to identify recurring contributing factors of occupational fatality within the Australian wild catch commercial fishing industry. Through the application of a systematic literature review of peer-reviewed academia, industry reports, coronial documents, and the critical review of industry-specific data, these aims have been achieved, albeit with limited certainty.Using industry contextualized fatality rates, commercial fishing in Australia (excluding aquaculture) is the most dangerous Australian occupation with a contextualized average annual fatality rate of 9.2 fatalities per 10,000 workers. By comparison, the next two highest industries identified were Agriculture  and Road Freight Transport .via the States' Workers Compensation regulator to Safe Work Australia. It appears this situation is caused by the specific exclusion in the legislation of fishing crew as workers, thereby removing the fishing crew employer's obligation to report incidents and injuries.However, the true rate of contextualized injury cannot be determined due to a lack of valid and robust industry data reported Multiple and extensive coronial investigations have not only repeatedly acknowledged the fishing industry as a highly dangerous occupation, but also have found vessel instability, lack of action by regulators, and lack of enforcement of safety regulations were recurrent themes, particularly in cases of multiple fatality.Further research is required to determine the true state of safety within the Australian wild catch commercial fishing industry. We recommended this research should focus on attitudes toward reporting within the ACFI; adoption of coronial recommendations; impacts of safety interventions; and vessel safety and regulatory compliance.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.GP was the lead researcher and primary contributer. WB and MC both provided a substantial contribution to the paper. All authors contributed to the article and approved the submitted version.Fisheries Research and Development Corporation 2017-231: to develop a national marine safety extension resource toolkit and to trial with all fisheries jurisdictions is supported by funding from the FRDC on behalf of the Australian Government.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Prostate cancer patients with disease that has invaded the liver have the worst outcomes. Within the liver, cancer cells are exposed to a unique microenvironment of liver specific cells and proteins. In general, interaction between the microenvironment and cancer is known to provide cues which alter cancer cell biology and behavior. This review aims to summarize current knowledge about the microenvironment of the liver, what predisposes prostate cancer to move to the liver, how the liver responds to prostate cancer being there, and how the liver responds to current treatment strategies. We aim to provide insight into this under-investigated area of prostate cancer research as if we can understand why liver metastasis is associated with such poor patient outcomes, we will be better placed to address this.Prostate cancer-associated deaths arise from disease progression and metastasis. Metastasis to the liver is associated with the worst clinical outcomes for prostate cancer patients, and these metastatic tumors can be particularly resistant to the currently widely used chemotherapy and hormonal therapies, such as anti-androgens which block androgen synthesis or directly target the androgen receptor. The incidence of liver metastases is reportedly increasing, with a potential correlation with use of anti-androgen therapies. A key player in prostate cancer progression and therapeutic response is the microenvironment of the tumor(s). This is a dynamic and adaptive collection of cells and proteins, which impart signals and stimuli that can alter biological processes within prostate cancer cells. Investigation in the prostate primary site has demonstrated that cells of the microenvironment are also responsive to hormones and hormonal therapies. In this review, we collate information about what happens when cancer moves to the liver: the types of prostate cancer cells that metastasize there, the response of resident mesenchymal cells of the liver, and how the interactions between the cancer cells and the microenvironment may be altered by hormonal therapy. Prostate cancer (PCa) is the fourth most commonly diagnosed cancer globally, with particularly high prevalence in western countries . When coSince PCa cells proliferate in response to androgens, anti-androgen therapies are commonly the drug of choice for inoperable PCa treatment. These act at the level of the androgen receptor (AR), binding to it and preventing its activation, hence inhibiting androgen-responsive gene transcription . Whilst Anti-androgen therapies, which are given systemically, have also been associated with other effects in the liver , althougThe vital role of ECM in disease progression is also seen in the primary site ,23 whereThe changes to the tumor microenvironment and cells therein highlight its importance in cell invasion and metastasis. The aim of this review is to collate the current knowledge of what types of PCa metastasize there, what happens to the liver when PCa invades, and what associations exist with current therapeutic options.The liver is a large organ which primarily filters blood coming from the digestive tract, but also has critical roles in metabolism and secretion. At a microscopic level, the liver is composed of liver lobules, which are roughly hexagonal in shape A. At theIn the primary site, cancer cells invade through the stroma and escape the primary site via intravasation into the vasculature, where they circulate until they leave the vasculature (extravasation) and colonize the liver. In the liver, cancer cells either undergo cell death, or they can remain in a dormant state, or they proliferate and form micro-metastases until growing enough to become a macroscopic metastatic lesion B.As previously summarized, many solid tumors metastasize to the liver . In a stLiver metastasis is associated with some of the worst clinical outcomes compared with other sites ,33. Out In general, AR status of PCa cells has an inverse correlation with neuroendocrine features B. PublicCompared to other metastatic sites for PCa, liver metastases reportedly have the highest fraction of genomic alterations and there are also potential liver specific alterations such as MYC amplification, PTEN deletion or PIK3CB amplification . PCa mayIn other cancers that invade the liver, measurable changes have been noted in liver function serum markers alanine transaminase (ALT), aspartate transaminase (AST), total bilirubin (TBIL), gamma glutamyltransferase (GGT), alkaline phosphatase (ALP), albumin (ALB), and carcinoembryonic antigen (CEA) ,45,46. SLiver metastases express the epithelial-characteristic adhesion protein E-cadherin at a level that is equivalent to or higher than matched primary tumors ,49,50. TAs stated earlier, PCa growth is dependent on androgens, which are male sex hormones that work through the androgen receptor (AR) . The AR One of the principal factors that determine the responsiveness and overall success of anti-androgen therapies is the site of metastasis. The poor clinical outcomes associated with visceral metastases, in particular liver metastases  Table 1Table 1, Reports also suggest that cases of liver metastases are increasing and this could possibly be linked to the use of anti-androgen therapies ,31,73. TThe influence of the microenvironment is seen throughout all stages of cancer development and progression and therefore, therapies to target cancers must consider the effect of (and on) the tumor microenvironment.Prostate development is reliant on the interactions between epithelial cells and the surrounding stroma in the microenvironment. The prostatic stroma is composed of several non-malignant cell types such as fibroblasts, smooth muscle cells, endothelial cells and immune cells . In cancAndrogen receptors are not just expressed in cancerous epithelial cells, but in multiple cell types of the prostate stroma ,96. StroThe role of AR in the metastatic microenvironments is generally under-investigated, this is particularly true for the liver. A number of articles have suggested that the liver is responsive to androgens and expresses AR both in the nucleus and cytoplasm (only determined in whole tissue extracts and hepatocytes) ,110,111.There is some data suggesting an association between hepatic AR and reduced immune infiltration  and enabIt is underappreciated that all cell types throughout the body express some form of nuclear/sex hormone receptor . Cell coLiver injury associated with anti-androgen therapies has been reported in the literature since as early as the 1940s . AnalysiA major concern of tissue response to injury is the possible formation of a pre-metastatic niche. A pre-metastatic niche is a microenvironment which is suitable/optimal for colonization by circulating tumor cells —the “soiThe fibrosis/wound healing activated in response to injury in the liver is similar to the changes observed in the microenvironment of cancer metastases discussed earlier . HepaticGiven the responsiveness of the liver to androgens, there is potential that anti-androgen therapies may contribute to reported liver injury associated with administration. A worrying potential result of this side-effect may be the creation of a microenvironment more hospitable to metastatic seeding and growth in certain patients.Metastasis to the liver has one of the worst cancer outcomes yet there is relatively little known about liver metastases, the role of the liver microenvironment, and why prognosis is so poor. It is important to investigate these aspects of the disease given the reported increase in cases. Current treatment options, including anti-androgen therapies, have limited success rates in liver metastasis cases. When comparing the effectiveness of anti-androgen therapies, patient with liver metastases were significantly less responsive than patients with only bone metastases ,31. In s


Prosperity creates extravagance. With economic development, rising consumer purchasing power, and expanding manufacturing sectors, demand for textiles and apparel is increasing daily. Unquestionably, it boosts national economies while producing unprecedented amounts of textile waste. The surge exacerbates environmental issues while also providing an opportunity to convert it into useful raw material through a circular economy (CE), a circular model in which virgin material use is reduced through reusing, recycling, and reproduction. Considering its significance, China and other Asian nations adopted this model long ago  that influence Indian consumers' purchase intention toward CTP. The final data sample collected online through Google Forms comprised 409 respondents from Indian consumers . The data were first screened for missing, inappropriate, and outlier responses before sending them out to establish a measurement model  using AMOS 24.0.The questionnaire was developed in two sections. The first section of the questionnaire was designed to ask about the demographic features of the respondents , awareness, and previous purchasing experience of CTPs (Yes/No). While the second section comprised seven latent variables . At the beginning of the questionnaire, the respondents were briefly introduced to the objectives of the study while informing them about the voluntariness of being a respondent in the survey. A seven-point Likert-type scale was used to capture the latent variables. To measure the latent variables, we borrowed validated scales from published sources. Measurement items (with their loadings and adoption sources) can be found in the appendix see .The study is focused on recruiting educated consumers from the National Capital Region (NCR) and Aligarh city of India. As the study is about assessing the nexus between environmental consciousness, knowledge of CTP, other cognitive variables, and purchase intention toward circular textile products, it is presumed that educated consumers might be more environmentally conscious and may have greater knowledge of CTPs. We adopted a bifold piloting approach for validating the questionnaire. In the first step, the questionnaire was examined by eight consumers and four consumer behavior and marketing researchers for the subjectivity and relevance of the measurement items used to measure the latent variables. After assimilating their suggestions and recommendations for altering the questionnaire, we advanced to a pilot survey taking a sample of 87 respondents from the NCR and Aligarh city. Upon checking the reliability statistics based on the pilot survey, we finalized the questionnaire and conducted the main survey in March 2022, adopting a systematic random mall-intercept sampling approach. We approached every fifth customer leaving the mall and asked them to participate in the survey while briefing them about the purpose and aims of the study. Those who agreed to participate in the survey were asked to scan a QR (code linked to an online Google Form questionnaire) for keeping anonymity and abiding by the social distancing precautionary norms. To every respondent, who scanned the QR code, we also offered a carry bag (a circular textile product) as a token of appreciation. Precisely, the survey lasted for 13 days (19th−31st March 2022), and about 600 consumers gave their consent and scanned the QR code for filling out the questionnaire. However, we obtained only 467 filled questionnaires until 31st March 2022.Before moving ahead with further statistical validation analysis (establishment of measurement model), we processed the data through a cleaning and screening process. Initially, we ensured that the data were not suffering from missing responses followed by unengaged responses. Upon evaluation, we found 16 missing cases and 23 unengaged responses and discarded them from the dataset. Further, we also checked for outlier responses applying Cook's distance approach and found that 19 responses were producing Cook's distance value over the threshold of 1 Stevens, ; hence tPost data cleaning and preparation process, we established the measurement model running a co-variance-based CFA model in AMOS 24.0. For achieving the model fit indices, standardized loadings, and average variance extracted (AVE) values (for convergence), we drew a CFA model taking all 25 observed items and allowing them to converge with their respective latent variables.In addition to scale reliability and convergence, the measurement model also needs to fulfill the criterion of discriminant validity. As per Fornell and Larcker  recommenThe current study conceptualizes the causal effect of certain cognitive variables  and the fundamental factors of the theory of planned behavior (TPB)  on Indian consumers' purchase intention toward circular textile products (CTPs). This study provides a novel multivariate dataset in the research domain of consumers' behavior toward circular economy, circular textile products, and textile waste management, particularly in the Indian context. Due to the sheer scantiness of the literature on consumer behavior and CTPs in the Indian context, empirical studies are required to understand the role of cognitive factors like EC, PB, PR, AT, SN, and PBC in predicting consumer purchase intentions toward CTPs. These empirical researches would contribute to the knowledge gap in the field, raising public awareness of CE and CTPs, and attracting business people and the government to create laws and regulations to encourage investment in CE-related infrastructure, technology, and education. As a result, small and medium-sized businesses would have new opportunities in India, and the circular business model would also create jobs, produce sustainable textiles, and preserve the environment. The distinctiveness of the dataset is the inclusion of a cognitive environmental factor, i.e., consumers' environmental consciousness along with perceived risks and benefits as attributional variables CTPs, while adopting one of the most widely applied theories, the TPB, across behavioral and intentional domains. Given the dearth of literature and knowledge gap in the research domain of consumers' behavior toward circular economy, circular textile products, and textile waste management in the Indian context, the current dataset would be of great use for the researchers in understanding the role of factors like EC, PB, PR, AT, SN, and PBC in shaping consumers' purchase intentions toward CTPs. Moreover, the dataset may also be used by local authorities for knowing the consumers' perceived level of adopting CTPs thus enabling them to formulate the policies for promoting CTPs accordingly. The findings from this dataset would be beneficial for the government to raise public awareness of CE and CTPs and create laws and regulations to encourage investment in CE-related infrastructure, technology, and education. As the data are multivariate and possess metric and latent properties, they can be used for complex modeling like mediation and moderated-mediation. Moreover, comparable distribution of the data across the categories of gender, awareness, and prior experience of CTPs also offers the likelihood of testing a moderation or multigroup SEM model.The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found in the article/Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.IA conceptualized the study, wrote the original draft, and performed the statistical analysis. MS developed the questionnaire and conducted the survey. SK performed the data curation, took care of the methodology, and wrote the second draft. IS and AC reviewed and edited the final draft. All authors contributed to the article 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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Acute kidney injury (AKI) is a major clinical problem associated with increased morbidity and mortality. Despite intensive research, the clinical outcome remains poor, and apart from supportive therapy, no other specific therapy exists. Furthermore, acute kidney injury increases the risk of developing chronic kidney disease (CKD) and end-stage renal disease. Acute tubular injury accounts for the most common intrinsic cause of AKI. The main site of injury is the proximal tubule due to its high workload and energy demand. Upon injury, an intratubular subpopulation of proximal epithelial cells proliferates and restores the tubular integrity. Nevertheless, despite its strong regenerative capacity, the kidney does not always achieve its former integrity and function and incomplete recovery leads to persistent and progressive CKD. Clinical and experimental data demonstrate sexual differences in renal anatomy, physiology, and susceptibility to renal diseases including but not limited to ischemia-reperfusion injury. Some data suggest the protective role of female sex hormones, whereas others highlight the detrimental effect of male hormones in renal ischemia-reperfusion injury. Although the important role of sex hormones is evident, the exact underlying mechanisms remain to be elucidated. This review focuses on collecting the current knowledge about sexual dimorphism in renal injury and opportunities for therapeutic manipulation, with a focus on resident renal progenitor stem cells as potential novel therapeutic strategies. Acute kidney injury (AKI) is not a self-limiting event but growing evidence in the literature suggests that any injury leads to progression to varying degrees of chronic kidney disease (CKD) ,2. The pClinical trials were identified in PubMed until 28 September 2022. The search keywords were gender/sex differences, acute kidney injury, and chronic kidney disease. The studies were selected and their references were reviewed for potential inclusion. Studies written in languages other than English were excluded. Two authors  reviewed all study abstracts. All selected studies were qualitatively analyzed.The endothelium;The inflammatory response to endothelial damage;Development of fibrosis;Damage repair and attempts at functional recovery.The evolution of acute renal damage into chronic renal damage involves various stages in succession up to the repairing processes of the damage, complete or partial depending on the severity of the damage. These processes follow one another with probabilistic and time-dependent mechanisms through different phases involving:(i)Endothelial dysfunction, vasoconstriction, and vascular congestion ;(ii)Interstitial inflammation and associated infiltration of monocytes/macrophages, neutrophils, T and B cells ,13;(iii)Fibrosis via myofibroblast recruitment and matrix deposition ,15;(iv)Tubular epithelial damage and dysregulated repair .From a pathophysiological point of view, microvascular integrity, changes in the behavior of leukocytes and pericytes, the ability to survive, and the attempt to restore tubular cell function are all characteristics of both AKI and chronic renal failure. The main pathological mechanisms that help to explain the transition from AKI to CKD include:The polyploidization of tubular cells;The proliferation of a small population of self-renewing renal progenitors .Thus, after ischemic injury, loss of nephron mass with hyperfiltration of the residual nephron, activation of the renin-angiotensin system (RAS), systemic hypertension, and subsequent glomerulosclerosis, have been described to pave the way from AKI to chronic renal failure ,18,19,20Endothelial dysfunction is characterized by the loss of the mechanisms that regulate vasodilation and vasoconstriction, mediated by endothelium-dependent activity and exerted by nitric oxide (NO), in response to vasomotor stimuli that involve a variation in systemic blood flow. The endothelial-derived NO is physiologically produced by the activity of eNOS  ,20. The + and CD8 + T lymphocytes could also play a protective role and affect the natural history of AKI although this has only been demonstrated in mouse models [After the initial phase of acute kidney injury, early inflammation is followed by pericytes-mediated infiltration of both residents and infiltrating circulating cells, which, as we have said, contribute to disease progression ,28. Takie models ,30. Conve models . Therefoe models .The interaction between activated macrophages, damaged cells, endothelial cells, and the growth factors connected to the damage is responsible for the development of a pro-fibrotic environment. This environment activates the pericytes to proliferate and evolve into myofibroblasts, further inducing the deposition of the extracellular matrix, the deposition of collagen, fibronectins, and other glycoproteins, and therefore extending renal fibrosis and promoting subsequent CKD evolution . AlthougAll of the molecular and cellular mechanisms described so far lead to the dysfunction of the tubular epithelial cells, which represents the true cause of the progression of renal damage towards CKD . In factThe authors reported that the targeting TC (tubular cells) polyploidization after the early AKI phase can prevent the AKI-CKD transition without influencing AKI lethality. Senolytic treatment prevents CKD by blocking repeated TC polyploidization cycles .Sexual dimorphism in renal injury has been acknowledged since the 1940s, and the possible role of sex hormones has been intensively investigated in the past decades . It has Gender differences in the etiopathogenesis of renal damage and its subsequent repair begin with the different constitutions and anatomical structures of the kidney. In fact, the size of the organ is greater in humans although the ratio between the length of the kidney and body height are homogeneous between the two sexes. There are conflicting data on the number of functional units as for some studies there are no differences in the number of glomeruli, while for others there is a reduction in the percentage of glomeruli in women in a value until to 15% . HutchenChanges in renal hemodynamics both in response to exogenous and endogenous events;Impaired release of vasoactive factors related to the inflammatory response  ;Production of substances with antioxidant properties ;Production of substances with a protective role against kidney damage and infections.Many aspects of renal function depend on the different hormonal structures existing between the two sexes. Potential mechanisms regulated by sex hormones are:The hallmark of a healthy endothelium is the appropriate synthesis of nitric oxide (NO) and subsequent relaxation by vascular endothelial cells in response to a vasodilator stimulus. While NO synthesis and NO mediated dilation are the necessary requirements for normal endothelial function, sex differences in vascular reactivity endothelin-I (ET-I) are mediated, at least in part, by differences in the expression and location of ET-I receptor subtypes. In general, women have a higher proportion of endothelial ET~R than ET-1 receptors in vascular smooth muscle, favoring greater dilation to attenuate systemic vasoconstrictor stimuli. Females have a higher expression of cyclooxygenase-2 and produce more prostaglandins and thromboxane in the renal medullary layer . FurtherRegarding the inflammatory and pro-fibrotic response and the production of antioxidants, some observations in experimental animals and in humans have shown that the rate of progression of renal disease is influenced by gender. Deterioration of renal function in patients with chronic renal disease is more rapid in men than in women. Potential mechanisms underlying this phenomenon include sex hormone receptor-mediated effects on glomerular hemodynamics, mesangial cell proliferation, and matrix accumulation, as well as effects on the synthesis and release of cytokines, vasoactive agents, and growth factors. Furthermore, estrogens can exert powerful antioxidant actions in the mesangial microenvironment, which can contribute to the protective effect against kidney damage typical only for the female gender . AdminisThe administration of estradiol attenuates glomerulosclerosis and tubulointerstitial fibrosis and therefore has a beneficial effect of limiting the progression of chronic kidney damage . FurtherRenal tubular cell death is a key process during AKI and correlates with the loss of renal function . As we hIn the kidney, cellular senescence is a process described in several states of renal repair and regeneration, including early AKI, the transition from AKI to CKD, and CKD progression. According to some studies, senescent cells accumulate in kidney diseases, and the activation of senescence mechanisms in tubular cells leads to failure of regeneration after AKI or AKI-to-CKD transition ,77. For More recently it has been observed that in AKI, transforming growth factor-β1 (TGF-β1), after being released, binds to its receptor and activates downstream SMAD2 and SMAD3 to regulate genes associated with renal fibrosis. Administration of estrogen suppresses TGF-β signaling pathways by promoting the degradation of Smad2 and Smad3, improving the response to kidney damage . HoweverGender differences referring to CKD are linked to socio-cultural, epidemiological, clinical, and treatment response factors. Women are the main victims of socio-cultural discrimination, as they show little attention to the disease which often results in a delay in diagnosis, a lesser awareness of its severity and its developmental potential, and a greater reluctance to access control compared to men ,86. ThisRegarding the gender differences related to the outcomes of the treatment, we have previously mentioned that the majority of patients who start dialysis early are men more than women. This male predominance is explained by the greater progression of renal biological damage attributed to it but also by a greater awareness of the disease from the earliest stages of onset. Women, on the other hand, especially those in their senior years, preferentially choose to practice conservative treatments, trying to procrastinate the most invasive treatments as much as possible ,92,93. TA significant body of evidence supports that the evolution of an acute kidney injury into a chronic kidney injury is characterized by gender differences that originate primarily from different anatomy and physiology in the renal tubule’s absorptive and secretory function between the two sexes. Beyond this difference, it would seem that in particular female subjects are less susceptible to acute kidney damage and are able to restore residual renal function more quickly due to the protective activity of estrogens. In contrast, the harmful effect of male hormones has been demonstrated, although other studies are needed to precisely characterize the molecular mechanisms involved. Less evident is the evidence showing gender differences in the repair and replication processes of damaged renal cells, mostly related to the severity of damage in males. On this last aspect, it will be necessary to concentrate on future studies.


Foodborne pathogens have become the subject of intense interest because of their high incidence and mortality worldwide. In the past few decades, people have developed many methods to solve this challenge. At present, methods such as traditional microbial culture methods, nucleic acid or protein-based pathogen detection methods, and whole-genome analysis are widely used in the detection of pathogenic microorganisms in food. However, these methods are limited by time-consuming, cumbersome operations or high costs. The development of nanopore sequencing technology offers the possibility to address these shortcomings. Nanopore sequencing, a third-generation technology, has the advantages of simple operation, high sensitivity, real-time sequencing, and low turnaround time. It can be widely used in the rapid detection and serotyping of foodborne pathogens. This review article discusses foodborne diseases, the principle of nanopore sequencing technology, the application of nanopore sequencing technology in foodborne pathogens detection, as well as its development prospects. The incidence of foodborne diseases is gradually increasing, which has aroused people’s attention to food safety. One of the main causes of foodborne illness is eating food contaminated with bacteria, viruses, or toxins such as Campylobacter, Salmonella, Listeria, Norovirus, etc. . AccordiIn order to handle this global challenge, rapid detection of foodborne pathogens is needed. In the last decades, some effective methods have been developed for the rapid detection of foodborne pathogens in food products . CurrentDNA can provide more interesting information from the perspective of preventing and controlling foodborne diseases. The detailed genetic information not only facilitates accurate detection and typing of pathogens but can also support their source attribution through phylogenetic analysis.Advances in sequencing technologies have facilitated whole-genome sequencing (WGS) and metagenomic analysis . SequencThis review first introduces the principles of nanopore sequencing and subsequently describes its application in several areas of foodborne disease research. Finally, current challenges and possible future improvements in nanopore sequencing are discussed.The detection of pathogenic microorganisms that may exist in food processing links and food is an effective means of preventing foodborne diseases . On the The idea of using nanopores for sequencing was first proposed in 1980 . After aNanopore sequencing identifies base sequences using electrical signals, which means it has the ability to directly detect individual molecules such as DNA, RNA, and peptides ,41. CompThe frequency of global food safety issues has led to higher requirements for the detection of current foodborne diseases. With the development of sequencing technology, WGS has become a powerful tool for the detection of foodborne pathogens . Today, Nanopore sequencing has powerful advantages for rapid WGS analysis of foodborne pathogens. One of the advantages of nanopore sequencing technology is the simple and fast library preparation process . The libClear sequence data generated by WGS provides strong evidence for the identification and typing of foodborne pathogens. In the past few decades, short-read sequencing technology has been widely used in the detection of foodborne pathogens. However, when testing for foodborne pathogens, especially bacteria, due to the limitation of sequencing read length, short-read sequencing is not satisfactory for target gene detection, mapping complex repetitive regions, and genome assembly. For example, short-read sequencing may miss some randomly distributed genomic segments, leading to false detection of bacterial virulence factors and resistance genes. The advent of nanopore sequencing has changed that. Nanopore sequencing does not require the chain reaction of DNA polymerase. In theory, the length of the DNA molecule determines the length of the reads. Long reads provide a more definitive way to align and match DNA or RNA sequences, providing high-quality, more complete, and contiguous genome assemblies . It not The emergence of antimicrobial resistance (AMR) among foodborne pathogens is recognized as a major public health concern, as AMRs may spread along the food chain, leading to widespread acquired resistance to some antimicrobials . CompareThe ability to directly detect RNA is a powerful advantage of nanopore sequencing technology . At presRNA modification has always been a focus of attention. RNA modification involves transcription, transport, translation, and other processes, and plays an important role in cellular physiological activities . There aNanopore sequencing technology has the potential to facilitate the in-depth study of many biological processes and help uncover the complexities of mRNA processing and modification in various pathogens.Metagenomics refers to the genomes of the total microbiota found in nature . In receMetagenomics targets all microbial genomes in the environment. While this allows skipping the culture step and directly sequencing the pathogen of interest, it also means that it is necessary to screen for target sequences from a complex genomic background . In factReal-time monitoring of nanopore sequencing provides the possibility for efficient enrichment of target sequences. Compared with the original results of second-generation sequencing, which are stored in the form of fluorescent signals that cannot be processed in real-time, nanopore sequencing can monitor sequencing data in real-time through the changing trend of electrical signals. This unique advantage means that reasonable judgments can be made based on the real-time data obtained during the sequencing process. Real-time sequencing monitoring has important applications for specific target sequencing. Adaptive sequencing is a new technology developed based on nanopore sequencing . AdaptivFood commodities are often threatened by multiple foodborne pathogens, not just one. Achieving multiple identifications of viable bacteria is necessary for a good monitoring method . MetagenMetagenomics can also be applied to pathogen population-level studies. This will help us understand the association process of pathogenic microorganisms with various environments and reveal the mechanism of interaction between microorganisms. Metagenomics analysis of the microbiota present in the food supply chain can reveal the composition and overall changes of the microbial population. Yang et al.  used metEstablishing an effective surveillance system for foodborne pathogens, rapid and accurate identification of pathogens during foodborne outbreaks, and traceability of food sources are critical to preventing the further spread of infection . In an iThe establishment of a real-time monitoring and traceability system based on nanopore sequencing is conducive to real-time monitoring and early warning of foodborne diseases. Ideally, real-time sequencing data from metagenomic analysis would allow for initial rapid screening and serotyping in the early stages of foodborne pathogens outbreaks. The metagenomics-based database is then complemented by WGS through specific cultures to complete the characterization of the complete characterization of foodborne pathogens and trace the food sources and nodes leading to outbreaks.Poultry and related products are an important source of foodborne pathogens such as Campylobacter, Salmonella, Listeria, and others . ChickenBy using nanopore sequencing technology-based metagenomics analysis, the gut microbiota of poultry can be rapidly sequenced at any time. Through sequence analysis, the contribution of the gut microbiota to host health and a new approach to bypass the colonization of the gut by foodborne pathogens to enhance poultry health and ultimately improve poultry product safety and quality may be uncovered.Coronavirus Disease 2019 (COVID-19) refers to pneumonia caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It is transmitted by direct contact and aerosol and can cause clinical symptoms such as fever, dry cough, and fatigue in patients . COVID-1The ability of nanopore direct RNA sequencing can effectively reduce the time wasted in library preparation and RT-PCR. Additionally, when detecting the possible presence of SARS-CoV-2 on frozen food packaging, nanopore sequencing-based metagenomic analysis can quickly obtain results from the environment and trace the most likely contamination links, preventing further spread of the virus. Most importantly, COVID-19 has now spread globally, but some countries still lack corresponding testing methods. One of the reasons is that second-generation sequencing instruments such as Illumina are generally expensive and require a suitable installation environment. The advantages of nanopore sequencing portability and low cost mean that this emerging technology can play an important role in the detection of local and national SARS-CoV-2. Nanopore sequencing technology provides a new strategy for rapid detection of SARS-CoV-2 in non-laboratory settings. This is helpful for people to quickly check for viruses that may be attached to the surface of refrigerated food and prevent the further spread of SARS-CoV-2 along the cold chain.The unique advantages of nanopore sequencing have good application prospects in the food industry. However, some existing limitations pose challenges to the large-scale application of nanopore sequencing to the food industry. Firstly, although nanopore sequencing is still improving, the overall error rate of sequencing results is still higher than that of traditional sequencing methods. The error rate of nanopore sequencing correlates with the identification of characteristic electrical signals. On the one hand, the fast DNA translocation speed is the main factor affecting the accuracy of sequencing results . The speFoodborne diseases have shown a high incidence in recent years. Detection of possible pathogenic microorganisms in food and processing environments is a better way to reduce the occurrence of foodborne diseases. As a third-generation sequencing technology, nanopore sequencing has the advantages of fast, unlabeled, long read length, real-time sequencing. This article reviews the principles of this technology, the application in WGS and metagenomics, and its contribution to establishing real-time surveillance systems, improving poultry production, and combating COVID-19. It plays an important role in promoting the development of foodborne pathogens detection and studying microbial communities, and triggering a new revolution in food safety.Although nanopore sequencing technology has shown excellent performance and promise in foodborne pathogens detection, various challenges need to be solved to improve continuously. Much research work is still needed to achieve large-scale applications of nanopore sequencing. At present, the accuracy of nanopore sequencing still needs to be improved. Enhanced identification of characteristic peaks of electrical signals and improved bioinformatics tools may be the future development direction to reduce the error rate of nanopore sequencing. In addition, since solid-state nanopores can be preserved for a long time and reused, they can be an effective tool to replace biological nanopores. However, the technical problems and low signal-to-noise ratio of solid-state nanopores need to be solved. In summary, nanopore sequencing is a technology with great potential, which holds great promise in the detection and typing of foodborne pathogens. The combination of nanopore sequencing and other technologies is beneficial for establishing a pathogen monitoring system based on nanopore sequencing and applying it to the field of food quality control.


Marine microplastic pollution (MMP) is becoming one of the most pressing environmental problems facing humanity today. The novel coronavirus epidemic has raised the issue of environmental contamination caused by large-scale improper disposal of medical waste such as disposable masks (DMs). To assess the impact of MMP caused by DMs and to seek solutions for the prevention and control of MMP, this study uses the Driving force-Pressure-State-Impact-Response (DPSIR) framework to establish a causal chain of MMP caused by DMs. The conclusion shows that the novel coronavirus epidemic has led to a surge in the use of DMs, which has brought pressure on resource constraints and environmental pollution at the same time. Improperly DMs enter the environment and eventually transform into MMP, which not only endangers the marine ecological system but also poses potential human health risks as well as economic and social hazards. In addition, further research on environmentally friendly masks (cloth masks and biodegradable masks) is essential to mitigate the environmental damage caused by the large-scale global use of DMs. This study provides a scientific and theoretical basis for the assessment of MMP from discarded DMs, and the findings of this study will provide a reference for the formulation of relevant policies. The emergence of the novel coronavirus COVID-19) disease with strong contagiousness has attracted global attention since December 2019 9 disease,4. SinceDMs are mainly made of polypropylene (PP), which is considered plastic waste after being discarded. Its entry into the environment can cause plastic pollution and release microplastics, severely threatening the aquatic environment and aquatic life once they enter freshwater and coastal areas . The datSeveral studies have focused on the MMP induced by the rapid growth of waste in DMs. Sangkham measured the generation of DMs and medical waste in Asia during the outbreak and discussed the emerging challenges in solid waste management during and after the pandemic . Jung etIn order to fill this gap, this study analyzes and explores the problem of MMP caused by DMs from a multidimensional perspective, including social, economic, and environmental perspectives. The structured approach provided by the DPSIR framework is used to examine, in detail, the interrelations among the five components to better understand the current complex pollution situation of marine microplastics and the potentially significant pollution risks in the future. First, the driving forces of DM usage are discussed. Second, the social and environmental pressures created to meet human demand are examined. Then, the physical, chemical, and quantity states of the DM contaminants and the impact of their resulting impacts on marine ecosystems, human health and socioeconomics are examined. Next, responses to regulate the driving forces, mitigate the pressures and states, and impacts of MMP are reviewed from both upstream and downstream perspectives. Finally, specific recommendations for preventing and controlling MMP from DMs are derived.MMP is a complex environmental problem that requires an adaptive management framework that is action-oriented, integrated with an approach which is interdisciplinary in nature, incorporating both social and ecological systems . The DPSThe DPSIR framework is one of the key conceptual frameworks that are now widely used in marine environmental issues. It has been applied to various marine environmental issues, such as social-ecological systems in coastal environments , social According to the EEA , the comWith the widespread use of the DPSIR framework in environmental studies, the definition of the five components of the framework and the relationships among them have been explained in more detail. (1)The “driving forces” are the most primitive factors that cause environmental change and refer to the social, economic and institutional changes that directly or indirectly trigger environmental stress. It can be defined as “social, demographic, socio-economic development and corresponding changes in lifestyles, as well as overall consumption levels and production patterns” . Rodrigu(2)The “pressures” refer to anthropogenic factors that are directly applied to environmental systems by driving forces and contribute to environmental change, “including emissions of material, physical and biological agents, and the use of resources and space by human activities” . Pressur(3)The “states” indicate both qualitative and quantitative measurements of pollutants or the current state of the environment or environmental parameters that may change due to pressures . It is w(4)The “impacts” refer to the feedback effects of natural system states on human health, socioeconomics, and ecosystems, which often arise from adverse environmental conditions and are the result of a combination of the first three elements . Impacts(5)The “responses” refer to social actions taken by humans to prevent, mitigate, or eliminate negative impacts , which iThe DPSIR framework is used to address the MMP from DMs, following a typical five-step procedure . In thisThe COVID-19 pandemic has severely impacted the health and livelihood of people worldwide. DMs have a great filtering effect on aerosols and droplets, which can prevent respiratory diseases. Wearing DMs effectively reduces the probability of being infected by novel coronavirus , which mTo avoid the crisis of economic downturn and communication blockage brought about by precautionary measures such as lockdowns and travel restrictions, people in different countries choose to wear DMs on a large scale, while maintaining social distancing, keeping good hand hygiene (hand washing), and avoiding public or crowded spaces as alternative measures to keep society functioning properly .Since 2020, health authorities in different countries have issued various recommendations for using face masks to protect against COVID-19, which tend to be dynamically adjusted  32]. Wh. Wh32]. The raw materials of DMs are mostly made of petroleum-based polymer-PP (PP) fiber, which is a non-renewable resource. Therefore, the massive use of DMs can cause a large consumption of natural resources. Furthermore, DMs are used in a wide range of applications and scenarios. They are likely to be directly discarded in municipal solid waste without safe disposal measures or directly in the environment. This creates new challenges for medical waste management, which will worsen especially for developing countries with inadequate waste management . Discarded DMs are found scattered in public places such as parks and streets all over the world . A studyThe DMs are made of melt-blown fabric, non-woven fabric, mask straps, and nose clips. Melt-blown fabric is the core material used to produce DMs, whose main component is PP. The melt-blown cloth consists of ultra-fine fibers with diameters of about 1–5 microns arranged randomly to form numerous tiny pores that trap dust due to the electrostatic effects. When the droplets containing various types of viruses approach the PP melt-blown fabric, they can be adsorbed on the surface of the melt-blown fabric and cannot penetrate. Thus, DM has a strong filtration property, sufficient to reject bacteria, suspended particles, liquid droplets, and aerosols. The inner layer, near the mouth and nose, is made of hot-rolled nonwoven fabric to absorb moisture and ensure that the wearer’s lips are dry and comfortable. The entire mask is designed to fold to improve its fit to the wearer’s face, blocking more than 90% of the 5μm particles. The structure of DMs varies slightly between standards, with disposable surgical masks and N95 masks having a high acceptance rate among health workers and the public . Their sExperimental results show that individual N95 masks and disposable surgical masks have approximately 11 and 4.5 g of PP and other plastic derivatives , respectively ,47. BecaThe use of DMs has reduced the spread of the virus in society while simultaneously causing severe environmental problems in terms of microplastic pollution. During the use of DMs, extremely fine nonwoven fibers tend to break off and form microplastics. Mechanical wear and tear between the fibers is further exacerbated by the repeated use of DMs over time, leading to extra microplastics. In addition, DMs may intercept microplastics in the air during use, thus increasing their microplastic carrying capacity . 21 units of microplastic into the environment [Discarded DMs enter the ocean through improper landfills and dumping treatment. They disintegrate into tiny plastic fragments under a range of physical and chemical effects, such as solar radiation, biological erosion, low-temperature weathering, tidal, wave washing, and so on. As the DMs gradually age and decompose in the environment, the entire DM will become completely microplastic and enter the ocean . Shen etironment . Using kironment . The avaUnlike other plastic products such as plastic bags and bottles, DMs are more likely to be damaged and decomposed in the natural environment, releasing additional microplastic fibers . The melDiscarded DMs entering the environment may not only entangle the bodies of marine wildlife but also release microplastics that are preyed upon by marine life, thus affecting normal growth and reproduction . ExperimMicroplastics have been found in organisms at different levels of the marine food chain ,62. The With the increasing amount of marine organisms caught and seafood supplied by aquaculture year by year, microplastic particles in these marine organisms and aquaculture products may eventually enter the human food chain. The pollution status of the marine environment by microplastic is a potential health problem for humans. It has been shown that harmful microorganisms could attach to plastic debris , increasFoods made from marine organisms, such as fish, are an important food source for humans. MMP raises concerns about global food security, which may eventually lead to the consequences of food shortages . In the To respond to the impact of MMP from DMs, especially the impact on marine ecosystems, the potential impact on human health, and the impact on the economy and society, a series of prevention and control strategies have been developed at different levels. According to the principles of source reduction and process management of MMP prevention and control , the resIn the context of the normalization of epidemic prevention and control, DMs have become an immediate need in people’s daily lives, and their demand cannot be reduced in the short term . The fun(1) Improving public participation in the proper disposal of DMsGuiding the public to properly dispose of DMs is the most effective way to properly prevent the problem of microplastic pollution at the source. Used DMs can greatly reduce the risk of environmental contamination after proper disposal such as disinfection and incineration ,78. At p(2) Strengthen the management of DM wasteDue to the disposable natures of DMs, recycling as a reduction pathway to achieve more limited results, and scientific management based on the disposal process will be sought to reduce the risk of MMP caused by DMs. The COVID-19 pandemic has increased the pressure on municipal waste management, which can lead not only to the spread of the virus but also to environmental problems if not handled properly . TherefoCurrently, several medical waste bins with clearly marked points are placed in public areas such as hospitals and communities to collect discarded DMs. They are packaged in double-layered medical waste bags and disposed of as general medical waste by specific personnel, municipal solid waste workers, and special waste management departments of companies . (3) Using cloth masks or biodegradable masks as an alternativeThe promotion of cloth masks can effectively reduce the consumption of DMs ,45. ClotThe development of biodegradable masks is another solution idea to reduce the risk of the DMs contamination. The advantage of biodegradable materials is their biodegradability through composting, which avoids environmental hazards at the source to some extent. The biodegradable polymer and bio-based material electrospun ensemble can be used as the main material of masks. Experiments revealed that this type of mask reaches 98% particle filtration efficiency during use, and its waste can be biodegraded within four weeks . In addiThe downstream responses mainly focus on recycling and reusing discarded DMs to reduce the risk of MMP. Medical plastic waste generated during the epidemic has a high calorific value compared to other conventional fuels, accounting for nearly 25% of the calorific value of municipal solid waste . Discard(1) Physical-mechanical recyclingImproving the process of mechanical recycling of DMs can produce the recycled product, recycled polyethylene, with better stiffness and strength, which enables physical and mechanical recycling ,91. The (2) Chemical recycling2, CH4, and CO, which suggests an environmentally benign disposal process [Multi-stage pyrolysis was used to catalyze the cracking of discarded DMs to generate H process ,93. Xian process . TherefoDMs, as a new type of microplastic pollutant, can continuously release microplastics into the marine environment through the water systems. However, the rigidity of their demand and single-use nature makes it difficult to establish closed-loop chain management of the entire life cycle such as source reduction, waste process control, and end-of-life recycling. This study is based on the analytical framework of DPSIR, which seeks more effective management measures to curb the MMP prevention and control brought by discarded DMs. The results of the study show the surge in demand for DMs’ uses under the three driving forces of human health risk, social demand, and mask policy promotion in the context of the COVID-19 epidemic, increased the risk of non-renewable resources such as oil tension, plastic waste increase, and microplastic flow into the environment, thus increasing the pressure on both resources and the environment. In addition, the physical-chemical composition of discarded DMs leads to waste ending up in the ocean in the form of large amounts of microplastics. In order to effectively reduce the impact on the marine ecosystem, human health, and socioeconomics caused by MMP from DMs, response mechanisms are proposed for upstream and downstream in a targeted manner.In view of this, countries around the world should guide the public on the proper disposal of DMs and educate the public on the environmental responsibilities that individuals should assume. Secondly, it is necessary to strengthen the management of DM waste and improve the infrastructure to help the public dispose of DMs reasonably. In addition, a system of rewards and penalties for recycling DMs could be developed as a complement to fully incentivize the public to dispose of DMs reasonably. Moreover, eco-friendly alternatives such as cloth masks and biodegradable masks with filtration efficiency that meet basic protection needs and have a longer life cycle can be developed. In addition, further research into the risks of MMP from DMs is essential, and new technologies should be developed to overcome the problems associated with the release of microplastics from DMs.


Recombinant therapeutic proteins (RTPs) are important parts of biopharmaceuticals. Chinese hamster ovary cells (CHO) have become the main cell hosts for the production of most RTPs approved for marketing because of their high-density suspension growth characteristics, and similar human post-translational modification patterns et al. In recent years, many studies have been performed on CHO cell expression systems, and the yields and quality of recombinant protein expression have been greatly improved. However, the expression levels of some proteins are still low or even difficult-to express in CHO cells. It is urgent further to increase the yields and to express successfully the “difficult-to express” protein in CHO cells. The process of recombinant protein expression of is a complex, involving multiple steps such as transcription, translation, folding processing and secretion. In addition, the inherent characteristics of molecular will also affect the production of protein. Here, we reviewed the factors affecting the expression of recombinant protein and improvement strategies in CHO cells. In recent years, the demand for biopharmaceuticals has been increasing and innovative and improved bioprocessing technologies are essential to meet the demand for industrial production of products. As an important part of biological drugs, recombinant therapeutic proteins (RTPs), especially RTPs represented by recombinant antibodies, have achieved good efficacy and great economic benefits and have received more and more attention. Mammalian cells have become the main host cells for the production of RTPs because of their ability to perform post-translational modifications (PTMs) such as correct folding and glycosylation of recombinant proteins. Since the production of tissue type plasminogen activator (tPA) in Chinese hamster ovary (CHO) cells in 1986, CHO cells have become the production host of most approved recombinant proteins and recombinant antibody drugs due to their high density suspension growth, PTMs similar to humanized cells, easy gene operation and process scale-up. This expression system has been used to produce 84% of the antibodies approved during 2015–2018, accounting for more than half of all approved antibodies during this period . By 2019With the advancement of CHO cell line development and process optimization, the yields of recombinant mAbs  of CHO cells have achieved as high as 5 g/L, or even more than 10 g/L . AlthougFrom gene structure to correctly folded protein products, a series of procedure are involved, such as transcription, translation, PTM, protein folding, and secretion et al. The nucleotide sequence of its coding region determines the amino acid sequence of the corresponding protein. Transcription process can control protein production in CHO cell, and the stability of mRNA is directly related to the number of translation products mRNA produced by transcription is prone to degradation, so the degradation rate of mRNA directly affects the expression level of protein . Mature When proteins are synthesized on ribosomes, signal recognition particle (SRP) in the cytoplasm recognizes signal peptides that newly generate 5∼30 amino acids at the N-terminus of proteins and function to transport proteins into the correct subcellular compartment . Next, SPolypeptide chains with complete primary structure can have normal biological activity only when they fold into the correct three-dimensional spatial structure. If the folding process is wrong and a misplaced spatial structure is formed, they will lose their biological function and may even cause diseases. Typically correctly folded proteins form small vesicles that leave the ER, which move toward the Golgi and fuse with its membrane. Transport inside the Golgi and transport of proteins from the Golgi to the plasma membrane are also mediated by vesicles. If the high concentration of heterologous protein exceeds the secretory capacity of CHO cells, it will lead to inefficient secretion, protein degradation, intracellular and extracellular aggregation, etc., which in turn affects the yield of protein . The inhPTMs, usually in two ways, through proteolytic cleavage and covalent modification through amino acids, may lead to changes in protein characteristics and function . When thAlthough the technology of producing recombinant protein by CHO cells has been more mature and a large number of recombinant proteins have been successfully produced, there are still some proteins that are DTE and proteins with low expression levels. To solve this problem, the main strategies mainly include ar the increasing the cell viability, viable cell density, and cell specific production rate (Qp) through some molecular and cell methods, using genetically engineered cell lines.Ribosomes have traditionally been considered deciphers of the 64-word genetic code translated into complex proteins, while ribosomes can also shape the transcriptome by controlling mRNA stability. In recombinant protein production, the expression rate, yield, and final product quality are affected by the codon bias of the relevant gene and the codon bias of the expression system . AlthougGene sequence optimization can also adjust the GC content of genes, avoid base duplications, and eliminat restriction enzyme recognition sites, and also avoid similarity to important RNA motifs located in open reading frames that may interfere with mRNA processing and translational function, because they may cause ribosome pausing, in addition to factors such as CpG content and TATA boxes. Another 5′ untranslated region (5′ UTR) insertion into the RNA hairpin structure, the “regulatory element (RGE)”, also improves expression . In addiIn mammalian cells, a highly complex process controlled by multiple DNA signaling elements and corresponding trans-acting factors is called transcription. In this cascade, promoters play a key role in integration and transcriptional signal processing, therefore, selecting the correct promoter, optimizing the combination of the promoter with different regulatory elements, and preventing promoter methylation can improve the expression and stability of recombinant proteins . In CHO Due to the structure of heavy chain (HC) and light chain (LC), the matching of HC and LC is need to be considered in the construction of expression vector. When free LC does not bind to HC, HC is misfolded, assembled and accumulated. LC peptides are very important for the efficient folding and assembly of Mabs. IgG antibody sequences with high aggregation/aggregation tendency are more likely to form Russell bodies in the ER lumen. LC and HC cannot be completely and correctly folded and assemble to form heterodimers in the endoplasmic reticulum and Golgi apparatus, which will cause inefficient assembly and affect antibody yield  and overIt has been found that random transgene insertions may be associated with position effects. Inefficient transgene expression is mainly due to transcriptional silencing, involving chromatin condensation, histone deacetylation and methylation at CpG sequences. By changing the structure of chromatin through specific chromosomal elements and maintaining chromatin in an open state, the transcription level of target genes can be increased. For example, ubiquitous chromatin opening element (UCOE) , as wellThe entire “CHO cell system” includes a variety of different cell lines, which are likely to come from the first isolation of clone, naturally immortalized CHO in 1956 . The proIn general, the factors that affect product quality depend on the type of RTPs and the rCHO cell line used. In a mathematical modeling of recombinant Mab manufacture in seven GS-CHO cell lines, the improving of Mab production through cell line modification should be cell line specific . The difIt is crucial to randomly integrate the transgene into CHO host cells and select the appropriate cell line to produce the protein of interest (POI). Generally, the most commonly used methods to engineer cell lines include gene overexpression and gene knockout, and the former method is to introduce the GOI into the host cell to realize the overexpression of POI. Knockout is more specific to delete a gene from the genome by chemically and radiation-induced random mutation or gene editing directed mutation, or to shut down its function and target genetic engineering, which is superior to random mutation. In this regard, the most advanced technologies mainly include zinc finger nucleases (ZFNs), transcription activator-like effector nuclease transcription activator-like effector nuclease (TALENs) and regularly clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-related protein 9 (Cas9) systems , which aMammalian cell lines are engineered by cell engineering strategies, such as anti-apoptotic engineering, metabolic engineering, cell cycle engineering, and protein PTM engineering, overexpression of dominant genes, gene knockout, and siRNA interference to inhibit unfavorable gene expression to improve the performance of cell lines, effectively improve cell viability, and improve the yield of recombinant proteins. In addition, non-coding RNAs technology can also improve and improve cell lines in growth, apoptosis inhibition, metabolism, yield, and the ability to express glycosylated recombinant proteins , with grCell apoptosis refers to the autonomous and orderly death of cells controlled by genes to maintain the stability of the internal environment, which can reduce apoptosis and prolong culture time during bioprocessing, thereby increasing volume product yield . OverexpMicroRNAs are defined as small molecules of 22–25 nucleotides that can regulate approximately 100 mRNA targets involved in one or more regulatory networks simultaneously. Studies have demonstrated that up-regulation or down-regulation of microRNAs in host cells can change productivity levels by regulating cellular processes, such as apoptosis, cell cycle, histone methylation, and cell growth  and otheMost metabolic engineering can reduce the accumulation of toxic by-products and improve protein production, which can regulate many biological process-related traits through CHO cell metabolic engineering, such as glycosylation . ChanginAlterations in cytoskeletal protein expression are thought to affect cellular processes associated with recombinant protein production, including transcription, cell cycle progression, metabolism, and secretory vesicle trafficking. Differential expression of cytoskeletal proteins has been observed in modified or gene-amplified cell lines , and botThe substances and energy required for biochemical reactions such as new cell synthesis and cell metabolism are obtained from the culture medium. It was found that amino acids as the backbone in the medium component had a significant effect on product formation and critical quality attributes of mAbs. Recombinant protein production requires high amino acids to support not only host cell growth and heterologous recombinant protein synthesis, but also provide raw materials as carbon and nitrogen sources for nucleotide, lipid, ATP, and NADPH synthesis . NutrienDuring the optimization of production process, the effects of culture medium on cell viability, metabolism, and product quality should be considered. In the early stage, necessary nutrients were provided by the serum of animal tissues or blood. Due to the regulatory limitations of mAb production, the serum-free medium formulation was invented, thus avoiding the use of serum in cell culture . There aUsing CHO mAb cell line, the fed batch culture was increased by 12-fold compared with batch culture, while the optimal choline chloride to glucose ratio of batch culture CHO cells could be optimized, the culture time could be shortened, and the protein yield could be improved . It was To better maintain product quality during culture, it is important to minimize the accumulation of host cell proteins in the culture medium, otherwise it will damage product quality. In the process of rCHO cell culture, there are thousands of host cell proteins (HCPs) in the culture supernatant, and the total number and number of different types of HCPs depend on the host cell type, culture method and culture time. Due to higher cell concentrations and longer culture cycles, the extracellular accumulation level of HCPs in fed batch cultures is much higher than that in batch cultures . Removal2 and O2 dissolved oxygen should also be coordinated.Cell culture parameters for Qp include partial pressure of carbon dioxide, osmolality, temperature, dissolved oxygen, and pH, and improvements in cell secretion, folding, and glycosylation are important ways to optimize mammalian cell production systems . The optMolecular chaperones are a family of proteins whose role is to assist in the folding and targeting of proteins in normal and stressed cells. Insufficient supply of chaperones limits correct protein folding in recombinant protein production. Intramolecular chaperones can help protein folding and assist protein subunits to correctly fold with multiple subunits to assemble into intact proteins  Fatima . FollowiSignal peptides transport proteins to the correct subcellular compartment, but natural signal peptides are not necessarily optimal . MoreoveAnother factor causing insufficient protein production is the inherent toxicity of proteins. Avoiding exposure of cells to high concentrations of protein, or optimizing cell lines to resist toxic proteins, can promote growth and then increase yield. Protein toxicity can be mitigated by a variety of methods. One approach is to change the protein itself to reduce its cytotoxicity modify the protein to produce a more stable, less toxic form, and the other option is to change the promoter in the expression vector rather than the POI. The inherent characteristics of molecules can also lead to easy degradation, aggregation and other adverse protein-protein interactions of proteins, which leads to cytotoxicity. If the GOI is determined to be toxic, then one option to increase yield is to adapt host cells and reduce growth process by-products . DecreasTo improve the protein production capacity of recombinant proteins in CHO cells, the bottlenecks in transcription, translation, PTMs, protein folding and secretion during the production process must be recognized, and solutions must be developed for each rate-limiting step. Cell engineering technology can precisely control the relative expression of multiple functional gene components, which in turn affects protein yield. New therapeutic applications are opened up using new protein forms such as bispecific antibodies and fusion proteins. An understanding of the critical quality attributes of RTPs during CHO cell culture and their contributing factors is critical to the production of high quality RTPs. The proper assembly of these new RTPs may be more complex, which may affect productivity and potency. The solution strategy can start from the molecular design of proteins, combined with appropriate cell line, vector engineering and process optimization, based on the understanding of folding mechanism and the understanding of potential bottlenecks, optimize protein secretion and prevent aggregation, maximize the yield of recombinant proteins, reduce large-scale production costs, and promote the development of biopharmaceuticals.


Intestinal environment disorder is a potential pathological mechanism of obesity. There is increasing evidence that disorders in the homeostasis of the intestinal environment can affect various metabolic organs, such as fat and liver, and lead to metabolic diseases. However, there are few therapeutic approaches for obesity targeting the intestinal environment. In this review, on the one hand, we discuss how intestinal microbial metabolites SCFA regulate intestinal function to improve obesity and the possible mechanisms and pathways related to obesity-related pathological processes . On the other hand, we discuss dietary management strategies to enrich SCFA-producing bacteria and target specific SCFA-producing bacteria and whether fecal bacteria transplantation therapy to restore the composition of the gut microbiota to regulate SCFA can help prevent or improve obesity. Finally, we believe that it will be of great significance to establish a working model of gut– SCFA– metabolic disease development in the future for the improvement this human health concern. Obesity is among the largest health epidemics of the twenty first century, with a prevalence of ~13% in the world's adult population, and it is a major contributor to global diseases such as diabetes, cardiovascular disease and cancer and premature death . ObesityTo date, there is growing evidence that the gut microbiota regulates the effects of diet and alters host metabolism and the incidence of metabolic disorders. The gut microbiota produces a wide range of metabolites that act as messengers between microorganisms and their hosts. Microorganisms produce these metabolites as intermediates in their constituent metabolic pathways to chemically modify specific dietary components through enzymatic reactions unrelated to normal metabolism. Most of these metabolites have beneficial effects on the host , 15. ShoEvidence from nearly a decade of studies has shown that obesity is associated with gut dysfunction . First, 2+ levels, which act as a secondary messenger to initiate biological effects and activate various downstream signaling events, such as protein phosphorylation and changes in cellular behavior , also known as free fatty acid receptors (FFARs), including GPR41 (FFAR3), GPR43 (FFAR2), and GPR109A, are mainly expressed by IECs, especially intestinal endocrine cells , 62, 63.behavior –68. The pression –71.Based on the response mechanism of SCFA receptor activation, many studies have proven that the activation/damage of SCFA receptors produces a significant response, especially in the intestinal tract, in early life  Figure . HFD int+-coupled transporters [monocarboxylate transporter (MCT)1/4] and Na+-coupled transporters [sodium-coupled monocarboxylate transporter (SMCT)1/2] transfer SCFA to colon epithelial cells and play specific roles in the absorption and utilization of SCFA in the intestine  . HDACs aBlautia is the only bacterium for which its abundance is negatively correlated with visceral fat area, which may be related to its ability to produce SCFA to regulate GPR41 and GPR43, promote fat decomposition and reduce fat accumulation , which is thought to be associated with obesity, has been shown to be significantly reduced in obese children ; on the other hand, SCFA production was increased by altering the abundance of Bacteroidetes, which produce acetate and propionate. Moreover, SCFA play a key role in supporting the differentiation of mucus-secreting goblet cells, promoting the maturation of Wnt3- and defensin-secreting Paneth cells, and promoting the proliferation of IECs in a GPR43/41-dependent manner (A. muciniphila can degrade human milk oligosaccharides (HMO) to produce acetate and propionate to maintain a healthy mucosal layer and metabolic state under in vitro culture conditions containing breast milk , carnitine palmitoyltransferase 1 (Cpt1), and hydroxymethylglutarate coenzyme A (HMG-CoA) synthase are all affected by A. muciniphila. In addition, Fiaf has been found to be related to obesity and can regulate lipid metabolism in different tissues, while A. muciniphila and its related SCFA metabolites can induce the expression of Fiaf, inhibit the generation of low-density lipoprotein (LDL), and maintain lipid homeostasis and metabolism in intestinal and peripheral tissues  has become a hot research topic –131. In t behind . In addit behind . This in obesity . All theObesity is a major global health problem, and its incidence is increasing each year. It is a chronic disease that affects various physiological systems, among which the intestinal tract has become the main target of study. In recent years, increasing evidence has shown that obesity is related to intestinal health. Studies have shown that the characteristics of the gut environment in obese individuals are related to the following aspects: intestinal immune responses promoting intestinal inflammation, reduction in intestinal microbial diversity and changes in intestinal microbial composition, damage to the integrity of the intestinal epithelial barrier, bacterial translocation, and increased LPS levels, decreased levels of intestinal hormones released by intestinal endocrine cells , and abnormalities in intestinal fat absorption and metabolism. These findings suggest that intestinal intervention is a promising target for the treatment of obesity and related metabolic diseases.in vivo, as well as intestinal permeability, markers of metabolic disorders, obesity and hypertension. Activation of SCFA transporter receptors can promote the transport of SCFA, increase the absorption and utilization of SCFA in the intestinal tract, regulate the concentration of SCFA in intestinal and extraintestinal tissues, reduce tissue inflammation caused by obesity, and regulate energy metabolism. (3) The SCFA non-receptor-dependent pathway inhibits the HDAC receptor-independent pathway. Interestingly, HDAC3, a specific HDAC, plays a significant role in integrating microbial signals to regulate intestinal homeostasis and regulate the expression of genes involved in lipid metabolism in a variety of tissues, especially through inhibiting transcription of the PPAR nuclear receptor family and inhibiting lipid oxidation. In addition, SCFA play a role in regulating gut microbes. The use of microbiome regulation has become an attractive strategy reported in several clinical studies. In this regard, the second part of this review summarized the use of microbial-oriented therapies to trigger the metabolism of intestinal microorganisms in the body, especially the enrichment of some SCFA-producing bacteria or the targeting of specific SCFA-producing bacteria, such as the representative A. muciniphila strain, to improve the intestinal environment to help obese adults lose weight. This is mainly done using the following two methods for enriching/targeting SCFA-producing bacteria to intervene in the occurrence and development of obesity. The first is the most common strategy: dietary management. SCFA-producing bacteria can be enriched/targeted by the use of certain dietary treatments or certain drugs to promote the production and transformation of SCFA by intestinal microorganisms. The second is a microbe-based therapy—FMT therapy—continuous FMT treatment improved the metabolic disorder of obese people, and could produce the effect mainly due to its effects on the metabolism of the gut microbes, and especially through the increase in microbial SCFA gene expression levels. However, it is worth noting that the microbiome is a complex ecosystem, and whether SCFA play a role directly or by regulating gut microbes remains to be explored. However, the clinical therapeutic effects of dietary management, drug therapy and fecal bacteria transplantation are still controversial and complicated, and there are inconsistent data on response rates and adverse events. Therefore, the physiological and pathophysiological functions of SCFA should be fully investigated, and we think in the future, further study of SCFA in obesity and related metabolic diseases and the mechanisms through which they affect the intestinal environment is required, and how to better apply the regulation of SCFA produced by gut microbes to treat diseases await exploration.In the past decade, biological studies combining animal models and human studies have shown that gut microbes produce a large number of metabolites that regulate host responses and play an important role in human health. As one of the important metabolites of intestinal microorganisms, SCFA have a variety of beneficial effects on host energy metabolism regulation, especially in obesity and related metabolic diseases. As a bridge between obesity and intestinal homeostasis, SCFA are closely related to the pathogenesis of obesity and related metabolic diseases. SCFA are thought to be ligands that activate cellular signaling cascades. Specific cell signaling receptors, such as GPCRs, MCT and SMCT, and the epigenetic process, and, namely, the inhibition of HDACs, regulates the intestinal environment in obesity. Based on this knowledge, the first part of this review summarized the dependent pathways through which SCFA activate SCFA-associated receptors: (1) The establishment of the SCFA-GPR43/41-GLP-1 axis induces the release of endogenous GLP-1 and other intestinal hormones by intestinal epithelial cells (Colon L cells) to stimulate insulin secretion to improve glucose homeostasis, especially in the early stages of life. (2) By activating SCFA transporters (MCT and SMCT), which are responsible for the entry and transcellular transfer of SCFA into the intestinal epithelium, these receptors are closely associated with higher concentrations of SCFA in serum and feces HY participated in the production, creation, and drawing of the manuscript. JG and QC participated in the revision, conception, and drafting of the manuscript. YT, DY, SQ, YB, JH, HC, and QC participated in the review and revision of the manuscript. All authors contributed to the article and approved the submitted version.This work was financially supported by the Science and Technology Program of Guangzhou, China (NO.202103000089), the Guangdong Demonstration Base for Joint Cultivation of Postgraduates (2019), the Science Foundation for Distinguished Young Scholars of Guangdong (2020B1515020026), and the National Natural Science Foundation of China (21804025).QC was employed by Guangzhou Rainhome Pharm & Tech Co., Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.