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Stroke is a medical condition in which occluded blood flow to the brain causes cell necrosis. The main types of stroke are ischemic (due to lack of blood flow with much higher prevalence) and hemorrhagic (due to bleeding with low prevalence). Ischemic stroke is caused by the reduction of blood to the brain tissue or complete occlusion of brain vessels by a blood clot following arterial plaques rapture of cerebral arteries due to atherosclerosis, cerebral myocardial infarction and small vascular lesion infarction. Inflammatory reactions, increased oxidative stress, cell death and autophagy are the most aggravating factors in this condition. Instead, hemorrhagic stroke is caused by spontaneous intracranial hemorrhage and subarachnoid hemorrhage, highly common in men. To prevent the possible causes of stroke, investigators attempted to study about the ways that may decrease the risk factors such as trauma, high arterial hypertension, alcohol, low-density lipoprotein and glycerides, tobacco and drugs. Physical activity is a potent inhibitory factor which reported to be effective in prevention of stroke and post-stroke rehabilitation. Aerobic, combined or strenuous activities protect brain tissue by balancing apoptotic and anti-apoptotic pathways, stimulating angiogenesis, reducing oxidative stress, increasing antioxidant activity, optimizing Integrity and preservation of the blood-brain barrier, improving nerve functions and preventing neuronal death. The mechanisms involved in rehabilitation after ischemic stroke with physical activity mostly refer to improved dendrites and synapses, synaptic flexibility, regulation of inotropic receptors with glutamate, increased BDNF, GAP43 and insulin-like growth factor. In patients with cognitive impairments following acute ischemic stroke, high intensity exercise improves processing timing and attention allocation, self-independence, walking ability, aerobic power and reduces memory degradation. Moreover, early start of physical activity after ischemic stroke inhibits the initial physiological response to stroke and prevents optimal recovery. In contrary, reports show positive effects of onset of physical exercise a day after stroke. In hemorrhagic stroke, exercise reduces systolic blood pressure, moderates resting blood pressure via parasympathetic regulations and triggers angiogenesis in the nervous system. Light to moderate or long-term physical training is recommended in comparison to short-term high-intensity training. In addition, early onset of physical activity during recovery after stroke may be beneficial.

Background: Coronaviruses were discovered in 1960. Large-sized living organisms from the Coronaviridae family, with single-stranded RNA of animal origin. Coronaviruses in humans can cause mild respiratory illness or severe respiratory illness. In 2020, the World Health Organization declared COVID-19 a global pandemic. The aim of this study is to use the Jaccard similarity coefficient to determine the similarity of COVID-19 behavior patterns in different seasons of the year. Methods: This study used machine learning systems and similarity metrics to determine the behavior pattern of COVID-19 in different seasons of the year. The location of research was the Mousa ibn Ja'far Hospital in Mashhad, and the time was from May 2020 to August 2021. The symptoms of affected patients were compared with the compiled dataset, and the similarity of patients was prepared in a similarity matrix, and the Jaccard correlation coefficient was calculated on the data. Finally, the analysis of strains from the beginning of emergence to the latest strain was examined. The performance indicators of the algorithm in the Jaccard similarity method showed a recall metric with a value of 0.94, a precision metric with a value of 1, an F1 score with a value of 0.86, and remove accuracy metric with a value of 0.76. The most important factors in the investigation include white blood cells, platelets, RT-PCR, CT SCAN, shortness of breath, fever, SPO2, and respiratory rate. Results: The transmission of the COVID-19 virus depends on several factors, including human interaction. The evidence of the collected data shows that people with COVID-19 have low lymphocyte count and it is very consistent with the results of recent studies. Due to the lack of a dataset, a comparative study was conducted and a dataset was collected. Conclusion: This study, leveraging machine learning algorithms, identified a clear seasonal correlation in the spread of COVID-19. Considering geographical and seasonal variations among patients, distinct symptoms were observed in each season corresponding to the prevalent strain during that period.

Background: Despite advances in medical treatments, readmission of stroke patients remains high and has been reported between 31% and 56.1% during the first year after discharge. The difference between the risk factors of readmission and the risk factors of stroke is not clear. The purpose of this study is: 1) to determine the preventable risk factors associated with stroke readmission and 2) to provide a conceptual model for preventable factors that effective in the readmission of stroke patients. Methods: This integrated review was performed according to Whittemore and Knafl (2005) method in five stages including problem identification, literature search, data evaluation, data analysis, and presentation. In order to find relevant articles, PubMed, Web of Science, CINAHL, Scopus databases and Google Scholar search engine were searched. The search was conducted using the keywords "stroke," "readmission," "recurrence," "re-hospitalization," "review," and "systematic review," for the period between January 2023 and September 2023, following the PRISMA guidelines. In addition to providing a qualitative synthesis of readmission factors categorized into categories, a conceptual model of these factors was also presented. Results: Out of a total of 3785 article titles, 38 articles were included in the study for the final analysis after screening and removing duplicates. The most important risk factors for readmission in four categories: (1) knowledge deficit about the comorbidities (such as hypertension, atrial fibrillation, diabetes), (2) unhealthy diet and medicine, (3) high-risk behaviors (smoking, alcohol consumption, and tobacco use disorder), and (4) psychological distress (depression and worry about the future). In addition, the conceptual model showed that the most important preventable factor in readmission of stroke patients is of knowledge deficit about comorbidities (especially hypertension). Conclusion: The most important preventable risk factors that are effective in the readmission of stroke patients are knowledge deficit regarding clinical risk factors, especially high blood pressure, high-risk behaviors and unhealthy diet and medicine. Therefore, more detailed care and follow-up programs should be designed for stroke patients after discharge.

Background: In health care, the well-being and flexibility of the operating room staff are of great importance due to the hard and stressful nature of their work. Therefore, this study was conducted to determine the effect of Stoic resilience training on the resilience of operating room staff. Methods: The present study was a semi-experimental pre-test-post-test intervention study with a control group. A study was conducted among 67 people operating room staff working in Imam Ali and Imam Hassan hospitals in Bojnord city in September 2023 In this research, the demographic check list and the Connor and Davidson standard resilience questionnaire were used to collect information. The educational intervention was also implemented using the “SeRenE” Stoic education package. This training package includes 4 exercises, which were used only 3 exercises per day and for 6 consecutive days (45 minutes per day) due to the resilience variable. Statistical analysis was done using SPSS version 24 and at a significance level of 0.05. Results: Based on the results, the total resilience score increased after the Stoic training (72.03±8.31) and showed a statistically significant difference with the control group (65.03±11.16) (P>0.05). The results showed that after Stoic training, mean of subscales of competence, trust in one’s instincts, tolerance of negative affect, positive acceptance of change and secure relationships, control as well as the total score of resilience increased in the training group. Although the mean score of spiritual influences dimension increased after the training, this increase was not statistically significant (P=0.097). Conclusion: The findings show that Stoic training had a positive effect on various aspects of resilience among operating room staff, whose effects are more obvious in some subscales such as trusting individual instincts, tolerance of negative emotions, and positive acceptance of change. In general, the results showed that people's resilience increased after Stoic training. It is recommended to include Stoic training programs in the training of health personnel and caregivers.

Background: Today, Methicillin-Resistant Staphylococcus Aureus (MRSA) has become one of the public health concerns due to its resistance to antimicrobial drugs, and this problem makes treating patients with infections caused by this bacterium difficult. Infections caused by methicillin-resistant Staphylococcus aureus (MRSA) strains are pervasive in both community and hospital settings, primarily attributable to Staphylococcus aureus' capacity to colonize areas like the nose or skin. In this study, with the aim of comparing phenotypic (disc diffusion method) and genotypic (PCR) methods, to detect methicillin-resistant Staphylococcus aureus isolated from patients of hospitals under supervision of Tehran university of medical sciences, and also detection of nor A, that is the one of the most important genes in efflux pump cluster genes. Methods: The present research was a cross- sectional study that was conducted from February 2022 to September 2023. In this research, 43 isolated strains of Staphylococcus aureus from wound discharge and blood samples, were collected from different departments of Tehran hospitals and had submitted to the research laboratory of the school of allied medical sciences in Tehran university of medical sciences. After identifying the strains, the resistance of the isolates to 14 types of antibiotics was checked by disk diffusion method. Results: Staphylococcus aureus diagnostic tests including gram staining on colonies, catalase, coagulase, DNase tests were performed and it was found that all strains were Staphylococcus aureus. In the next step, all samples were resistant to Cloxacillin by disc diffusion method, and the presence of mec A gene in them was confirmed by PCR method, thus the presence of MRSA strains was confirmed from the genotypic point of view. Of the 43 Staphylococcus aureus strains, 26 samples were identified as having the nor A gene by PCR and electrophoresis. Conclusion: The results of the present research have shown that the prevalence of Staphylococcus aureus bacteria in hospital samples is significant and resistance to methicillin and ciprofloxacin has increased in the strains of this bacteria.

Background: Identifying the epidemiological aspects of central nervous system (CNS) tumors is the first step in implementing management protocols to control the condition of these tumors. We aimed to examine the epidemiology and histopathology of both benign and malignant tumors of the CNS in one of the referral and university centers in the east of Iran. Methods: This cross-sectional study was conducted on all files of patients admitted to Qaem Hospital in Mashhad City, Iran, in a period of 10 years from March 2009 to February 2018 with a definitive diagnosis of benign or malignant tumors of the CNS, including tumors of the brain, cerebellum, spinal cord, or meningeal membranes. Information sources included the patients' physical files and the hospital information system (HIS). The statistical software SPSS version 28.0 for Windows (IBM SPSS, Armonk, New York, USA) was used for the statistical analysis. Results: In total, 775 patients with benign and 771 patients with malignant CNS tumors were included in the study. Regarding epidemiological aspects of benign tumors, the incidence rate of women was almost twice that of men (68.47% versus 31.53%), with an overall average age of 45.31±19.81 years. The most common benign tumors were meningioma (72.77%), followed by schwannoma (13.67%). Regarding malignant brain tumors, the mean age of affected patients was 36.64±19.67 years, with males accounting for 53.04% of cases and females for 46.96%. The most frequent type of tumor was glioblastoma (32.68%), followed by diffuse astrocytoma (16.47%). Both benign and malignant CNS tumors were associated with significant hospital mortality; in-hospital mortality rates for benign and malignant tumors were 10.1% and 17.5%, respectively. Tumor type and its grade were the main determinants of early death in malignant CNS tumors. Conclusion: The epidemiological characteristics of benign and malignant tumors in our study community were similar to the reports presented in other communities. Knowledge of these characteristics provides the possibility of managing patients and reducing morbidity and mortality related to these tumors.

Background: In the last decade, the use of microwave ovens throughout the world, including Iran, has increased significantly. Therefore, it is important to understand the knowledge, attitude, and behavior of microwave oven use among employees of the Eastern Health Center to promote safe and responsible practices in the workplace. Assessing their familiarity and attitudes with microwave ovens, this study aims to identify potential areas for improvement and training. This, in turn, can create a safer and more efficient work environment for all involved. Methods: In this cross-sectional study in 2022, the study population was all employees working in the health center and comprehensive health service centers affiliated with the East of Shahid Beheshti University of Medical Sciences, numbering 162 people. The research tool was a questionnaire adapted from Nadiri's thesis (2015). After collecting the questionnaires, the data was obtained by SPSS 26 software and were analyzed using Pearson's correlation coefficient, multiple regression, independent t-test, and one-way ANOVA. Results: Although the attitude (36.35±3.579) and the behavior (61.16±6.402) towards using microwave ovens are favorable, there is still room for improvement of knowledge and awareness. Knowledge has a positive and significant effect on behavior (P=0.002, B=0.245) and attitude (P=0.001, B=0.263), which shows that improving knowledge about the safe and responsible use of microwave devices can lead to behavior. and a more favorable attitude among employees. In addition, the attitude has a strong positive and significant effect on behavior (P=0.001, B=0.417), and promoting a positive attitude toward using microwave devices can also lead to more favorable behavior. However, the relatively weak effect of awareness on attitude indicates that other factors may also play a role in determining the attitude toward using microwave devices. Conclusion: These findings highlight the importance of educational and awareness campaigns to promote the safe and responsible use of microwave devices among healthcare workers.

Background: Exercise programs can lead to different physiological adaptations, but the effects of low-volume, low-frequency HIIT protocols with varying interval structures have not been thoroughly investigated. This study aimed to explore the impact of HIIT with high compression (HC) and low compression (LC), with or without berberine (BBR) supplementation, on hematological parameters in pre-diabetic men. Methods: This semi-experimental study was conducted between October and December 2021 at Mazandaran University. Fifty-four overweight/obese men with a mean age of 48.6±6.6 years, a body mass index of 30.7±7.3 kg/m², and a body fat percentage of 34.4±4.3% were randomly and equally divided into one of six groups: HC, LC, HC+BBR, LC+BBR, BBR, and control. The HC group (2:1 work-to-rest ratio) and LC group (1:1 work-to-rest ratio) underwent training programs comprising 2-4 sets of 8 exercises at an intensity of 80-95% of their maximum heart rate twice a week for 8 weeks. Hematological responses to Bruce's incremental exercise test were measured before and after the intervention. Data were analyzed using a two-way ANOVA with Bonferroni's post hoc test, with a significance level set at P0.05). Following the 8-week intervention, there were significant decreases in white blood cells (WBCs) in the LC and LC+BBR groups, and in lymphocytes across all intervention groups except BBR (all, P

Background: Wolff-Parkinson-White syndrome is a rare but well-known disease that predisposes a person to cardiac arrhythmias. But sometimes this syndrome is accompanied by heart failure in the affected person. Several causes have been proposed for this complication including recurrent or incessant tachyarrhythmias that are frequently found in symptomatic (especially children) Wolf-Parkinson-White syndrome patients causing heart dysfunction and dilation and dilated cardiomyopathy, and also pre-excitation-related dyssynchrony leading to progressive ventricular remodeling and dilation. In this report, a patient is introduced who has improved his heart failure by radio-frequency ablation of free wall type of this syndrome. Case Presentation: A 35-year-old man who had a history of Wolff-Parkinson-White syndrome from 8 years ago and suffered from dilatation and reduced left ventricular ejection fraction in recent years was presented with a pre-excited atrial fibrillation attack at the emergency department. The initial surface ECG showed positive delta wave in all precordial leads and negative QRS complexes in interior leads with QRS duration of about 200 ms. He had undergone electrophysiology study and ablation at the left postero-lateral accessory pathway. After ablation of accessory pathway within the months (from November 2022 until June 2023), left ventricular function was gradually improved and the symptoms of the patient's shortness of breath were also decreased. Conclusion: The existence of heart failure in patients with Wolff-Parkinson-White syndrome can be due to various reasons including the presence of an accessory pathway and the dyssynchrony of intraventricular contraction which is caused by premature excitation of the connected part of the left ventricle by accessory atrioventricular pathway. Although in order to rule out the possibility of the incidental association of the accessory pathway with primary dilated cardiomyopathy and to investigate the segmental dyskinesia, it is necessary to perform diagnostic measures such as echocardiography and cardiac computerized tomography and magnetic resonance imaging, ablation of such accessory pathway not only controls arrhythmic attacks but also leads to the improvement of the left ventricular systolic function even in a middle age patient.

Background: Mucormycosis is a rare and aggressive opportunistic fungal infection that has grown significantly in recent years. This infection is rarely seen in healthy people. Mucormycosis usually appears as an acute infection with manifestations in the rhino-cerebral, pulmonary and skin areas, and sometimes its manifestations can be seen as a widespread infection. The special importance of mucormycosis is due to its high mortality rate, which leads to death in 75 to 80 percent of cases. The specific susceptibility of some patients to mucormycosis points to the importance of iron absorption in the pathogenesis of mucormycosis, therefore, we decided to investigate the relationship between serum iron and ferritin levels and mucormycosis disease in patients with underlying factors predisposing to COVID-19. Methods: This study is a case-control type, in which patients with mucormycosis after contracting COVID-19 and also with a history of diabetes mellitus as the case group and patients with COVID-19 and a history of diabetes mellitus are considered as the control group and the serum level of iron and ferritin will be measured and compared in both groups and the outcome of the study will be determined based on the obtained results.The study took place in hospitals of the Kermanshah university of medical sciences in the Kermanshah city from March 2021 to March 2022. Results: In this study, 38 patients were examined in two groups of patients with mucormycosis along with COVID-19 and diabetes in the case group and patients with COVID-19 and diabetes in the control group with an average age of 63 years. In this study, there was no significant difference between the average age in the two studied groups. However, a significant difference was observed between serum iron and ferritin levels in two groups. Conclusion: Hyperferritinemia is considered not only as an indicator of the systemic inflammatory process in the infection of COVID-19, but also indicates an increase in free iron level, which, as a result, contributes to the growth and spread of the fungus (mucormycosis).

This paper underscores the imperative for enhanced data disaggregation within the Australian Burden of Disease Studies (ABDS). While the ABDS offers a detailed assessment of disease burden, it falls short in providing systematic, disaggregated data – key to equitable healthcare and informed policymaking. Given Australia’s rich linguistic, ethnic, and cultural tapestry, aggregated health data often obscures the true extent of health disparities among diverse groups. The absence of detailed health data can precipitate unforeseen inequities with profound societal repercussions, including social unrest, diminished trust in healthcare and governance, economic downturns, educational gaps, mental health crises, political challenges, and stigmatisation. Such disparities undermine confidence in health systems and advisories, potentially fostering scepticism towards official health communications. Health disparities can lead to economic inadequacies, inflated healthcare expenditures, and stunted economic growth. Communities suffering from poor health are economically disadvantaged, and unexpected health inequities can derail educational achievements, particularly for students from underprivileged backgrounds who may face additional obstacles due to health-related absences or resource scarcity. The mental health burden from health disparities can escalate community-wide psychological distress, manifesting in heightened depression, anxiety, and trauma rates. The stigmatisation of certain groups exacerbates societal divisions and impedes unity. Politically, health inequities demand attention, with leaders facing scrutiny over their handling of these issues. Nevertheless, such challenges can catalyse community solidarity and advocacy for systemic change, fostering resilience. Addressing these disparities necessitates a comprehensive strategy encompassing disaggregated data access, equitable healthcare provision, policy reform, and community involvement. The ABDS 2023 report that Australians lost 5.6 million years of potential healthy life, with chronic disease imposing a more significant toll than premature mortality. The primary contributors to this burden were cancers, mental health conditions, and substance abuse disorders. However, this collective data fails to illuminate the disparate disease impacts on culturally, ethnically, and linguistically diverse populations. The ABD Study highlighted that in 2018, Indigenous Australians lost nearly 240,000 years of healthy life due to illness and early death, equating to 289 years per 1,000 individuals. Conditions like diabetes, cardiovascular diseases, renal disorders, strokes, and respiratory issues were more prevalent among individuals with limited English proficiency compared to fluent speakers. Gestational diabetes rates were notably higher in South Asian, Vietnamese, and African migrants compared to the native-born populace. The article emphasises the critical role of disaggregated health data in shaping effective health policies, optimising resource allocation, and promoting equitable health outcomes aligned with the Sustainable Development Goals. It advocates for integrating such data in public health practices to mitigate health disparities and enhance the welfare of all Australians. Ensuring the widespread availability of legally mandated disaggregated health data is vital for identifying, monitoring, and addressing health disparities within Australia’s multicultural society.

Older adults worldwide are facing disproportionate levels of isolation and loneliness. The current frameworks for understanding social isolation and loneliness include factors such as the physical and mental health of the individuals, loss of friends and family, level of education, relationships, and the built environment. While these models are useful, they fail to consider the individual experiences of older adults holistically; as an example, they do not include older adults’ relationship with themselves as they navigate the many challenges of life. In this article, I propose a novel framework for describing social isolation and loneliness in older adults that includes relationships to their changing bodies and experiences, to history and literature, and to nature and current events. Considering this revised framework, I summarize my observations as a teaching artist using Bharatanatyam, a 2,000-year-old Indian traditional dance form, in alleviating loneliness and isolation. Outcomes are in the form of qualitative narratives that are thematically united and presented. Given the highly communicative and relational nature of Bharatanatyam, I hypothesize that immersion in Bharatanatyam will enable connections of various kinds. This article describes three ways in which Bharatanatyam is particularly well-suited to build connections; these are 1. Connection with oneself in body, mind, and psyche; 2. Connection to tradition and history and 3. A systematic structure of relating to others, to the nature and environment, and current events.

Allergic asthma, a type of chronic airway inflammation, is a global health concern because of its increasing incidence and recurrence rates. Camellia sinensis L. yields a variety type of teas, which are also used as medicinal plants in East Asia and are known to have antioxidant, anti-inflammatory, and immune-potentiating properties. Here, we examined the constituents of C. sinensis L. extract (CSE) and evaluated the protective effects of CSE on allergic asthma by elucidating the underlying mechanism. To induce allergic asthma, we injected the sensitization solution (mixture of ovalbumin (OVA) and aluminum hydroxide) into mice intraperitoneally on days 0 and 14. Then, the mice were exposed to 1% OVA by a nebulizer on days 21 to 23, while intragastric administration of CSE (30 and 100 mg/kg) was performed each day on days 18 to 23. We detected five compounds in CSE, including (-)-epigallocatechin, caffeine, (-)-epicatechin, (-)-epigallocatechin gallate, and (-)-epicatechin gallate. Treatment with CSE remarkably decreased the airway hyperresponsiveness, OVA-specific immunoglobulin E level, and inflammatory cell and cytokine levels of mice, with a decrease in inflammatory cell infiltration and mucus production in lung tissue. Treatment with CSE also decreased the phosphorylation of nuclear factor-κB (NF-κB) and the expression of matrix-metalloproteinase (MMP)-9 in asthmatic mice. Our results demonstrated that CSE reduced allergic airway inflammation caused by OVA through inhibition of phosphorylated NF-κB and MMP-9 expression.

The increased proportion of women in the workplace and the labor force aging have been demanding investigations of the link between menopause and occupational health issues, especially in healthcare settings. Evidence on the association between menopause and occupational burnout in healthcare settings is still inconclusive. Therefore, we aimed to evaluate the association between menopause and burnout among clinical and non-clinical workers in different occupational health environments. A multi-center, cross-sectional study, applying the Oldenburg Burnout Inventory (OBI) was conducted from September 2021 to March 2023 in University Medical Center (UMC) hospitals in Astana, Kazakhstan. The study involved 125 physicians and nurses and 82 non-clinical administrative and service staff. We found that 63.9% of respondents had disengagement and 61.7% had exhaustion. The affiliated clinical setting was associated with disengagement (p = 0.034), with the highest prevalence among employees in surgical departments (76.9%), while a higher prevalence of exhaustion was found in individuals with different work experience (p = 0.023) and among those who were dissatisfied with their work environment (74.3%). While burnout was identified in almost two-thirds of respondents, the self-reported menopause status of participants was not significantly related to either disengagement (p = 0.34) or exhaustion (p = 0.73), even though a higher prevalence of both was revealed among the postmenopausal group. We propose that healthcare management should understand the importance of burnout among postmenopausal healthcare workers and facilitate open communication and a supportive work environment.

The endosomal sorting complexes required for transport (ESCRT) machinery is an evolutionarily conserved cytosolic protein complex that plays a crucial role in membrane remodeling and scission events across eukaryotes. Initially discovered for its function in multivesicular body (MVB) formation, the ESCRT complex has since been implicated in a wide range of membrane-associated processes, including endocytosis, exocytosis, cytokinesis, and autophagy. Recent advances have elucidated the ESCRT assembly pathway and highlighted the distinct functions of the various ESCRT complexes and their associated partners. Among the ESCRT complexes, ESCRT-III stands out as a critical player in membrane remodeling, with its subunits assembled into higher-order multimers capable of bending and severing membranes. This review focuses on the ESCRT-III complex, exploring its diverse functions in cellular processes beyond MVB biogenesis. We delve into the molecular mechanisms underlying ESCRT-III-mediated membrane remodeling and highlight its emerging roles in processes such as viral budding, autophagosome closure, and cytokinetic abscission. We also discuss the implications of ESCRT-III dysregulation in neurodegenerative diseases. The versatile membrane remodeling capabilities of ESCRT-III across diverse cellular processes underscore its importance in maintaining proper cellular function. Furthermore, we highlight the promising potential of ESCRT-III as a therapeutic target for neurodegenerative diseases, offering insights into the treatments of the diseases and the technical applications in related research fields.

Taste buds, the neuroepithelial organs responsible for the detection of gustatory stimuli in the oral cavity, arise from stem/progenitor cells among nearby basal keratinocytes. Using genetic lineage tracing, Lgr5 and Lgr6 were suggested as the specific markers for the stem/progenitor cells of taste buds, but recent evidence implied that taste buds may arise even in the absence of these markers. Thus, we wanted to verify the genetic lineage tracing of lingual Lgr5- and Lgr6-expressing cells. Unexpectedly, we found that antibody staining revealed more diverse Lgr5-expressing cells inside and outside the taste buds of circumvallate papillae than was previously suggested. We also found that, while tamoxifen-induced genetic recombination occurred only in cells expressing the Lgr5 reporter GFP, we did not see any increase in the number of recombined daughter cells induced by consecutive injections of tamoxifen. Similarly, we found that cells expressing Lgr6, another stem/progenitor cell marker candidate and an analog of Lgr5, also do not generate recombined clones. In contrast, Lgr5-expressing cells in fungiform papillae can transform into Lgr5-negative progeny. Together, our data indicate that lingual Lgr5- and Lgr6-expressing cells exhibit diversity in their capacity to transform into Lgr5- and Lgr6-negative cells, depending on their location. Our results complement previous findings that did not distinguish this diversity.

With the popularity of co-creation research in public health and other fields, there is a need to strengthen its evidence-base by developing a framework based on meta-theoretical principles. The lack of applying meta-theoretical principles in co-creation research impedes the theory- and evidence building. Critical realism seems a promising candidate for providing meta-theoretical principles to enrich the evidence base of co-creation research in public health. To this purpose we searched for relevant papers on critical realism methodological principles, clarified and subsequently applied such principles to a co-creation public health case study. We provide explanatory steps to apply five principles; 1) focusing on understanding an event, like childhood overweight, 2) exploring the broader structure and context surrounding the event, 3) constructing hypotheses about the underlying mechanism(s) of an event, 4) empirical testing to corroborate those hypotheses, and 5) using multiple methods and triangulation. Further, this study shows that critical realism can enrich co-creation research in public health by iteratively building theory and evidence following the five proposed principles.

Preventing disease and maintaining the health of the elderly are crucial goals for an aging population, with obesity and immune function restoration being of paramount importance. Obesity, particularly visceral obesity characterized by excessive fat accumulation around the abdominal organs, is linked to chronic conditions such as diabetes, hypertension, cardiovascular diseases, and immune dysfunction. Globally, obesity is considered a disease, prompting significant research interest in its treatment. Therefore, it is essential to explore potential therapeutic and preventive strategies to address obesity and the decline in immune function brought about by aging. Tenebrio molitor larvae (TML), commonly known as ‘mealworms,’ are rich in unsaturated fatty acids, including oleic and linoleic acids, and essential amino acids, such as isoleucine and tyrosine. In this study, we aimed to investigate the effects of the consumption of TML oil and mealworm fermented extract (MWF-1) on obesity and immunological changes in aged obese mice. Our data showed reduced body fat in 23-week-old C57BL/6 mice fed processed TML products for 6 weeks. Additionally, the characteristically high levels of serum triglycerides decreased by treating with TML oil. The immune responsiveness results confirmed an increase in B cells by treating with MWF-1, while cytokine levels (interferon-gamma, tumor necrosis factor-alpha, interleukin-2, and −6) were restored to levels similar to young mice. These results suggest that TML oil and MWF-1 are promising dietary supplements for addressing obesity and restoring immune function.

Environmental health professionals play a significant role in preventing and addressing public health problems. Improving this area of practice continues to be a key strategy of the Australian Government; however, achieving this outcome presents several challenges. These challenges relate to the changing context of the practice and the complexities inherent in the practice itself. To address this problem, we investigated the qualitatively different ways environmental health professionals experienced their practice in Australia to establish a new conceptualization of practice. Phenomenographic qualitative methods underpinned this study, involving open-ended, semi-structured interviews with 19 environmental health professionals from diverse backgrounds and practice settings. The study revealed four qualitatively different ways of experiencing the professional practice of environmental health: ‘protecting’, ‘helping’, ‘collaborating’, and ‘leading and innovating’. These different ways were logically linked by five themes of expanding awareness to form a Holistic Experiential Description of Practice (HEDP), representing a new and novel conceptualization of the professional practice of environmental health. We propose that these findings provide a more useful way to conceptualize this area of practice than the current descriptions allow.

Given that the skin is the largest tissue in the human body, performing external barrier functions with innate and adaptive immunity and undergoing substantial changes during aging, it is under investigation as a major target of various bioactive molecules. In the present study, we examined the biological activity of the senolytic piperlongumine by analyzing alterations in mRNA expression of notable skin genes using transformed aneuploid immortal epidermal keratinocytes, HaCaT cells. We observed that piperlongumine increased the mRNA expression of genes playing critical roles in skin barrier function. In addition, piperlongumine increased expression enzymes involved in the synthesis of ceramide, a major component of intercellular lipids. Furthermore, we measured the protein levels of various cytokines secreted by epidermal keratinocytes and found changes in the release of GRO-αβγ, CCL5, and MCP1. Additionally, we observed that piperlongumine treatment modulated the expression of keratinocyte-specific aging markers and influenced telomerase activity. Based on these findings, piperlongumine could regulate the physiological activity of epidermal keratinocytes to induce beneficial effects in human skin by regulating important skin-related genes.

Exposure to toxic molecules from food or oral medications induces toxicity in colon cells that cause various human diseases; however, in vitro monitoring systems for colon cell toxicity are not well established. Stress granules are nonmembranous foci that form in cells exposed to cellular stress. When cells sense toxic environments, they acutely and systemically promote stress granule formation, with Ras GTPase-activating protein-binding protein 1 (G3BP1) acting as a core component to protect their mRNA from abnormal degradation. Here, we knocked in green fluorescent protein (GFP)-coding sequences into the C-terminal region of the G3BP1 gene in a human colon cell line through CRISPR-Cas9-mediated homologous recombination and confirmed the formation of stress granules with the G3BP1-GFP protein in these cells under cellular stress exposure. We demonstrated the formation and dissociation of stress granules in G3BP1-GFP expressing colon cells through real-time monitoring using a fluorescence microscope. Furthermore, we validated the toxicity monitoring system in the established colon cell line by observing stress granule formation following exposure to dihydrocapsaicin, bisphenol A, and sorbitol. Taken together, we established a stress granule reporter system in a colon cell line, providing a novel assessment for the real-time monitoring of colon toxicity in response to various chemicals.

The system forming ovarian follicles is developed to investigate in vitro folliculogenesis in a confined environment to obtain functional oocytes. Several studies have reported the successful generation of fully functional oocytes using mouse-induced pluripotent stem cells (iPSCs) and mouse female germline stem cells (fGSCs) as sources of stem cells for in vitro gametogenesis models. In addition, human oogonia have been generated through heterologous co-culture of differentiated human primordial germ cell-like cells (hPGCLCs) with mouse germline somatic cells, although oocyte formation remains challenging. Thus, studies on in vitro ovarian formation in other species are utilized as an introductory approach for in vitro mammalian gametogenesis by understanding the differences in culture systems between species and underlying mechanisms. In this study, we optimized the method of the entire oogenesis process from rat embryonic gonads. We identified well-maturated MII oocytes from rat gonads using our constructed method. Moreover, we generated the first successful in vitro reconstitution of xenogeneic follicles from mouse primordial germ cells (PGCs) and rat somatic cells. We also established an appropriate culture medium and incubation period for xenogeneic follicles. This method will be helpful in studies of xenogeneic follicular development and oocyte generation.

The cytoplasmic FMR1-interacting protein 2 (CYFIP2) have diverse molecular functions in neurons, including the regulation of actin polymerization, mRNA translation, and mitochondrial morphology and function. Mutations in the CYFIP2 gene are associated with early-onset epilepsy and neurodevelopmental disorders, while decreases in its protein levels are linked to Alzheimer's disease (AD). Notably, previous research has revealed AD-like phenotypes, such as dendritic spine loss, in the hippocampal CA1 pyramidal neurons of 12-month-old Cyfip2 heterozygous mice but not of age-matched CA1 pyramidal neuron-specific Cyfip2 conditional knock-out (cKO) mice. This study aims to investigate whether dendritic spine loss in Cyfip2 cKO mice is merely delayed compared to Cyfip2 heterozygous mice, and to explore further neuronal phenotypes regulated by CYFIP2 in aged mice. We characterized dendrite and dendritic protrusion morphologies, along with excitatory/inhibitory synapse densities in CA1 pyramidal neurons of 17-month-old Cyfip2 cKO mice. Overall dendritic branching was normal, with a reduction in the length of basal, not apical, dendrites in CA1 pyramidal neurons of Cyfip2 cKO mice. Furthermore, while dendritic protrusion density remained normal, alterations were observed in the length of mushroom spines and the head volume of stubby spines in basal, not apical, dendrites of Cyfip2 cKO mice. Although excitatory synapse density remained unchanged, inhibitory synapse density increased in apical, not basal, dendrites of Cyfip2 cKO mice. Consequently, a cell-autonomous reduction of CYFIP2 appears insufficient to induce dendritic spine loss in CA1 pyramidal neurons of aged mice. However, CYFIP2 is required to maintain normal dendritic length, dendritic protrusion morphology, and inhibitory synapse density.

The effective promotion of wound healing poses a substantial challenge for clinical treatment. Despite evidence supporting the role of extracellular vesicles (EVs) in this process, their therapeutic potential is currently restrict by challenges in targeting and maintaining them. The manufacturing process for rhCol III, or recombinant human collagen III, is stable, and the rejection rate is low. We used a cross-linking method to prepare a rhCol III incorporated sodium alginate (SA) hydrogel, which enabled to accomplish an EV sustained release that was site-specific. Cell viability through MTT assay, proliferation and ROS generation were performed with MC3T3-E1cell lines. In addition, diabetic wounds are characterised by an environment of hyper-inflammation and elevated oxidative stress. The rhCol III/SA-EVs hydrogel, which is a delivery vehicle with anti-inflammatory and antioxidant characteristics, promotes wound healing in this setting. The In vivo effectiveness of the created wound dressing on a diabetic wound model was examined in this study. After 21 days of treatment, the wound dressing significantly (p

Background: One of the key obstacles to the healing of diabetic wound is the persistence of active inflammation. We previously demonstrated the potential of cell-free fat extract (CEFFE) to promote the healing of diabetic wounds, and annexin A5 (A5) is a crucial anti-inflammatory protein within CEFFE. This study aimed to evaluate the therapeutic potential of A5 in diabetic wounds. Methods: A5 was loaded into GelMA hydrogels and applied to skin wounds of diabetic mice in vivo. The diabetic wounds with the treatment of GelMA-A5 were observed for 14 days and evaluated by histological analysis. Accessment of inflammation regulation were conducted through anti-CD68 staining, anti-CD86 and anti-CD206 staining, and qRT-PCR of wound tissue. In presence of A5, macrophages stimulated by lipopolysaccharide (LPS) in vitro, and detected through qRT-PCR, flow cytometry, and immunocytofluorescence staining. Besides, epithelial cells were co-cultured with A5 for epithelialization regulation by CCK-8 assay and cell migration assay. Results: A5 could promote diabetic wound healing and regulate inflammations by promoting the transition of macrophages from M1 to M2 phenotype. In vitro experiments demonstrated that A5 exerted a significant effect on reducing pro-inflammatory factors and inhibiting the polarization of macrophages from M0 toward M1 phenotype. A5 significantly promoted the migration of epithelial cells. Conclusion: Annexin A5 has a significant impact on the regulation of macrophage inflammation and promotion of epithelialization.

Objective: Herein we propose a combined action of collagen type I (CA) or synthetic collagen-like-peptide functionalized with the cell adhesive RGD motif (PEG-CLP-RGD) hydrogels and selected growth factors to promote chondrogenic differentiation of human muscle-derived stem cells (hMDSCs) under normal and reduced oxygen conditions. Methods: hMDSCs were set for differentiation towards chondrogenic lineage using BMP-7 and TGF-β3. Cells were seeded onto hydrogels loaded with growth factors (75ng/scaffold) and cultured for 28 days under normal (21%) and severe hypoxic (1%) conditions. Chondrogenesis was evaluated by monitoring collagen type II and GAG deposition, and quantification of ACAN expression by RT-PCR. Results: Sustained release of TGFβ3 from the hydrogels was observed, 8.7 ± 0.5% of the initially loaded amount diffused out after 24 h from both substrates. For the BMP-7 growth factor, 14.8 ± 0.3% and 18.2 ± 0.6% of the initially loaded amount diffused out after 24 h from CA and CLP-RGD, respectively. The key findings of this study are: i) the self-supporting hydrogels themselves can stimulate hMDSC chondrogenesis by inducing gene expression of cartilage-specific proteoglycan aggrecan and ECM production; ii) the effect of dual BMP-7 and TGF-β3 loading was more pronounced on CA hydrogel under normal oxygen conditions; iii) dual loading on PEG-CLP-RGD hydrogels did not have the synergistic effect, TGF-β3 was more effective under both oxygen conditions; iv) BMP-7 can improve chondrogenic effect of TGF-β3 on CA scaffolds, and hydrogels loaded with both growth factors can induce cartilage formation in hMDSC cultures. Conclusion: Our results support the potential strategy of combining implantable hydrogels functionalized with differentiation factors toward improving cartilaginous repair.

Introduction: Endotoxin is a typical pyrogen derived from the outer membrane of Gram-negative bacteria. In fabricating cell-based medicinal products, it is necessary to control endotoxin in the process and the products. In the quality control tests of our clinical study, endotoxin concentration in the culture supernatant of autologous oral mucosal epithelial cell sheets exceeded the criterion value. Therefore, endotoxin measurements were conducted to clarify the cause of the endotoxin contamination. Methods: The reagents used to prepare the culture medium, the unused culture medium, and the culture supernatants were diluted with pure water. Endotoxin concentrations in the diluted samples were measured. Results: Endotoxin was detected in both the unused culture medium and the culture supernatant of the epithelial cell sheets at higher concentrations than the criterion value. Therefore, endotoxin concentrations in the reagents used to prepare the culture medium were measured and were found to be below the criterion value, except for cholera toxin. On the other hand, three lots of cholera toxin products were used for the measurement, and the endotoxin concentrations were higher than the criterion value. The results indicate that the endotoxin contamination is caused by the cholera toxin product. Conclusions: To prevent endotoxin contamination in cell-based medicinal products, endotoxin concentrations in reagents used for the fabrication should be measured in the facility conducting clinical research or confirmed by an adequate certificate of analysis from the manufacturers of the reagents.

Understanding the composition and function of cells constituting tissues and organs is vital for unraveling biological processes. Single-cell analysis has allowed us to move beyond traditional methods of categorizing cell types. This innovative technology allows the transcriptional and epigenetic profiling of numerous individual cells, leading to significant insights into the development, homeostasis, and pathology of various organs and tissues in both animal models and human samples. In this review, we delve into the outcomes of major investigations using single-cell transcriptomics to decipher the cellular composition of mammalian teeth and periodontal tissues. The recent single-cell transcriptome-based studies have traced in detail the dental epithelium-ameloblast lineage and dental mesenchyme lineages in the mouse incisors and the tooth germ of both mice and humans; unraveled the microenvironment, the identity of niche cells, and cellular intricacies in the dental pulp; shed light on the molecular mechanisms orchestrating root formation; and characterized cellular dynamics of the periodontal ligament. Additionally, cellular components in dental pulps were compared between healthy and carious teeth at a single-cell level. Each section of this review contributes to a comprehensive understanding of tooth biology, offering valuable insights into developmental processes, niche cell identification, and the molecular secrets of the dental environment.

Cerebrovascular accidents, also known as strokes, are the leading cause of permanent disability in society, presenting significant socioeconomic and healthcare costs. They can be caused by ischemic factors or hemorrhages, with ischemic strokes being the most common among the population. Therapies for patients suffering from this condition are limited and primarily focus on acute-phase treatment. In recent years, there has been an increase in cellular therapies, employing Stem Cells to mitigate or eliminate the consequences arising from this disease. Mesenchymal Stem Cells (MSCs) hold substantial therapeutic potential in Nervous System pathologies due to their low antigenicity and capacity to differentiate into various human tissues, such as adipogenic, chondrogenic, and osteogenic tissues. This study conducts a literature review using the “clinical trials” and “Pubmed” database, summarizing all ongoing clinical trials for ischemic strokes that utilize MSCs as treatment.

Background: The senescence of endothelial cells is of great importance involving in atherosclerosis (AS) development. Recent studies have proved the protective role of mesenchymal stem cell-derived extracellular vesicles in AS, herein, we further desired to unvei their potential regulatory mechanisms in endothelial cell senescence. Methods: Senescence induced by H2O2 in primary mouse aortic endothelial cells (MAECs) was evaluated by SA-β-gal staining. Targeted molecule expression was detected by qRT-PCR and Western blotting. The biological functions of MAECs were determined by CCK-8, flow cytometry, transwell, and tube formation assays. Oxidative injury was assessed by LDH, total and lipid ROS, LPO and MDA levels. The proliferation of adipose-derived mesenchymal stem cell (ADSCs) was analyzed by EdU assay. Effect of ADSCs-derived extracellular vesicles (ADSC-EVs) on AS was investigated in HFD-fed ApoE−/− mice. Results: miR-674-5p was up-regulated, while C1q/TNF-related protein 9 (CTRP9) was down-regulated in H2O2-induced senescent MAECs. CTRP9 was demonstrated as a target gene of miR-674-5p. miR-674-5p inhibition restrained senescence, oxidative stress, promoted proliferation, migration, and angiogenesis of H2O2-stimulated MAECs via enhancing CTRP9 expression. Moreover, treatment with ADSC-EVs inhibited H2O2-induced senescence and dysfunction of MAECs through regulating miR-674-5p/CTRP9 axis. In the in vivo AS mouse model, ADSC-EVs combination with miR-674-5p silencing slowed down AS progression via up-regulation of CTRP9. Conclusion: ADSC-EVs repressed endothelial cell senescence and improved dysfunction via promotion of CTRP9 expression upon miR-674-5p deficiency during AS progression, which might provide vital evidence for ADSC-EVs as a promising therapy for AS.

Background: Quercetin (QU) plays an important role in treating periodontitis; however, the mechanism through which microRNAs regulate Th17 cell differentiation has not been determined. Methods: QU was administered intragastrically to periodontitis rats once a day for one month. The morphology of alveolar bone was observed by micro-CT, gingival tissue structure was observed by HE staining, IL-6, TNF-α, IL-17A, RORγt, FOXP3 and IL-10 were detected by immunohistochemical staining, and Th17 and Treg cells in the peripheral blood were detected by flow cytometry. CD4+T cells were induced to differentiate into Th17 cells in vitro. Cell viability was determined by CCK8, and IL-17A and RORγt were detected by qPCR. Th17 cells were detected by flow cytometry, microRNA sequencing and bioinformatics analysis were used to screen key microRNAs, the phenotypic changes of Th17 cells were observed after overexpressed microRNAs via mimics. TargetScan database, in situ hybridization, and dual-luciferase reporter experiment were used to predict and prove target genes of microRNAs. The phenotype of Th17 cells was observed after overexpression of microRNA and target gene. Results: Compared with periodontitis group, the distance from cementoenamel junction(CEJ) to alveolar bone(AB) was decreased, the structure of gingival papilla was improved, IL-6, TNF-α, IL-17, and RORγt were downregulated, FOXP3 and IL-10 were upregulated, the proportion of Th17 decreased and Treg increased in peripheral blood after QU treatment. Compared with Th17 cell group, mRNA levels of IL-17A and RORγt were decreased, and proportion of Th17 cells was significantly lower in the coculture group. MiR-147–5p was low in control group, upregulated in Th17 cell group, and downregulated after QU intervention, it's eight bases were inversely related to 3′UTR of Clip3, miR-147–5p with Clip3 were co-located in cells of periodontal tissue. Compared with those in Th17-mimicsNC + QU cells, the mRNA levels of RORγt and IL-17A upregulated, and proportion of Th17 cells increased in Th17-miR-147–5p + QU cells. The miR-147–5p mimics inhibited the luciferase activity of the WT Clip3 3′UTR but had no effect on the Mut Clip3 3′UTR. Clip3 was significantly downregulated after the overexpression of miR-147–5p. Mimics transfected with miR-147–5p reversed the decrease in the proportion of Th17 cells induced by QU, while the overexpression of Clip3 antagonized the effect of miR-147–5p and further reduced the proportion of Th17 cells. Moreover, the overexpression of miR-147–5p reversed the decreases in the mRNA levels of IL-17 and RORγt induced by QU treatment, while pcDNA3.1 Clip3 treatment further decreased the mRNA levels of IL-17 and RORγt. Conclusion: QU reducing inflammatory response and promoting alveolar bone injury and repair, which closely relative to inhibit the differentiation of CD4+T cells into Th17 cells by downregulating miR-147–5p to promote the activation of Clip3.

Introduction: Mesenchymal stem cells (MSCs) are increasingly used for intra-articular injections in the treatment of knee osteoarthritis. The aim of this study was to use scanning electron microscopy (SEM) to compare the morphological characteristics of synovial and adipose MSCs. Methods: Synovium and adipose tissues were concurrently harvested from eight patients with knee osteoarthritis. Suspensions of both synovial and adipose MSCs were examined to identify the presence of microspikes. In addition to this study, the MSC suspensions in four patients were applied to abraded porcine cartilage discs and observed 10 s, 10 min, and 1 h later. Results: The median percentage of cells exhibiting microspikes was 14% for synovial MSC suspensions and 13% for adipose MSC suspensions; this difference was not statistically significant (n = 8). No notable differences were detected in the number of adherent cells or in the proportion of cells displaying microspikes or pseudopodia. Strong correlations were found between the proportion of cells with pseudopodia and the number of attached cells for both synovial (r = 0.92, n = 12) and adipose (r = 0.86, n = 12) MSCs, with no significant difference in the correlation coefficients between the two groups. Conclusion: SEM analysis revealed no obvious differences in morphological characteristics during MSC adhesion to cartilage for either synovial or adipose MSCs.

Introduction: In this multicenter clinical study, we aimed to investigate the efficacy and safety of the transhepatic arterial administration of granulocyte-colony stimulating factor (G–CSF)–mobilized autologous peripheral blood (PB)-CD34+ cells compared with standard therapy in patients with decompensated cirrhosis type C. Methods: Patients were randomly assigned (2:1) to the CD34+ cell transplant (CD34+ cell) or standard-of-care (SOC) group and followed up for 52 weeks. The primary endpoints were the non-progression rate of Child-Pugh (CP) scores at 24 weeks post-enrollment and the safety of the protocol treatment. Results: Fourteen patients (CD34+ cell group: 10; SOC group: 4) were enrolled. CP scores at 24 weeks had a non-progression rate of 90% in the CD34+ cell group and 100% in the SOC group, with no significant difference between groups. Importantly, 4 out of 10 patients in the CD34+ cell group exhibited an improvement from decompensated to compensated cirrhosis, whereas all patients in the SOC group remained in decompensated cirrhosis. With regard to secondary endpoints, a trend toward increased serum albumin levels in the CD34+ cell group was noted. Serious adverse events (SAEs) occurred in three patients in the CD34+ cell group and in one patient in the SOC group. No causal relationship was observed between all SAEs and G-CSF, leukapheresis, or cell transplantation in the CD34+ cell group. No patients died and no hepatocellular carcinoma occurred within the study period. Conclusions: PB-CD34+ cell infusion therapy may have the potential to circumvent the decompensated stage of cirrhosis, thus avoiding the need for liver transplantation.

ABSTRACTTyrosine kinase inhibitors (TKIs) have emerged as a potential treatment strategy for glioblastoma multiforme (GBM). However, their efficacy is limited by various drug resistance mechanisms. To devise more effective treatments for GBM, genetic characteristics must be considered in addition to pre-existing treatments. We performed an integrative analysis with heterogeneous GBM datasets of genomic, transcriptomic, and proteomic data from DepMap, TCGA and CPTAC. We found that poor prognosis was induced by co-upregulation of heat shock protein family A member 5 (HSPA5) and fibroblast growth factor receptor 1 (FGFR1). Co-up regulation of these two genes could regulate the PI3K/AKT pathway. GBM cell lines with co-upregulation of these two genes showed higher drug sensitivity to PI3K inhibitors. In the mesenchymal subtype, the co-upregulation of FGFR1 and HSPA5 resulted in the most malignant subtype of GBM. Furthermore, we found this newly discovered subtype was correlated with homologous recombination deficiency (HRD) In conclusion, we discovered novel druggable candidates within the group exhibiting co-upregulation of these two genes in GBM, suggest potential strategies for combination therapy.

ABSTRACTExtracellular vesicles (EVs), transporting diverse cellular components, play a crucial role in intercellular communication in numerous physiological and pathological processes. EVs have also been recognized as a drug delivery platform for therapeutic purposes and cell-free regenerative medicine. While various approaches have focused on increasing EV production for efficient use therapeutic use of EVs, enhancing the quality of EVs, such as ensuring efficient uptake by their target cells, has not been widely explored. In this study, we linked a negative membrane curvature-forming inverse BAR (IBAR) domain with an integrin β tail-binding talin F3 domain to create the IBAR-F3 fusion protein. We observed that IBAR-F3 can trigger filopodia-like membrane protrusions and attract integrins to those protrusion-rich regions, when expressed in Chinese hamster ovary cells expressing integrin αIIbβ3. Surprisingly, the expression of IBAR-F3 also induced a robust production of EVs, which were then efficiently taken up by nearby cells in an integrin-dependent manner. Moreover, IBAR triggered integrin activation, presumably by inducing negative membrane curvature that likely disrupts the interaction between the integrin α and β transmembrane domain. Therefore, we suggest that IBAR-F3 should be utilized to promote both EV production and efficient uptake mediated by integrins. Furthermore, the negative curvature-inducing integrin activation suggests that integrins on EVs can be activated by the nanoscale change in the curvature of the EV without the need for conventional machinery to activate integrin inside the EVs.

ABSTRACTUnlike vertebrates, the number of toothed taxa in invertebrates is very few, with leeches being the only tooth-bearing organisms in the phylum Annelida. Copious studies have been conducted regarding vertebrate teeth; however, studies regarding the structure and function of invertebrate teeth are limited. In this study, the tooth structure of leeches, specifically Hirudo nipponia and Haemadipsa rjukjuana, was revealed, which showed sharp and pointed teeth along the apex of three jaws. Understanding conserved signaling regulations among analogous organs is crucial for uncovering the underlying mechanisms during organogenesis. Therefore, to shed light on the evolutionary perspective of odontogenesis to some extent, we conducted de novo transcriptome analyses using embryonic mouse tooth germs, Hirudo teeth, and Helobdella proboscises to identify conserved signaling molecules involved in tooth development. The selection criteria were particularly based on the presence of tooth-related genes in mice, Hirudo teeth, and Helobdella proboscis, wherein 4113 genes were commonly expressed in all three specimens. Furthermore, the chemical nature of leech teeth was also examined via TEM-EDS to compare the chemical composition with vertebrate teeth. The examination of tissue-specific genetic information and chemical nature between leeches and mice revealed chemical similarities between leech and mice teeth, as well as conserved signaling molecules involved in tooth formation, including Ptpro, Prickle2, and Wnt16. Based on our findings, we propose that leech teeth express signaling molecules conserved in mice and these conserved tooth-specific signaling for dental hard tissue formation in mice would corresponds to the structural formation of the toothed jaw in leeches.

ABSTRACTThe role of ferroptosis-associated gene SLC7A11 in esophageal cancer progression is largely unknown, therefore, the effects of blocking SLC7A11 on esophageal squamous cell carcinoma (ESCC) cells are evaluated. Results showed that SLC7A11 was overexpressed in ESCC tissues both in mRNA and protein levels. Blocking SLC7A11 using Erastin suppressed the proliferation and colony formation of ESCC cells, decreased cellular ATP levels, and improved ROS production. Sixty-three SLC7A11-binding proteins were identified using the IP-MS method, and these proteins were enriched in four signaling pathways, including spliceosome, ribosome, huntington disease, and diabetic cardiomyopathy. The deubiquitinase inhibitors PR-619, GRL0617, and P 22077 could reduce at least 40% protein expression level of SLC7A11 in ESCC cells, and PR-619 and GRL0617 exhibited suppressive effects on the cell viability and colony formation ability of KYSE30 cells, respectively. Erastin downregulated GPX4 and DHODH and also reduced the levels of β-catenin, p-STAT3, and IL-6 in ESCC cells. In conclusion, SLC7A11 was overexpressed in ESCC, and blocking SLC7A11 using Erastin mitigated malignant phenotypes of ESCC cells and downregulated key ferroptosis-associated molecules GPX4 and DHODH. The therapeutic potential of targeting SLC7A11 should be further evaluated in the future.

ABSTRACTThe ring finger protein 113A (RNF113A) serves as an E3 ubiquitin ligase and a subunit of the spliceosome. Mutations in the RNF113A gene are associated with X-linked trichothiodystrophy (TTD). However, the cellular roles of RNF113A remain largely unknown. In this study, we performed transcriptome profiling of RNF113A knockout (KO) HeLa cells using RNA sequencing and revealed the upregulation of NRF2 pathway-associated genes. Further analysis confirmed that the KO of RNF113A promotes nuclear localization of the NRF2 protein and elevates the mRNA levels of NRF2 target genes. RNF113A KO cells showed high levels of intracellular reactive oxygen species (ROS) and decreased resistance to cell death following H2O2 treatment. Additionally, RNF113A KO cells more sensitively formed stress granules (SGs) under arsenite-induced oxidative stress. Moreover, RNF113A KO cells exhibited a decrease in glutathione levels, which could be attributed to a reduction in GLUT1 expression levels, leading to decreased glucose uptake reactions and lower intracellular glucose levels. These alterations potentially caused a reduction in ROS scavenging activity. Taken together, our findings suggest that the loss of RNF113A promotes oxidative stress-mediated activation of the NRF2 pathway, providing novel insights into RNF113A-associated human diseases.

Stem cells (SCs) play a crucial role in tissue repair, regeneration, and maintaining physiological homeostasis. Exercise mobilizes and enhances the function of SCs. This review examines the effects of acute and chronic aerobic and resistance exercise on the population of SCs in healthy and diseased individuals across different age groups. Both acute intense exercise and moderate regular training increase circulating precursor cells CD34+ and, in particular, the subset of angiogenic progenitor cells (APCs) CD34+/KDR+. Conversely, chronic exercise training has conflicting effects on circulating CD34+ cells and their function, which are likely influenced by exercise dosage, the health status of the participants, and the methodologies employed. While acute activity promotes transient mobilization, regular exercise often leads to an increased number of progenitors and more sustainable functionality. Short interventions lasting 10–21 days mobilize CD34+/KDR + APCs in sedentary elderly individuals, indicating the inherent capacity of the body to rapidly activate tissue-reparative SCs during activity. However, further investigation is needed to determine the optimal exercise regimens for enhancing SC mobilization, elucidating the underlying mechanisms, and establishing functional benefits for health and disease prevention. Current evidence supports the integration of intense exercise with chronic training in exercise protocols aimed at activating the inherent regenerative potential through SC mobilization. The physical activity promotes endogenous repair processes, and research on exercise protocols that effectively mobilize SCs can provide innovative guidelines designed for lifelong tissue regeneration. An artificial neural network (ANN) was developed to estimate the effects of modifying elderly individuals and implementing chronic resistance exercise on stem cell mobilization and its impact on individuals and exercise. The network's predictions were validated using linear regression and found to be acceptable compared to experimental results.

Introduction: Acute kidney injury (AKI) is a common health problem that leads to high morbidity and potential mortality. The failure of conventional treatments to improve forms of this condition highlights the need for innovative and effective treatment approaches. Regenerative therapies with Renal Progenitor Cells (RPCs) have been proposed as a promising new strategy. A growing body of evidence suggests that progenitor cells differentiated from different sources, including human embryonic stem cells (hESCs), can effectively treat AKI. Methods: Here, we describe a method for generating RPCs and directed human Embryoid Bodies (EBs) towards CD133+CD24+ renal progenitor cells and evaluate their functional activity in alleviating AKI. Results: The obtained results show that hESCs-derived CD133+CD24+ RPCs can engraft into damaged renal tubules and restore renal function and structure in mice with gentamicin-induced kidney injury, and significantly decrease blood urea nitrogen levels, suppress oxidative stress and inflammation, and attenuate histopathological disturbances, including tubular necrosis, tubular dilation, urinary casts, and interstitial fibrosis. Conclusion: The results suggest that RPCs have a promising regenerative potential in improving renal disease and can lay the foundation for future cell therapy and disease modeling.

ABSTRACTThe COVID-19 pandemic has significantly impacted human life, posing serious physical and psychological threats, particularly to the elderly. While individuals of all ages are susceptible to contracting COVID-19, older people face a heightened risk of developing various diseases due to age-related immunophysiological changes and preexisting health conditions. The interplay between immune health and physical activity is believed to hold even greater significance during a pandemic. Recent findings from our research indicate that the intervention of square stepping exercise (SSE), characterized by a rhythmic and controlled stepping pattern, resulted in increased levels of Brain-Derived Neurotrophic Factor (BDNF) in the elderly. BDNF, known to influence not only nerve cells but also immune cells, suggests a potential link between SSE and immune system modulation. Consequently, this exercise regimen holds promise in counteracting age-related immunophysiological changes, fine-tuning immune responses, and mitigating the severity of potential new virus outcomes, such as ‘Disease X.’ This review aims to underscore the significance of integrating SSE as a home-based program, serving as a potent tool to enhance immune resilience, prepare for future potential pandemics, and empower older individuals during challenging times. Through the practice of SSE, older adults may strengthen their ability to navigate the challenges posed by pandemics and maintain a sense of control over their well-being.

ABSTRACTBiological rhythms play a crucial role in temporally regulating behavioral, physiological, and cellular processes within our bodies. One prominent example is the circadian rhythm, which enables our bodies to anticipate external cues and regulate our internal processes accordingly. The circadian rhythm is controlled by a molecular feedback loop known as the circadian clock, present in nearly all cells. The regulation of genes involved in mitochondrial function is no exception. Key aspects such as oxidative phosphorylation, mitochondrial biogenesis, and mitochondrial morphology are regulated by the circadian clock. Functional changes in mitochondria can retrogradely affect the circadian rhythm. Furthermore, there are also transcriptional circadian clock-independent rhythms within mitochondria. This review discusses mitochondrial rhythms independently or in communication with the circadian clock in the nucleus at the cellular level.

Background: Gelatin hydrogel nonwoven fabrics (Genocel) are three-dimensional gelatin scaffolds that provide cells with space for proliferation, migration, and differentiation. They are expected to be an effective wound healing modality to treat intractable wounds, such as diabetic foot ulcers, because they enhance early neovascularization when used as a skin substitute. In this study, we explored the healing process of Genocel applied to skin defects in diabetic mice and compared it with that of a conventional skin substitute, Pelnac. Methods: Genocel and Pelnac sheets were used to treat skin defects on the backs of diabetic mice. On days 7 and 14, the remaining wound area was evaluated and specimens were harvested for HE, Azan, anti-CD31, CD68, and CD163 staining to assess neoepithelialization, granulation tissue formation, capillary formation, and macrophage infiltration. Results: Wounds treated with Genocel showed a wound healing process comparable to that of wounds treated with Pelnac. No significant differences were observed in the remaining wound area, neoepithelial length, granulation formation, number of pan-macrophages, or M2 ratio on days 7 and 14. The only significant difference was the number of induced M2 macrophages, which was higher in Pelnac group than in the Genocel group on day 7 (p

ABSTRACTTumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has chemotherapeutic potential as a regulator of an extrinsic apoptotic ligand, but its effect as a drug is limited by innate and acquired resistance. Recent findings suggest that an intermediate drug tolerance could mediate acquired resistance, which has made the main obstacle for limited utility of TRAIL as an anti-cancer therapeutics. We propose miRNA-dependent epigenetic modification drives the drug tolerant state in TRAIL-induced drug tolerant (TDT). Transcriptomic analysis revealed miR-29 target gene activation in TDT cells, showing oncogenic signature in lung cancer. Also, the restored TRAIL-sensitivity was associated with miR-29ac and 140-5p expressions, which is known as tumor suppressor by suppressing oncogenic protein RSK2 (p90 ribosomal S6 kinase), further confirmed in patient samples. Moreover, we extended this finding into 119 lung cancer cell lines from public data set, suggesting a significant correlation between TRAIL-sensitivity and RSK2 mRNA expression. Finally, we found that increased RSK2 mRNA is responsible for NF-κB activation, which we previously showed as a key determinant in both innate and acquired TRAIL-resistance. Our findings support further investigation of miR-29ac and -140-5p inhibition to maintain TRAIL-sensitivity and improve the durability of response to TRAIL in lung cancer.

ABSTRACTParkinson’s disease (PD) often results in hippocampal dysfunction, which leads to cognitive and emotional challenges and synaptic irregularities. This study attempted to assess behavioral anomalies and identify differentially expressed genes (DEGs) within the hippocampus of a hemiparkinsonian rat model to potentially uncover novel genetic candidates linked to hippocampal dysfunction. Striatal 6-hydroxydopamine (6-OHDA) infusions were performed unilaterally in the brains of adult SD rats, while dopaminergic impairments were verified in rats with 6-OHDA-lesioned striata. RNA sequencing and gene expression analysis unveiled 1018 DEGs in the ipsilateral rat hippocampus following 6-OHDA infusion: 631 genes exhibited upregulation, while 387 genes were downregulated (with FDR-adjusted p-value 1.5). Gene ontology analysis of DEGs indicated that alterations in the hippocampi of 6-OHDA-lesioned rats were primarily associated with synaptic signaling, axon development, behavior, postsynaptic membrane, synaptic membrane, neurotransmitter receptor activity, and peptide receptor activity. The Kyoto Encyclopedia of Genes and Genomes analysis of DEGs demonstrated significant enrichment of the neuroactive ligand–receptor interaction, calcium signaling pathway, cAMP signaling pathway, axon guidance, and notch signaling pathway in rat hippocampi that had been subjected to striatal 6-OHDA infusion. STRING analysis confirmed a notable upregulation of eight hub genes (Notch3, Gng4, Itga3, Grin2d, Hgf, Fgf11, Htr3a, and Col6a2), along with a significant downregulation of two hub genes (Itga11 and Plp1), as validated by reverse transcription-quantitative polymerase chain reaction. This study provides a comprehensive transcriptomic profile of the hippocampi in a hemiparkinsonian rat model, thereby offering insights into the signaling pathways underlying hippocampal dysfunction.

ABSTRACTSonic vibration (SV), or vibroacoustic therapy, is applied to enhance local and systemic blood circulation and alleviate pain using low-frequency sine wave vibrations. However, there is limited scientific data on the mechanisms through which the benefits are achieved. In this study, we investigated the impact of SV on inflammatory responses by assessing cytokine secretion in both in vivo and in vitro models. After inducing inflammatory responses in mice and macrophages, we studied cytokine expression and the symptoms of inflammatory diseases in response to three frequencies (14, 45, or 90 Hz) of SV stimulation at 0.5 m/s2 of amplitude. The results showed that SV at 90 Hz significantly increased interelukin-10 (IL-10) secretion in mice who were administered lipopolysaccharides (LPS) and increased the expression of IL-10 transcripts in peritoneal exudate cells and macrophages. Furthermore, SV at 90 Hz improved LPS-induced lethality and alleviated symptoms in a colitis model. In conclusion, this study scientifically proves the anti-inflammatory effects of vibration therapy through its ability to increase IL-10 expression.

ABSTRACTCa2+ is a key secondary messenger that determines sperm motility patterns. Mammalian sperm undergo capacitation, a process to acquire fertilizing ability, in the female reproductive tract. Capacitated sperm change their flagellar waveform to develop hyperactivated motility, which is crucial for successful sperm navigation to the eggs and fertilization. The sperm-specific channel, CATSPER, and an ATPase transporter, PMCA4, serve as major paths for Ca2+ influx and efflux, respectively, in sperm. The ionic paths coordinate Ca2+ homeostasis in the sperm, and their loss-of-function impairs sperm motility, to cause male infertility. In this review, we summarize the physiological significance of these two Ca2+ gates and suggest their potential applications in novel male contraceptives.

Background: This study aimed to investigate the impact of intrauterine adhesions (IUA) therapy and endometrial receptivity by implanting autologous bone marrow mesenchymal stem cells (BMSCs) into the Interceed and subsequently placing them in the uterine cavity of rats. Methods: Fifty rats were divided into 5 groups according to the random number table method (10 rats in each group). Following the development of the IUA model through mechanical injury, the animals were categorized into different treatment groups: the IUA model (intrauterine perfusion of saline), Interceed therapy (intrauterine placement of Interceed), BMSCs therapy (intrauterine perfusion of BMSCs), BMSCs + Interceed therapy (intrauterine placement of BMSCs + Interceed), and a control group (intrauterine perfusion of saline). The Hematoxylin-eosin (HE) staining technique was employed to identify and assess the pathological alterations in the endometrium. Additionally, it facilitated the quantification of endometrial glands and the determination of endometrial thickness. Masson staining was used to detect fibrosis in rat uterus. The number of microvascular density (MVD) was detected by immunohistochemistry (IHC). Real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) and Western blot were used to detect the levels of leukemia inhibitory factor (LIF), integrin ανβ3, and vascular endothelial growth factor (VEGF) in uterine tissue. Male and female rats were combined in cages for reproductive and conception evaluation. Results: In comparison to the control, the number of endometrial glands in the IUA model was significantly reduced, and the degree of endometrial thinning and fibrosis was significantly increased (p 0.05). The number of endometrial glands, endometrial thickness, and MVD in the BMSCs therapy group were significantly increased. Moreover, the expressions of LIF, integrin ανβ3, and VEGF in uterine tissue exhibited a significant increase, leading to a comparatively higher pregnancy rate (p

Diabetic ureteral injury (DUI) is a condition characterized by damage to the ureter, causing functional and morphological changes in the urinary system, which have a significant impact on a quality of life and requires appropriate medical treatment. The present study describes to novel design of luteolin (LT), a type of natural flavonoid, encapsulated selenium nanoparticles (Se NPs) to attain therapeutic potential for DUI. The physico-chemical characterizations of prepared Se NPs have benefitted zeta potential (−18 mV) and particle size (10–50 nm). In vitro assays were demonstrated the potential of LT-SeNPs by HEK 293 cells stimulated by STZ for DUI. Cytotoxicity assays on HEK 293 and NIH-3T3 showed >90% cell viability, which demonstrates the suitability of the nanoformulation for DUI treatment. The LT-SeNPs significantly inhibits the NLRP3 inflammasome through Nrf2/ARE pathway, which benefits for DUI treatment. The developed LT-SeNPs could be an effective formulation for the DUI therapy.

Regarded as the most promising treatment modality for retinal degenerative diseases, retinal pigment epithelium cell replacement therapy holds significant potential. Common retinal degenerative diseases, including Age-related Macular Degeneration, are frequently characterized by damage to the unit comprising photoreceptors, retinal pigment epithelium, and Bruch's membrane. The selection of appropriate tissue engineering materials, in conjunction with retinal pigment epithelial cells, for graft preparation, can offer an effective treatment for retinal degenerative diseases. This article presents an overview of the research conducted on retinal pigment epithelial cell tissue engineering, outlining the challenges and future prospects.