Activation Development Research Articles

PKM2-mediated STAT3 phosphorylation promotes acute liver failure via regulating NLRP3-dependent pyroptosis.

Acute liver failure (ALF) is a life-threatening clinical syndrome characterized by high-grade inflammation and multi-organ failure. Our previous study shows that targeting the M2 isoform of pyruvate kinase (PKM2) to inhibit macrophage inflammation may be a promising strategy for ALF treatment. however, the mechanism by which PKM2 regulates the inflammatory response is unclear. Here we demonstrate that PKM2 contributes to ALF by modulating NLRP3-mediated pyroptosis activation in liver macrophages. The specific knockout of PKM2 in myeloid cells reduces mortality and alleviates hepatic injury in D-galactosamine/LPS-induced ALF mice. Single-cell transcriptome analysis suggests that NLRP3 inflammasome activation of macrophages involves in ALF, knockout of PKM2 in macrophages reduces the expression of NLRP3, and activation of pyroptosis. Pharmacological inhibition of the PKM2 nuclear translocation, but not glycolytic activity, protects mice from ALF. Pharmacological and genetic inhibition of PKM2 attenuates NLRP3-mediated pyroptosis activation and consequently reduces the release of IL-1β and IL-18 by macrophages. Mechanistically, PKM2 translocates into the nucleus and combines with STAT3, enhancing its phosphorylation and recruitment to the NLRP3 promoter region, thereby increasing NLRP3 expression. This work defines PKM2 acts as an important nonmetabolic regulator of NLRP3 that modulates pyroptosis activation in macrophages and guides future therapeutic strategies development for ALF.

Testing perioperative meloxicam analgesia to enhance welfare while preserving model validity in an inflammation-induced seizure model

Despite the international effort to improve laboratory animal welfare through the 3R principles (Reduce, Refine, Replace), many scientists still fail to implement and report their assessment of pain and well-being, likely due to concerns regarding the potential effects of analgesics on experimental outcomes. This study aimed to determine whether refining our viral encephalitis model with perioperative analgesia could enhance well-being and recovery after intracerebral virus infection without impacting disease outcomes. We routinely use the Theiler’s Murine Encephalomyelitis Virus (TMEV) model to study virus-induced epilepsy. Given the crucial role of immune cell activation in acute seizure development, we evaluated the effects of the non-steroidal anti-inflammatory drug (NSAID) meloxicam on inflammation, neurodegeneration, and neuronal cell proliferation at 7 days post-infection (dpi). Overall, the impact of virus infection on well-being was less severe than anticipated, and meloxicam treatment did not affect well-being or nest building behavior in TMEV-infected mice. Furthermore, meloxicam treatment did not influence key experimental readouts such as seizure burden, central inflammatory response, neurodegeneration, or neuronal proliferation within the hippocampus. Notably, animals experiencing seizures displayed heightened inflammatory responses and neurodegeneration, which were not influenced by meloxicam treatment. In summary, perioperative analgesia did not compromise key outcome measures such as seizure frequency, inflammation, and neurodegeneration or -regeneration in the TMEV model. However, it also did not add any significant benefits to well-being in the first week after intracranial injections.

Основные проблемы реализации государственной жилищной политики (на примере Республики Саха (Якутия))

The relevance of the study is due to the search for models of effective interaction between the central and regional authorities on the implementation of state housing policy. The object of the study is the state housing policy, the subject of the study is the main trends in the implementation and development of state housing policy in the Republic of Sakha (Yakutia). The main goal of the work is to reveal the content and problems of state housing policy implementation in the Republic of Sakha (Yakutia). Research objectives are as follows: to study the phenomenon of state housing policy in the Russian Federation, its goals, objectives and basic principles of implementation; to consider the issue of state regulation of housing policy; to analyze the state of housing policy in the Republic of Sakha (Yakutia) and trends in its implementation. The methodological basis of the study is based on analytical, comparative, statistical and systemic methods of scientific knowledge, which allow structuring and analyzing the implementation of key areas of state housing policy at the federal and regional levels. The use of these methods contributed to the formation of an objective picture of the state of regional housing policy in the Republic of Sakha (Yakutia) and identified the main trends recorded in the results of the study. The author defines the principles and foundations of the theoretical and methodological part of the housing policy implementation and development in the region; identifies further priority areas for the regional state housing policy development, taking into account the content of the regulatory framework, features and specifics of implementation and improvement programs. The Republic of Sakha (Yakutia) has its own features in the housing policy development, such as independent regulation of conflict situations, additional subsidy and benefit programs for special categories of the population, organizing the solution of the emergency fund issue by coordinating the activities of regional and federal developers. However, the main problems due to which solutions to issues in the field of regional state housing policy implementation are not revealed have become the limited amount of finance and the natural conditions of our region.

Business cycle in residential construction in Poland 2007–2022

This article explores the dynamic interplay between the business cycle and the housing market in Poland from 2007 to 2022. It examines the complex relationship between economic cycles and the residential property sector, focusing on the impact of government intervention and market fluctuations. The research shows that the housing market is highly sensitive to external factors. It highlights the central role of the National Bank of Poland (NBP) in shaping the housing market through changes in interest rates and credit availability. The COVID-19 pandemic temporarily disrupted developer activity and housing demand, highlighting the vulnerability of the market to unexpected shocks. In addition to observations, this study calls for a critical analysis of housing policies, identifying potential shortcomings and offering recommendations for improvement. It underlines that economic crises are an inherent part of housing market cycles, promoting market cleansing and healthy competition. Finally, this research emphasises that the housing market is intertwined with broader economic trends. It highlights the need for central banks to strike a balance between managing inflation and supporting economic growth. This study contributes to a deeper understanding of the relationship between the housing market and the business cycle, providing valuable insights for policymaking and investment decisions.

Risk Prioritizing with Weighted Failure Mode and Effects Analysis and Fuzzy Step-Wise Weight Assessment Ratio Analysis: An Application Software Service Provider Company in the Defense Industry

With the development of technology, the need for software and software products to manage, control, and develop activities in many sectors is increasing daily. In order to create suitable software that will meet the needs of businesses and customers, the software application must be tested in detail before reaching the end user. For this reason, software testing processes are gaining importance in software development activities. This article discusses which errors are critical to solve in complex situations for the reliability and quality of the software product and the relationship between errors. In this study, the classical FMEA method was primarily used to identify and prioritize errors in an ongoing project of a company that provides software services in the defense industry. Later, to eliminate the shortcomings of the classical FMEA method, a new model, the weighted FMEA method (which calculates the risk priority score with five sub-severity components), was developed and applied. In the newly developed weighted FMEA method, the weights were determined by the fuzzy SWARA (Step-Wise Weight Assessment Ratio Analysis) method since the weights of the severity subcomponents were not the same. The risk priority number (RPN) of error types was calculated using classical FMEA and weighted FMEA. Since the RPNs calculated with weighted FMEA are calculated with more subcomponents, the chances of the RPNs’ errors appearing the same are much less than the RPNs calculated with classical FMEA. This situation indicates that the RPNs calculated with weighted FMEA are obtained from a more profound analysis.

Transcriptome and epigenome dynamics of the clonal heterogeneity of human induced pluripotent stem cells for cardiac differentiation

Human induced pluripotent stem cells (hiPSCs) generate multiple clones with inherent heterogeneity, leading to variations in their differentiation capacity. Previous studies have primarily addressed line-to-line variations in differentiation capacity, leaving a gap in the comprehensive understanding of clonal heterogeneity. Here, we aimed to profile the heterogeneity of hiPSC clones and identify predictive biomarkers for cardiomyocyte (CM) differentiation capacity by integrating transcriptomic, epigenomic, endogenous retroelement, and protein kinase phosphorylation profiles. We generated multiple clones from a single donor and validated that these clones exhibited comparable levels of pluripotency markers. The clones were classified into two groups based on their differentiation efficiency to CMs—productive clone (PC) and non-productive clone (NPC). We performed RNA sequencing (RNA-seq) and assay for transposase-accessible chromatin with sequencing (ATAC-seq). NPC was enriched in vasculogenesis and cell adhesion, accompanied by elevated levels of phosphorylated ERK1/2. Conversely, PC exhibited enrichment in embryonic organ development and transcription factor activation, accompanied by increased chromatin accessibility near transcription start site (TSS) regions. Integrative analysis of RNA-seq and ATAC-seq revealed 14 candidate genes correlated with cardiac differentiation potential. Notably, TEK and SDR42E1 were upregulated in NPC. Our integrative profiles enhance the understanding of clonal heterogeneity and highlight two novel biomarkers associated with CM differentiation. This insight may facilitate the identification of suboptimal hiPSC clones, thereby mitigating adverse outcomes in clinical applications.Graphical

Drug addiction resulting from the abusive use of opioids: a literature review

The severity of drug addiction resulting from the abusive use of opioids, primarily starting from chronic pain treatments, represents a serious threat to public health and social well-being. This study, through a literature review, analyzed the transition from therapeutic use to opioid abuse and consequent addiction, focusing on oxycodone. This review article aimed to understand the pharmacodynamics of opioids and their relationship with neuroinflammation, discussing biopsychosocial vulnerability factors, and better comprehending how healthcare professionals may assist in addressing the consequences of opioid abuse and its social and economic impact, as well as possible preventive and intervention measures. The methodology involved a qualitative analysis of scientific articles published between 2000 and 2024, based on rigorous inclusion and exclusion criteria. The results highlighted the central role of neuroinflammation and toll-like receptor 4 (TLR4) receptor activation in tolerance development and the association of social factors with dependency, in addition to the socioeconomic and public health impacts stemming from opioid abuse. In conclusion, multidisciplinary interventions, stricter public policies, and monitoring systems are essential to mitigate the consequences of inappropriate opioid use, while awareness strategies and less abuse-prone therapeutic alternatives are fundamental for safer management.

Utility of First-Morning-Voided Urinary Total Luteinizing Hormone in Detecting the Onset of Central Puberty

Introduction: Early morning basal serum luteinizing hormone (S-LH) ≥0.3 IU/L is a specific marker for the onset of central puberty. In this study, we aimed to investigate the sensitivity and specificity of the first-morning-voided (FMV) total urinary LH (U-LH) to replace this marker. Methods: We re-analyzed our previously published data set of 297 children (145 boys and 152 girls, aged 5–15 years, across Tanner stages 1 through 5) using receiver operating characteristic (ROC) analysis and determined cutoff values for FMV total U-LH in predicting early morning S-LH concentration at or above 0.3 IU/L. We also determined S-LH and serum follicle-stimulating hormone (S-FSH) concentrations in girls at different stages of sexual maturation. Results: ROC analysis showed that FMV total U-LH levels of 0.60 and 0.63 IU/L in girls and boys, respectively, predicted early morning S-LH levels of 0.3 IU/L or higher with 97.4% sensitivity and 90.6% specificity. Higher cutoff levels for U-LH (0.78 IU/L for boys and 0.79 IU/L for girls) yielded 94.7% specificity at the expense of a relatively lower level of sensitivity (94.1%). The areas under the curve were 0.98 in boys and 0.99 in girls, respectively. Additionally, the increase in FMV total U-LH (or S-LH) levels identified the activation of central pubertal development at the mean age of 10.3 (10.3) in boys and 10.5 (10.6) in girls. The S-FSH concentrations of the six biochemically prepubertal girls with thelarche, ranging between 2.3 and 2.7 IU/L, were significantly higher than those measured in biochemically and clinically prepubertal girls of the same 10–12-year-old age group and significantly lower than those measured in both biochemically and clinically pubertal girls (p = 0.039 and p = 0.018, respectively). Conclusions: A FMV total U-LH concentration of 0.6 IU/L or above reliably reflects pubertal morning S-LH levels and is effective in detecting the onset of central puberty, which occurs at similar ages in both sexes. Concurrent S-FSH or noninvasive FMV U-FSH determinations may be useful in the differential diagnosis of isolated thelarche.

Sensitivity and uncertainty analysis of neutron activation source terms based on statistical sampling method

The calculation of neutron activation source terms is an essential task in the radiation of nuclear reactors, and its sensitivity and uncertainty (S&U) analysis can help better identify and control the influencing factors and safety margin of activation source terms. In this paper, we studied the statistical sampling strategies for the S&U analysis of activation source terms, established the calculation process of sensitivity coefficient and uncertainty, and the S&U analysis module based on sampling methods was integrated for the proprietary developed activation computation program ABURN. Two sampling ways, Monte Carlo and Latin hypercube sampling treatments, were employed to figure out the cases of pure decay single chain, pure activation single chain, and complex reaction network. The sensitivity coefficients and uncertainty of nuclide inventory were evaluated by taking the uncertainty of decay constant or reaction cross-section into account. The simulation results indicate that after introducing the LHS sampling method, the activation calculation program ABURN can improve computational efficiency in sensitivity and uncertainty analysis. Subsequent results demonstrated that the sensitivity coefficients and uncertainty solutions based on the sampling methods in the ABURN program were in good agreement with the analytical solutions and the FISPACT program, which verified the accuracy of the approaches and program in this paper.

Developing translational products for adapting evidence-based physical activity interventions in rural communities

The development and distribution of educational materials is a key strategy to support the implementation of evidence-based interventions (EBIs). Rural communities have higher rates of physical inactivity and face higher burden of many diseases that increased physical activity can prevent. To support the translation of a developed physical activity intervention for adults in micropolitan communities (10,000-50,000 people), called Active XXXX, the University of XXXX Prevention Research Center for Rural Health (PRC-RH) created a toolkit and supplemental resources designed to guide implementers through the implementation of the intervention. Through a community-engaged process, the PRC-RH underwent three phases of review and evaluation of the developed products. The first phase involved the Community Advisory Board from the pilot intervention, the second involved the PRC-RH State Advisory Board and public health practitioners from across the state, and the third involved micropolitan leaders and micropolitan health department staff. The feedback received through these three phases resulted in changes to the developed products to improve usability, readability, and clarity. The feedback also resulted in the development of additional materials to further support the implementation of the intervention. The success the PRC-RH experienced in the review process can be attributed to the strong, established partnerships with practitioners across the state who represented a variety of community roles and organizations. The developed materials can be used to improve physical activity rates in rural and micropolitan communities, in turn reducing chronic diseases and improving the quality of life for rural residents.

Key Aspects of the Integration of the Donetsk People’s Republic into the Economic Space of the Russian Federation

The article considers the problems of integration of the new region - Donetsk People’s Republic into the economic field of the Russian Federation. The main tasks to be solved in the liberated territories are given. It is suggested to form a state programme aimed at solving these problems. It is revealed that one of the key problems limiting further economic growth, along with the ongoing military operations, is the outflow of able-bodied population. As a strategic goal of socio-economic development of the Republic for the next 10 years, it is proposed to restore infrastructure, modernize industry and structural reform of the economy, increase the population, as well as the quality and duration of life. To achieve this goal, three directions are considered: formation and accumulation of human capital; creation of space for human capital development; creation of appropriate economic environment. The stages for the realization of goals and tasks have been identified. It has been determined that industry should form the basis of the economy of the reviving Donbas. It is necessary to develop manufacturing industries, knowledgeintensive and complex production. It is of fundamental importance to improve the quality of economic growth - to build and move along the supply and value chains from the first links, with a low specific weight of added value in the price of goods, to the next links, with a higher specific weight of added value. Priority sectors of the Republic are identified. It was noted that the activation of economic development cannot be carried out without reforming the existing system of state administration in the Republic. An important task is to transfer the functioning of public authorities to the technology of strategic and programme-target planning and budgeting.

Platelets as mediators of neuropsychiatric and neurodegenerative diseases

Numerous studies showing platelets' role in mechanisms beyond hemostasis have sparked interest in investigating all the pathways in which they may be involved. A growing body of evidence indicates that platelets play a key role in immune response. Platelets carry various membrane receptors and release many bioactive molecules that recruit and activate immune cells. Consequently, platelets have a significant immunoregulatory role in infectious, inflammatory, and degenerative diseases. Moreover, immune cells contribute to neuronal development, neural plasticity, and neuroglial activation. The interaction between platelets and immune cells reveals an additional regulatory mechanism of brain function. This review explores the relationship between platelets and the central nervous system (CNS). It highlights the role of platelets in the development of severe neurodegenerative and neuropsychiatric diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS) and depression.

Activation function optimization scheme for image classification

Activation function has a significant impact on the dynamics, convergence, and performance of deep neural networks. The search for a consistent and high-performing activation function has always been a pursuit during deep learning model development. Existing state-of-the-art activation functions are manually designed with human expertise except for Swish. Swish was developed using a reinforcement learning-based search strategy. In this study, we propose an evolutionary approach for optimizing activation functions specifically for image classification tasks, aiming to discover functions that outperform current state-of-the-art options. Through this optimization framework, we obtain a series of high-performing activation functions denoted as Exponential Error Linear Unit (EELU). The developed activation functions are evaluated for image classification tasks from two perspectives: (1) five state-of-the-art neural network architectures, such as ResNet50, AlexNet, VGG16, MobileNet, and Compact Convolutional Transformer, which cover computationally heavy to light neural networks, and (2) eight standard datasets, including CIFAR10, Imagenette, MNIST, Fashion MNIST, Beans, Colorectal Histology, CottonWeedID15, and TinyImageNet which cover from typical machine vision benchmark, agricultural image applications to medical image applications. Finally, we statistically investigate the generalization of the resultant activation functions developed through the optimization scheme. With a Friedman test, we conclude that the optimization scheme is able to generate activation functions that outperform the existing standard ones in 92.8% cases among 28 different cases studied, and −x⋅erf(e−x) is found to be the best activation function for image classification generated by the optimization scheme.

ERVcancer: a web resource designed for querying activation of human endogenous retroviruses across major cancer types

Human endogenous retroviruses (HERVs) comprise approximately 8% of the human genome, co-opted into the dynamic regulatory network of cellular potency in early embryonic development. In recent studies, resurgent HERVs' transcriptional activity has been frequently observed in many types of human cancers, suggesting their potential functions in the occurrence and progression of malignancy. However, a dedicated web resource for querying the relationship between the activation of HERVs and cancer development is lacking. Here, we construct a database to explore the sequence information, expression profiles, survival prognosis, and genetic interactions of HERVs in diverse cancer types. Our database currently contains RNA sequencing data of 580 HERVs across 16,246 samples, including that of 6478 tumoral and 634 normal tissues, 932 cancer cell lines, as well as 151 early embryonic and 8051 human adult tissues. The primary goal is to provide an easily accessible and user-friendly database for professionals in the fields of bioinformatics, pathology, pharmacology, and related areas, enabling them to efficiently screen the activity of HERVs of interest in normal and cancerous tissues and evaluate the clinical relevance. The ERVcancer database is available at http://kyuanlab.com/ervcancer/.

Leptin A deficiency affecting the mitochondrial dynamics of aged oocytes in medaka (Oryzias latipes)

Mitochondrial dysfunction and metabolic disorder have been associated to age-related subfertility, however, the precise molecular mechanism controlling the development of fertile oocytes in aging females remains elusive. Leptin plays an important role in the maintenance of energy homeostasis, as both excessive or insufficient levels can affect the body weight and fertility of mice. Here, we report that leptin A deficiency affects growth and shortens reproductive lifespan by reducing fertility in medaka (Oryzias latipes). Targeted disruption of lepa (lepa−/−) females reduced their egg laying and fertility compared to normal 3-month-old females (lepa+/+ sexual maturity), with symptoms worsening progressively at the age of 6 months and beyond. Transcriptomic analysis showed that differentially expressed genes involved in metabolic and mitochondrial pathways were significantly altered in lepa−/− ovaries compared with the normal ovaries at over 6 months old. The expression levels of the autophagy-promoting genes ulk1a, atg7 and atg12 were significantly differentiated between normal and lepa−/− ovaries, which were further confirmed by quantitative polymerase chain reaction analysis, indicating abnormal autophagy activation and mitochondrial dysfunction in oocyte development lacking lepa. Transmission electron microscopy observations further confirmed these mitochondrial disorders in lepa-deficient oocytes. In summary, these research findings provide novel insights into how leptin influences female fertility through mitochondrial-mediated oocyte development.

Neuromuscular response of young athletes during plyometric and sprint exercises

The objective was to analyse the neuromuscular response during jumping and sprint exercises in young athletes and adults. Young athletes were divided into 2 groups: indoor soccer (SOC, n = 12) and rugby (RUG, n = 12) and adults were physical education students (PE, n = 12). Sport groups were trained systematically for their sport for 5 years and performed resistance training at least for 2 years. Neuromuscular response was evaluated using a vertical jump test (CMJA), 15-meter sprint test (SPRI) and a rebound test at 3HZ (REB). Force and electromyography were measured during all tests. Leg stiffness (Kvert), rate of force development (RFD) and muscle activation were calculated and analysed. Pre activation and contact EMG were measured for all tests. EMG signal was normalized by CMJA. There were no differences in maturation level between young sport groups as shown by Mirwald’s formula (p = .897). Significant differences were found in favour of RUG vs SOC during CMJA (p = .029). For SPRI and REB, there were no statistical differences between groups for RFD (p = .585) and (p = .056). Kvert showed no group differences among CMJA (p = .396), SPRI (p = .329) and REB (p = .429). It is concluded that a systematic training in young athletes allows the accelerated development of neuromuscular performance.

What drives cryptocurrency pump and dump schemes: Coin versus market factors?

This paper investigates both coin-specific and market-based factors that drive cryptocurrency pump-and-dump schemes. It analyzes a data set comprising 1457 pump events that occurred from January 3, 2018, to January 2, 2022. Empirical findings, derived from binary cross-sectional regression models, reveal several characteristics that increase the likelihood of cryptocurrencies being pumped. These include lower market capitalization, lower trading volume, greater social media popularity, increased developer activity, and fewer exchanges trading them. Furthermore, the study employs count time-series models to examine market-based factors. The results indicate that periods of higher volatility or uncertainty are associated with an increase in pre-announced pump-and-dump activities. Additionally, the analysis shows that macroeconomic factors and specific time-related effects – such as Sundays, certain months, and the COVID-19 period – are significant in explaining the frequency of pump occurrences. Based on these findings, the article discusses several targeted recommendations.

Trans-Interacting Plasma Membrane Proteins and Binding Partner Identification.

Plasma membrane proteins (PMPs) play critical roles in a myriad of physiological and disease conditions. A unique subset of PMPs functions through interacting with each other in trans at the interface between two contacting cells. These trans-interacting PMPs (tiPMPs) include adhesion molecules and ligands/receptors that facilitate cell-cell contact and direct communication between cells. Among the tiPMPs, a significant number have apparent extracellular binding domains but remain orphans with no known binding partners. Identification of their potential binding partners is therefore important for the understanding of processes such as organismal development and immune cell activation. While a number of methods have been developed for the identification of protein binding partners in general, very few are applicable to tiPMPs, which interact in a two-dimensional fashion with low intrinsic binding affinities. In this review, we present the significance of tiPMP interactions, the challenges of identifying binding partners for tiPMPs, and the landscape of method development. We describe current avidity-based screening approaches for identifying novel tiPMP binding partners and discuss their advantages and limitations. We conclude by highlighting the importance of developing novel methods of identifying new tiPMP interactions for deciphering the complex protein interactome and developing targeted therapeutics for diseases.

Valsartan as a prophylactic treatment against breast cancer development and niche activation: What molecular sequels follow chronic AT-1R blockade?

AimsTransactivation of insulin-growth-factor-receptor (IGF-1R) by angiotensin-II-type-1-receptor (AT-1R) was only demonstrated in vascular-smooth-muscle cells and has never been tested in breast-cancer (BC). This investigation addressed the impact of chronic AT-1R blockade by valsartan (Val) on possible concurrent AT-1R/IGF-1R signaling inhibition, regressing BC-tumor-microenvironment (TME) cellular components activation, and hindering BC development. Main methodsThe effect of different Val doses (10, 20, 40 & 80 mg/kg/day for 490 days) was tested on dimethylbenz(a)anthracene (DMBA)-induced progesterone-promoted-BC in rats. The influence on intratumoral/circulating angiotensin-II (ANG-II) levels and AT-1R/Mas-R immunofluorescent-expression were assessed. The potential AT-1R/IGF-1R crosstalk within TME-BC-stem-cells (BCSCs) and cancer-associated-fibroblasts (CAFs) was evaluated by fluorescently marking these cells and locating the immunofluorescently-stained AT-1R/IGF-1R in them using confocal-laser-microscopy and further quantified by flow cytometry. In addition, the molecular alterations following blocking AT-1R were inspected including determining Src; crucial for IGF-1R transactivation by AT-1R, Notch-1; IGF-IR transcriptional-regulator, and PI3K/Akt &IL-6/STAT expression. Further, the suppression of CSCs' capabilities to maintain pluripotency, stemness features, epithelial-to-mesenchymal-transition (EMT), and angiogenesis was evaluated by assessing NANOG gene, aldehyde-dehydrogenase (ALDH), N-cadherin and vascular-endothelial-growth-factor (VEGF), respectively. Furthermore, the proliferative marker; Ki-67, was detected by immunostaining, and tumors were histologically graded using Elston-Ellis-modified-Scarff-Bloom-Richardson method. Key findingsProphylactic Val significantly reduced tumor size, prolonged latency, reduced tumor histopathologic grade, decreased circulating/intratumoral-ANG-II levels, increased Mas-R, and decreased AT1R expression. AT-1R/IGF-1R were co-expressed with a high correlation coefficient on CAFs/BCSCs. Moreover, Val significantly attenuated IGF-1R transactivation and transcriptional regulation via Src and Notch-1 genes' downregulation and reduced Src/IGF-IR-associated PI3K/Akt and IL-6/STAT3 signaling. Further, Val significantly decreased intratumoral NANOG, ALDH, N-cadherin, VEGF, and Ki-67 levels. SignificanceChronic Val administration carries a potential for repurposing as adjuvant or conjunct therapy for patients at high risk for BC.

Leisure class stratification among Chinese residents: Evidence from the CGSS

Amidst rapid societal progression in China, leisure has become a crucial component of Chinese residents’ daily lives. However, the unequal distribution of social resources across social strata significantly affects their leisure patterns and practices. This study utilizes data from the Chinese General Social Survey (CGSS) spanning 2006, 2010, and 2017, analyzing the frequency and types of leisure engagement as dependent variables through mean, variance, and OLS regression analyses. The findings indicate considerable leisure stratification within Chinese society, both subjectively and objectively; there are significant differences in leisure participation frequency and type among different social strata, particularly in developed leisure activities. The conclusions of this study may aid in understanding the current state of leisure class stratification among Chinese residents, while its practical recommendations could help mitigate the issues of leisure stratification within Chinese society.