Search

The proper differentiation and reorganization of the intestinal epithelial cell population is critical to mucosal regeneration post injury. Label retaining cells (LRCs) expressing SRY-box transcription factor 9 (SOX9) promote epithelial repair by replenishing LGR5+ intestinal stem cells (ISCs). While, LRCs are also considered precursor cells for enteroendocrine cells (EECs) which exacerbate mucosal damage in inflammatory bowel disease (IBD). The factors that determine LRC-EEC differentiation and the effect of intervening in LRC-EEC differentiation on IBD remain unclear. In this study, we investigated the effects of a natural anthraquinone called aloe emodin (derived from the Chinese herb rhubarb) on mucosal healing in IBD models. Our findings demonstrated that aloe emodin effectively interfered with the differentiation to EECs and preserved a higher number of SOX9+ LRCs, thereby promoting mucosal healing. Furthermore, we discovered that aloe emodin acted as an antagonist of free fatty acid receptors (FFAR1), suppressing the FFAR1-mediated Gβγ/serine/threonine-protein kinase (AKT) pathway and promoting the translocation of forkhead box protein O1 (FOXO1) into the nucleus, ultimately resulting in the intervention of differentiation fate. These findings reveal the effect of free fatty acid accessibility on EEC differentiation and introduce a strategy for promoting mucosal healing in IBD by regulating the FFAR1/AKT/FOXO1 signaling pathway.

Abstract The catering industry plays an essential role in providing life services. Understanding its spatial patterns offers insights into the economic, cultural and spiritual image of a society. Especially in urban settings, the catering industry is often considered a key element for improving the competitiveness of cities. With rapid urbanization and economic growth in China, the catering industry has become the main driving force to stimulate China’s service sectors. In this study, we conducted a comprehensive spatial analysis to explore the distribution patterns by calculating kernel density and applying the geographically weighted regression (GWR) model with 4.49 million restaurants across 336 cities in China in 2020. The restaurants were categorized into four types: Chinese restaurants (CRs), Western restaurants (WRs), fast-food restaurants (FFRs), and dessert and drink restaurants (DDRs). We incorporated a diverse set of socio-economic indicators to explore potential causal influences, including population size and density, GDP, etc. Our study revealed a gradual decrease in restaurant density from southeast to northwest China, with high density observed in the Pearl River Economic Delta, Yangtze River Economic Delta, Chongqing, and Chengdu regions. In terms of the potential influencing factors, we observed that in west and southwest regions, density appeared to be more affected by GDP per unit area, total tourism revenue, disposable income per capita of urban residents, and total retail sales of social consumption. While in northeast areas, restaurant density was more affected by total retail sales of social consumption, GDP per unit area, number of urban population, and the proportion of tertiary industry in GDP. These insights serve as a direct scientific foundation for informing the strategic planning of different types of restaurants at municipal, provincial, and regional levels.

Abstract Background Aortic dissection (AD) is a macrovascular disease which is pathologically characterized by aortic media degeneration.This experiment aims to explore how iron deficiency (ID) affects the function of vascular smooth muscle cell (VSMC) and participates in the occurrence and development of AD by regulating gene expression. Methods The relationship between iron and AD was proved by Western-blot (WB) and immunostaining experiments in human and animals. Transcriptomic sequencing explored the transcription factors that were altered downstream. WB, flow cytometry and immunofluorescence were used to demonstrate whether ID affected HIF1 expression through oxygen transport. HIF1 signaling pathway and phenotypic transformation indexes were detected in cell experiments. The use of the specific HIF1 inhibitor PX478 further demonstrated that ID worked by regulating HIF1. Results The survival period of ID mice was significantly shortened and the pathological staining results were the worst. Transcriptomic sequencing indicated that HIF1 was closely related to ID and the experimental results indicated that ID might regulate HIF1 expression by affecting oxygen balance. HIF1 activation regulates the phenotypic transformation of VSMC and participates in the occurrence and development of AD in vivo and in vitro.PX478, the inhibition of HIF1, can improve ID-induced AD exacerbation.

Abstract Background Diabetic cardiomyopathy (DCM), a serious complication of diabetes, leads to structural and functional abnormalities of the heart and ultimately evolves to heart failure. IL-37 exerts a substantial influence on the regulation of inflammation and metabolism. Whether IL-37 is involved in DCM is unknown. Methods The plasma samples were collected from healthy controls, diabetic patients and DCM patients, and the level of IL-37 and its relationship with heart function were observed. The changes in cardiac function, myocardial fibrosis and mitochondrial injury in DCM mice with or without IL-37 intervention were investigated in vivo. By an in vitro co-culture approach involving HG challenge of cardiomyocytes and fibroblasts, the interaction carried out by cardiomyocytes on fibroblast profibrotic activation was studied. Finally, the possible interactive mediator between cardiomyocytes and fibroblasts was explored, and the intervention role of IL-37 and its relevant molecular mechanisms. Results We showed that the level of plasma IL-37 in DCM patients was upregulated compared to that in healthy controls and diabetic patients. Both recombinant IL-37 administration or inducing IL-37 expression alleviated cardiac dysfunction and myocardial fibrosis in DCM mice. Mechanically, hyperglycemia impaired mitochondria through SIRT1/AMPK/PGC1α signaling, resulting in significant cardiomyocyte apoptosis and the release of extracellular vesicles containing mtDNA. Fibroblasts then engulfed these mtDNA-enriched vesicles, thereby activating TLR9 signaling and the cGAS-STING pathway to initiate pro-fibrotic process and adverse remodeling. However, the presence of IL-37 ameliorated mitochondrial injury by preserving the activity of SIRT1-AMPK-PGC1α axis, resulting in a reduction in release of mtDNA-enriched vesicle and ultimately attenuating the progression of DCM. Conclusions Collectively, our study demonstrates a protective role of IL-37 in DCM, offering a promising therapeutic agent for this disease. Graphical abstract Hyperglycemia aggravates mitochondrial injury through SIRT1/AMPK/PGC1α signaling, resulting in significant cardiomyocyte apoptosis and the release of extracellular vesicles containing mtDNA in DCM mice. Fibroblasts then engulf these mtDNA-enriched vesicles, activating TLR9 signaling and the cGAS-STING pathway to initiate profibrotic process and adverse remodeling. However, both exogenous and endogenous IL-37 ameliorate mitochondrial injury by preserving the activity of SIRT1-AMPK-PGC1α axis, and reducing the release of mtDNA-enriched vesicles, which attenuates the progression of DCM

ObjectiveTo evaluate the antitumor effects of diisopropylamine dichloroacetate (DADA) alone or in combination with chemotherapy/radiotherapy/immunotherapy in NSCLC and explore the underlying mechanisms involved.MethodsMTT, UV spectrophotometry, flow cytometry, fluorescence microscopy, and clonogenic survival assays were used. In LLC mouse models, the antitumor effects of radiotherapy, DADA, and the anti-PD-1 antibody alone or in combination were evaluated, and the T cell numbers were evaluated in different groups.ResultsDADA significantly inhibited lactate production and promoted apoptosis in NSCLC in vitro. Compared with pemetrexed or DADA alone, the combination of DADA with pemetrexed significantly inhibited proliferation and promoted apoptosis (p

Summary: This study introduces a novel virtual cursor control system designed to empower individuals with neuromuscular disabilities in the digital world. By combining eye-tracking with motor imagery (MI) in a hybrid brain-computer interface (BCI), the system enhances cursor control accuracy and simplicity. Real-time classification accuracy reaches 87.92% (peak of 93.33%), with cursor stability in the gazing state at 96.1%. Integrated into common operating systems, it enables tasks like text entry, online chatting, email, web surfing, and picture dragging, with an average text input rate of 53.2 characters per minute (CPM). This technology facilitates fundamental computing tasks for patients, fostering their integration into the online community and paving the way for future developments in BCI systems.

The global prevalence of nonalcoholic fatty liver disease (NAFLD) has reached 30 %, with an annual increase. The incidence of NAFLD-induced cirrhosis is rapidly rising and has become the leading indicator for liver transplantation in the US. However, there are currently no US Food and Drug Administration-approved drugs for NAFLD. Increasing evidence underscores the close association between NAFLD and bile acid metabolism disorder, highlighting the feasibility of targeting the bile acid signaling pathway for NAFLD treatment. The farnesoid X receptor (FXR) is an endogenous receptor for bile acids that exhibits favorable effects in ameliorating the metabolic imbalance of bile acids, lipid disorders, and disruption of intestinal homeostasis, all of which are key characteristics of NAFLD, making FXR a promising therapeutic target for NAFLD. The present review provides a comprehensive overview of the diverse mechanisms through which FXR improves NAFLD, with particular emphasis on its involvement in regulating bile acid homeostasis and the recent advancements in drug development targeting FXR for NAFLD treatment.

The damage of integrated epithelial epithelium is a key pathogenic factor and closely associated with the recurrence of ulcerative colitis (UC). Here, we reported that vanillic acid (VA) exerted potent therapeutic effects on DSS-induced colitis by restoring intestinal epithelium homeostasis via the inhibition of ferroptosis. By the CETSA assay and DARTS assay, we identified carbonic anhydrase IX (CAIX, CA9) as the direct target of VA. The binding of VA to CA9 causes insulin-induced gene-2 (INSIG2) to interact with stromal interaction molecule 1 (STIM1), rather than SREBP cleavage-activating protein (SCAP), leading to the translocation of SCAP-SREBP1 from the endoplasmic reticulum (ER) to the Golgi apparatus for cleavage into mature SREBP1. The activation of SREBP1 induced by VA then significantly facilitated the transcription of stearoyl-CoA desaturase 1 (SCD1) to exert an inhibitory effect on ferroptosis. By inhibiting the excessive death of intestinal epithelial cells caused by ferroptosis, VA effectively preserved the integrity of intestinal barrier and prevented the progression of unresolved inflammation. In conclusion, our study demonstrated that VA could alleviate colitis by restoring intestinal epithelium homeostasis through CA9/STIM1-mediated inhibition of ferroptosis, providing a promising therapeutic candidate for UC.

Intensive care units (ICUs) are specialized environments dedicated to the management of critically ill patients, who are particularly susceptible to drug-resistant bacteria. Among these, carbapenem-resistant Gram-negative bacteria (CR-GNB) pose a significant threat endangering the lives of ICU patients. Carbapenemase production is a key resistance mechanism in CR-GNB, with the transfer of resistance genes contributing to the extensive emergence of antimicrobial resistance (AMR). CR-GNB infections are widespread in ICUs, highlighting an urgent need for prevention and control measures to reduce mortality rates associated with CR-GNB transmission or infection. This review provides an overview of key aspects surrounding CR-GNB within ICUs. We examine the mechanisms of bacterial drug resistance, the resistance genes that frequently occur with CR-GNB infections in ICU, and the therapeutic options against carbapenemase genotypes. Additionally, we highlight crucial preventive measures to impede the transmission and spread of CR-GNB within ICUs, along with reviewing the advances made in the field of clinical predictive modeling research, which hold excellent potential for practical application.

Early childhood music education has garnered recognition for its unique contribution to cognitive, emotional, and social development in children. Nevertheless, the industry grapples with numerous challenges, including a struggle to adapt traditional educational paradigms to new curriculum reforms, and an excessive emphasis on skill training at the expense of nurturing a love for music and aesthetics in children. To navigate these challenges and explore growth strategies for the early childhood music education industry, we initiated a comprehensive approach that involved distributing surveys to practitioners and parents and engaging experts for insightful discussions. Consequently, we proposed an analytical method based on dynamic social networks in conjunction with Intuitionistic Fuzzy Sets (IFS), Analytic Hierarchy Process (AHP), and Strengths, Weaknesses, Opportunities, and Threats (SWOT) analysis, collectively referred to as IFS-AHP-SWOT. This integrated methodology synergizes the capabilities of dynamic social networks, IFS, AHP, and SWOT analysis to offer a nuanced perspective on industry development strategies. The findings underscore that institutions within the early childhood music education industry need to adopt a development strategy that leverages their strengths and opportunities to foster sustainable growth. Ultimately, this research aims to provide critical decision-making support for industry practitioners, policymakers, and researchers, contributing significantly to the ongoing discourse on strategic development in the early childhood music education industry.

In brain imaging segmentation, precise tumor delineation is crucial for diagnosis and treatment planning. Traditional approaches include convolutional neural networks (CNNs), which struggle with processing sequential data, and transformer models that face limitations in maintaining computational efficiency with large-scale data. This study introduces MambaBTS: a model that synergizes the strengths of CNNs and transformers, is inspired by the Mamba architecture, and integrates cascade residual multi-scale convolutional kernels. The model employs a mixed loss function that blends dice loss with cross-entropy to refine segmentation accuracy effectively. This novel approach reduces computational complexity, enhances the receptive field, and demonstrates superior performance for accurately segmenting brain tumors in MRI images. Experiments on the MICCAI BraTS 2019 dataset show that MambaBTS achieves dice coefficients of 0.8450 for the whole tumor (WT), 0.8606 for the tumor core (TC), and 0.7796 for the enhancing tumor (ET) and outperforms existing models in terms of accuracy, computational efficiency, and parameter efficiency. These results underscore the model’s potential to offer a balanced, efficient, and effective segmentation method, overcoming the constraints of existing models and promising significant improvements in clinical diagnostics and planning.

Glycolytic metabolism enzymes have been implicated in the immunometabolism field through changes in metabolic status. PGK1 is a catalytic enzyme in the glycolytic pathway. Here, we set up a high-throughput screen platform to identify PGK1 inhibitors. DC-PGKI is an ATP-competitive inhibitor of PGK1 with an affinity of Kd = 99.08 nmol/L. DC-PGKI stabilizes PGK1 in vitro and in vivo, and suppresses both glycolytic activity and the kinase function of PGK1. In addition, DC-PGKI unveils that PGK1 regulates production of IL-1β and IL-6 in LPS-stimulated macrophages. Mechanistically, inhibition of PGK1 with DC-PGKI results in NRF2 (nuclear factor-erythroid factor 2-related factor 2, NFE2L2) accumulation, then NRF2 translocates to the nucleus and binds to the proximity region of Il-1β and Il-6 genes, and inhibits LPS-induced expression of these genes. DC-PGKI ameliorates colitis in the dextran sulfate sodium (DSS)-induced colitis mouse model. These data support PGK1 as a regulator of macrophages and suggest potential utility of PGK1 inhibitors in the treatment of inflammatory bowel disease.

Legubicin, a novel prodrug based on doxorubicin, has both albumin-binding and legumain-activating properties. The aim of this study was to develop and validate a UHPLC-MS/MS method for investigating the in vivo pharmacokinetics and tissue distribution profiles of legubicin in rats and tumor-bearing mice following intravenous administration, and to compare this prodrug with the positive control drug doxorubicin. The study employed a UHLC-MS/MS method to determine the levels of albumin-bound of legubicin and two metabolites (free Leu-DOX and DOX) in plasma, tumor, and tissue samples. This method was validated for good selectivity, high sensitivity, excellent extraction recovery, and short run time. The results showed that legubicin was present in the circulation in vivo mainly in a protein-bound form with larger AUC values and lower clearance and distribution, and essentially released small amounts of doxorubicin. Compared to administration of equimolar doses of doxorubicin, legubicin showed increased exposure of the active drug in the tumor and decreased the level of the active drug in the heart and kidney. This study provides valuable information on the pharmacokinetics and tissue distribution of legubicin, implicating its potential as a novel and effective drug candidate for anti-cancer therapies.

Medical image segmentation is essential to image-based disease analysis and has proven to be significantly helpful for doctors to make decisions. Due to the low-contrast of some medical images, the accurate segmentation of medical images has always been a challenging problem. The experiment found that UNet with current loss functions cannot capture subtle information in target contours or regions in low-contrast medical images, which are crucial for subsequent disease diagnosis. We propose a robust loss by incorporating the difference in average radial derivative (ARD), length and region area to further help the network to achieve more accurate segmentation results. We evaluated the proposed loss function using UNet as the base segmentation network compared to five conventional loss functions on one private and four public medical image datasets. Experimental results illustrate that UNet with the proposed loss function can achieve the best segmentation performance, even better than the outstanding deep learning models with original loss functions. Furthermore, three representative datasets were chosen to validate the effectiveness of the proposed δ ARD loss function with seven different models. The experiments revealed δ ARD loss’s plug-and-play feature and its robustness over multiple models and datasets.

An indoor localization system based on the RSSI-APIT algorithm is designed in this study. Integrated RSSI (received signal strength indication) and non-ranging APIT (approximate perfect point-in-triangulation test) localization methods are fused with machine learning in order to improve the accuracy of the indoor localization system. The system focuses on the improvement of preprocessing and localization algorithms. The primary objective of the system is to enhance the preprocessing of the acquired RSSI data and optimize the localization algorithm in order to enhance the precision of the coordinates in the indoor localization system. In order to mitigate the issue of significant fluctuations in RSSI, a technique including the integration of Gaussian filtering and an artificial neural network (ANN) is employed. This approach aims to preprocess the acquired RSSI data, thus reducing the impact of multipath effects. In order to address the issue of low localization accuracy encountered by the conventional APIT localization algorithm during wide-area localization, the RSSI ranging function is incorporated into the APIT localization algorithm. This addition serves to further narrow down the localization area. Consequently, the resulting localization algorithm is referred to as the RSSI-APIT positioning algorithm. Experimental results have demonstrated the successful reduction of inherent localization errors within the system by employing the RSSI-APIT positioning algorithm. The present study aims to investigate the impact of the localization scene and the number of anchors on the RSSI-APIT localization algorithm, with the objective of enhancing the performance of the indoor localization system. The conducted experiments demonstrated that the enhanced system exhibits several advantages. Firstly, it successfully decreased the frequency of anchor calls, resulting in a reduction in the overall operating cost of the system. Additionally, it effectively enhanced the accuracy and stability of the system’s localization capabilities. In a complex environment of 100 m2 in size, compared with the traditional trilateral localization method and the APIT localization algorithm, the RSSI-APIT localization algorithm reduced the localization error by about 2.9 m and 1.8 m, respectively, and the overall error was controlled within 1.55 m.

Based on the hourly rainfall data and other conventional data from 52 surface weather stations， and the National Centers for Environmental Prediction （NCEP） Final Analysis （FNL） data， the synoptic circulation patterns for the short-time heavy rainfall over the Qinghai Plateau are classified into three categories， namely the westerly airflow pattern， the subtropical high pattern， and the plateau low vortex-shear line pattern.Results show that the short-time heavy rainfall over the Qinghai Plateau occurs in the area east of 95°E， with the center in the southeast of the plateau.It mainly occurs from May to September， with the maximum in August， followed by July.For the diurnal variation， the short-time heavy rainfall occurs most from 17:00 to 22:00 （Beijing Time）， i.e.， the nightfall to midnight.The influence systems of the westerly airflow pattern are the high-level trough and the straight westerly short-wave trough.The dynamical instability caused by the vertical wind shear induces the short-time heavy rainfall.For the subtropical high pattern， the thermal instability caused by the low-level southerly or easterly warm-humid airflows results in the short-time heavy rainfall.For the plateau low vortex-shear line pattern， the plateau heating， and the weak cold airflow strenthen the low-level frontal area and trigger the short-time heavy rainfall.The composite analysis shows that the South Asian high， the subtropical westerly jet in the upper troposphere， the short-wave trough in the middle-lower troposphere， the shear line， the southerly warm-humid airflow， and the plateau heating field are the main influence systems for the short-time heavy rainfall.The convergence of water vapor from the Indian monsoon， the southeast of the western Pacific subtropical high and the northwest of the westerly trough is conducive to the short-time heavy rainfall in eastern Qinghai.

Since the reform and opening-up, China has made remarkable achievements in economic growth, but also led to a substantial increase in carbon emissions. The Chinese government has actively formulated energy intensity reduction targets and taken carbon emission reduction measures. The paper investigates the impact of energy intensity reduction targets on carbon emissions using a dynamic spatial Durbin model based on panel data from 30 provinces in China from 2006 to 2019. The results show that energy intensity reduction targets promote the reduction of local carbon emissions, but have a positive spillover effect on carbon emissions in adjacent regions. Meanwhile, green technology innovation has a non-linear moderating effect between energy intensity reduction targets and carbon emissions. Energy intensity reduction targets promote carbon emission reduction when green technology innovation is less than a threshold, while the promotion effect disappears when green technology innovation exceeds a threshold. The mechanism analysis shows that energy consumption structure is a channel through which energy intensity reduction targets affect carbon emissions in both local and adjacent regions. Further research found that peer competitive pressure promotes carbon emission reduction and alleviates pollution spillover, while central assessment pressure increases carbon emissions and aggravates pollution spillover. Based on the above findings, this study provides suggestions for policymakers aiming at carbon emission reduction by implementing target management policies and optimizing target management systems.

Pneumocystis pneumonia (PCP) is an opportunity acquired infection, which is usually easy to occur in patients with AIDS, organ transplantation, and immunosuppressive drugs. The prevention and treatment must be necessary for PCP patients with immunocompromise. And the oxidants are currently a typical regimen, including sulfanilamide, dapsone, primaquine, etc. Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an X-linked gene-disease that affects about 400 million people worldwide. The lack of G6PD in this population results in a decrease in intracellular glutathione synthesis and a weakening of the detoxification ability of the oxidants. As a result, oxidants can directly damage haemoglobin in red blood cells, inducing methemoglobin and hemolysis. When patients with G6PD deficiency have low immunity, they are prone to PCP infection, so choosing drugs that do not induce hemolysis is essential. There are no clear guidelines to recommend the drug choice of this kind of population at home and abroad. This paper aims to demonstrate the drug choice for PCP patients with G6PD deficiency through theoretical research combined with clinical cases.

Abstract Background With China’s population ageing rapidly, stroke is becoming one of the major public health problems. Nurses are indispensable for caring for older patients with acute and convalescent stroke, and their working experiences are directly linked to the quality of care provided. The study aims to investigate registered nurses’ experiences of caring for older stroke patients. Methods A qualitative descriptive design was adopted. Data were collected via semi-structured interviews with 26 registered nurses about their lived experiences of caring for older stroke patients. Thematic analysis was used to analyze the data. Results Two main themes were identified. First, the nurses identified an obvious gap between their ideal role in elderly care and their actual practice. The unsatisfactory reality was linked to the practical difficulties they encountered in their working environment. Second, the nurses expressed conflicting feelings about caring for older stroke patients, displaying a sense of accomplishment, indifference, annoyance, and sympathy. Caring for older stroke patients also affects nurses psychologically and physically. The nurses were clear about their own roles and tried their best to meet the elderly people’s needs, yet they lack time and knowledge about caring for older stroke patients. The factors influencing their working experiences extend beyond the personal domain and are linked to the wider working environment. Conclusions Sustaining the nursing workforce and improving their working experiences are essential to meet the care needs of older people. Understanding nurses’ lived working experiences is the first step. At the individual level, nurse mangers should promote empathy, relieve anxiety about aging, and improve the job satisfaction and morale of nurses. At the institutional level, policymakers should make efforts to improve the nursing clinical practice environment, increase the geriatric nursing education and training, achieve a proper skill mix of the health workforce, and overall attract, prepare and sustain nurses regarding caring for older people in a rapidly aging society.

Abstract Background Breast cancer is one of the most serious diseases threatening women’s health. Early screening based on ultrasound can help to detect and treat tumours in the early stage. However, due to the lack of radiologists with professional skills, ultrasound-based breast cancer screening has not been widely used in rural areas. Computer-aided diagnosis (CAD) technology can effectively alleviate this problem. Since breast ultrasound (BUS) images have low resolution and speckle noise, lesion segmentation, which is an important step in CAD systems, is challenging. Results Two datasets were used for evaluation. Dataset A comprises 500 BUS images from local hospitals, while dataset B comprises 205 open-source BUS images. The experimental results show that the proposed method outperformed its related classic segmentation methods and the state-of-the-art deep learning model RDAU-NET. Its accuracy (Acc), Dice similarity coefficient (DSC) and Jaccard index (JI) reached 96.25%, 78.4% and 65.34% on dataset A, and its Acc, DSC and sensitivity reached 97.96%, 86.25% and 88.79% on dataset B, respectively. Conclusions We proposed an adaptive morphological snake based on marked watershed (AMSMW) algorithm for BUS image segmentation. It was proven to be robust, efficient and effective. In addition, it was found to be more sensitive to malignant lesions than benign lesions. Methods The proposed method consists of two steps. In the first step, contrast limited adaptive histogram equalization (CLAHE) and a side window filter (SWF) are used to preprocess BUS images. Lesion contours can be effectively highlighted, and the influence of noise can be eliminated to a great extent. In the second step, we propose adaptive morphological snake (AMS). It can adjust the working parameters adaptively according to the size of the lesion. Its segmentation results are combined with those of the morphological method. Then, we determine the marked area and obtain candidate contours with a marked watershed (MW). Finally, the best lesion contour is chosen by the maximum average radial derivative (ARD).

This paper examines the effects and mechanism of the financialization of manufacturing enterprises on total factor productivity (TFP). Thus, it provides evidence of the economic consequences of corporate financialization from the perspective of productivity. Using the panel data of China's listed manufacturing companies from 2007 to 2018, the level of corporate financialization is measured using the proportion of financial assets in the total assets. The results show that the deepening of the financialization of manufacturing enterprises significantly reduces TFP and the magnitude of the impacts of different types of financial assets variates. In addition, the effects of corporate financialization on TFP are heterogeneous in terms of their significance and degrees in different types of enterprises as well as in different levels of enterprises' TFP. The further analysis of the influencing mechanism shows that corporate financialization has different effects on the TFP of manufacturing enterprises through technological innovation and resource allocation efficiency.

Objective: This study aimed to describe the implementation of the surgical safety check policy and the surgical safety checklist for invasive procedures outside the operating room (OR) and evaluate its effectiveness. Methods: In 2017, to improve the safety of patients who underwent invasive procedures outside of the OR, the hospital quality and safety committee established the surgery safety check committee responsible for developing a new working plan, revise the surgery safety check policy, surgery safety check form, and provide training to the related staff, evaluated their competency, and implemented the updated surgical safety check policy and checklist. The study compared the data of pre-implementation (Apr to Sep 2017) and two post-implementation phases (Apr to Sep 2018, Apr to Sep 2019). It also evaluated the number of completed surgery safety checklist, correct signature, and correct timing of signature. Results: The results showed an increase in the completion rate of the safety checklist after the program implementation from 41.7% (521/1,249) to 90.4% (3,572/3,950), the correct rates of signature from 41.9% (218/521) to 99.0% (4,423/4,465), and the correct timing rates of signature from 34.4% (179/521) to 98.5% (4,401/4,465), with statistical significance (P

To reduce the increasingly severe air pollution caused by rapid industrialization, China has introduced a National Industrial Relocation Demonstration Zones (NIRDZs) policy. This paper takes the NIRDZs as a quasi-natural experiment and employs the difference-in-differences (DID) method to test the effects of industrial relocation on air pollution based on panel data of 285 prefecture-level cities from 2003 to 2018. Results show that the NIRDZs have an inhibitory effect on SO2 emissions, although their local effect is significant in the first 5 years and their spillover effect only occurs within 50–100 km. Mechanism analysis reveals that the NIRDZs reduce air emissions by rationalizing and upgrading the industrial structure. Additionally, further discussions suggest that cities with moderate administrative areas and abundant natural resources should be prioritized as pilot cities, and industries including nonferrous metals, steel, automotive, new energy, new materials, and producer services should be designated as priority industries.

Ovarian cancer (OV) is a deadly gynecological cancer. The tumor immune microenvironment (TIME) plays a pivotal role in OV development. However, the TIME of OV is not fully known. Therefore, we aimed to provide a comprehensive network of the TIME in OV. Gene expression data and clinical information from OV patients were obtained from the Cancer Genome Atlas Program (TCGA) database. Non-negative Matrix Factorization, NMFConsensus, and nearest template prediction algorithms were used to perform molecular clustering. The biological functions of differentially expressed genes (DEGs) were identified using Metascape, gene set enrichment analysis (GSEA), gene ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. The copy number variations (CNVs), single nucleotide polymorphisms (SNPs) and tumor mutation burden were analyzed using Gistic 2.0, R package maftools, and TCGA mutations, respectively. Estimation of STromal and Immune cells in MAlignant Tumor tissues using Expression data and CIBERSORT were utilized to elucidate the TIME. Moreover, external data from the International Cancer Genome Consortium (ICGC) and ArrayExpress databases were used to validate the signature. All 361 samples from the TCGA OV dataset were classified into Immune Class and non-Immune Class with immune signatures. By comparing the two classes, we identified 740 DEGs that accumulated in immune-related, cancer-related, inflammation-related biological functions and pathways. There were significant differences in the CNVs between the Immune and non-Immune Classes. The Immune Class was further divided into immune-activated and immune-suppressed subtypes. There was no significant difference in the top 20 genes in somatic SNPs among the three groups. In addition, the immune-activated subtype had significantly increased proportions of CD4 memory resting T cells, T cells, M1 macrophages, and M2 macrophages than the other two groups. The qRT-PCR results indicated that the mRNA expression levels of RYR2, FAT3, MDN1 and RYR1 were significantly down-regulated in OV compared with normal tissues. Moreover, the signatures of the TIME were validated using ICGC cohort and the ArrayExpress cohort. Our study clustered the OV patients into an immune-activated subtype, immune-suppressed subtype, and non-Immune Class and provided potential clues for further research on the molecular mechanisms and immunotherapy strategies of OV.

Hazardous material road transport accidents pose a serious threat to public life, property and the environment. Therefore, studying the factors influencing road transport accidents involving hazardous materials can help identify the main causes behind them and contribute to the adoption of specific and targeted measures to reduce casualty rates and improve traffic safety. However, most existing research either adopted methods based on statistical analysis or neglected to further evaluate the spatial relationships. This study aims to use the eXtreme Gradient Boosting (XGBoost) algorithm to analyze hazardous material road transport accident data from seven regions of China. Considering the rarity of these events, the classification performance of different methods is compared based on precision, recall, F-score and Area Under Curve (AUC). The results indicate that the proposed XGBoost method has the best modeling performance. There is some variation between regions in the features that have a significant impact on accident severity. The influence of the same feature on the severity of an accident even varies from region to region. The aforementioned results provide a theoretical basis for exploring the issues, sustainability, challenges, and tasks of safe transportation activities for hazardous materials in the future. These results can help regions develop targeted prevention and response policies to efficiently reduce the incidence and severity of accidents.

COVID-19 is a highly contagious respiratory disease, which mainly affects the lungs. Critically ill patients are easily complicated by cytokine storms, acute respiratory distress syndrome (ARDS), and respiratory failure, which seriously threaten their lives. Pulmonary fibrosis (PF) is a common interstitial lung disease, and its pathogenesis may involve the participation of a variety of immune cells and inflammatory factors. Current studies have shown that patients with COVID-19 may be complicated by pulmonary fibrosis, and patients with pulmonary fibrosis may also be at higher risk of contracting COVID-19 than healthy people. Pulmonary fibrosis is an important risk factor leading to the aggravation of COVID-19 disease. COVID-19 complicated by cytokine storm and ARDS mechanism pathways are similar to the pathogenesis of pulmonary fibrosis. The potential interaction between pulmonary fibrosis and COVID-19 can cause acute exacerbation of the patient’s condition, but the potential mechanism between the two has not been fully elucidated. Most of the drug treatment programs for COVID-19-related pulmonary fibrosis are currently formulated about the relevant guidelines for idiopathic pulmonary fibrosis (IPF), and there is no clear drug treatment program recommendation. This article aims to summarize the relevant mechanism pathways of COVID-19 and pulmonary fibrosis, explore the interrelationships and possible mechanisms, and discuss the value and risks of existing and potential COVID-19-related pulmonary fibrosis treatment drugs, to provide reference for anti-fibrosis treatment for patients.

Systemic lupus erythematosus (SLE) is a kind of chronic diffuse connective tissue illness characterized by multisystem and multiorgan involvement, repeated recurrence and remission, and the presence of a large pool of autoantibodies in the body. Although the exact cause of SLE is not thoroughly revealed, accumulating evidence has manifested that intake of probiotics alters the composition of the gut microbiome, regulating the immunomodulatory and inflammatory response, which may be linked to the disease pathogenesis. Particularly, documented experiments demonstrated that SLE patients have remarkable changes in gut microbiota compared to healthy controls, indicating that the alteration of microbiota may be implicated in different phases of SLE. In this review, the alteration of microbiota in the development of SLE is summarized, and the mechanism of intestinal microbiota on the progression of immune and inflammatory responses in SLE is also discussed. Due to limited reports on the effects of probiotics supplementation in SLE patients, we emphasize advancements made in the last few years on the function and mechanisms of probiotics in the development of SLE animal models. Besides, we follow through literature to survey whether probiotics supplements can be an adjuvant therapy for comprehensive treatment of SLE. Research has indicated that intake of probiotics alters the composition of the gut microbiome, contributing to prevent the progression of SLE. Adjustment of the gut microbiome through probiotics supplementation seems to alleviate SLE symptoms and their cardiovascular and renal complications in animal models, marking this treatment as a potentially novel approach.

For high-energy π0 mesons, the angle between the two final-state photons decreases with the increase in the energy of the π0, which enhances the probability of overlapping electromagnetic showers. The performance of the cluster splitting algorithm in the EMC reconstruction is crucial for the mass resolution measurement of π0 with high energy. The cluster splitting algorithm is based on the theoretical lateral distribution of the electromagnetic showers. A simple implementation of the lateral distribution can be described as a (multi-)exponential function. In a realistic electromagnetic calorimeter, considering the granularity of the detector, the measured energy in a cell is actually the integral of the theoretical energy deposition, which deviates from the exponential function. Based on the simulation of the barrel EMC in the P¯ANDA experiment, a cluster splitting algorithm with a new lateral energy development function is developed. The energy resolution of overlapping showers with high energy has been improved.

The study on the vehicle pause rate in the expressway service area provides a theoretical basis for the evaluation and layout optimization of the social and economic adaptability of the expressway service area. This paper constructs a prediction model based on the analysis of explanatory variables using wavelet neural network (WNN) and genetic algorithm (GA). Eight variables, such as major road traffic flow and the distances to neighboring service areas, are selected as input parameters. The pause rates of a freight truck and passenger car are the prediction output. The data from 23 pairs of service areas in Henan province are used to train the model. The GA is used to optimize the initial weights, thresholds, and translation coefficients of the WNN. The experimental results show that the GA-WNN model has a higher prediction precision and a better fitting ability compared with the GA-BP and the WNN prediction models, which can overcome the shortcomings of slow convergence and local optimum of traditional WNN, and combine the advantages of GA and WNN to improve prediction accuracy effectively. The research of this paper can provide new ideas and methods to pause rate prediction of the expressway service area.

Abstract Background Major depressive disorder (MDD) is a common psychiatric disorder. With systematic antidepressant treatment, 50–75% of patients have a treatment response but require 4–6 weeks to have their symptoms alleviated. Therefore, researchers anticipate the development of novel fast-acting antidepressants. Previous studies have revealed that the decrease of bio-energetic metabolism may contribute to the occurrence of depression, while our team has found adenosine triphosphate (ATP) and phosphocreatine (PCr) to be fast-acting antidepressants in the depressed-animal model. ATP and PCr have already been widely prescribed clinically as energy supplements for cells. This will be the first clinical attempt of the intravenous administration of ATP and PCr combined with orally administered fluoxetine in MDD. Methods This is a single-center, randomized, double-blind, placebo-controlled pilot study. A total of 42 patients will be divided randomly into three groups. Patients will receive an intravenous administration of ATP or PCr or saline twice daily combined with orally administered fluoxetine (20 mg/day) for the first 2 weeks and fluoxetine monotherapy for the following 4 weeks. Follow-up assessment will be completed at week 10. Feasibility outcomes will include percentages of patient eligibility, intention to use medication, willingness to participate, drug adherence, completion of the scheduled assessment, retention, drop-out, etc. Physical examination results, Side Effect Rating Scale, adverse events, results from blood tests, electroencephalogram, and electrocardiograph will be recorded for safety evaluation of the augmentation therapy. The trends of efficacy will be evaluated by the reduction rate of the Hamilton Depression Rating Scale, the mean change of the Clinical Global Impression Scale, and the Patients Health Questionaire-9 items. Discussion In our study, ATP and PCr will be given by intravenous infusion. Thus patients will be hospitalized for the initial 2 weeks for safety concern. Hospitalization will be an impact factor for the recruitment, participation, drop-out, efficacy, results, etc. The evaluation of our feasibility outcomes, study setting, safety of augmentation therapy and possible efficacy trends among groups, will facilitate a full-scale trial design and sample size calculation. Trial registration NCT03138681. Registered on 3 May 2017. First patient: 4 May 2017.

Abstract is missing (Short communication)

With aging of population, aging-related neurodegenerative diseases have become a major public health concern. Oxidative stress and neuroinflammation have been reported to play important roles in the aging process. Ginsenoside Rg1 (Rg1) is the main active ingredient in ginseng, and may be a potential agent for neurodegenerative diseases. In the present study, we investigated the effects of Rg1, tempol (ROS scavenger) and apocynin (NOX inhibitor) treatment for 9 weeks on cognitive performance, neuronal damage, and NOX2 and NLRP1 inflammasome expressions in 8-month old SAMP8 mice. The results showed that Rg1 alleviated learning and memory impairment and neuronal damage in SAMP8 mice. Meanwhile, Rg1 could reduce production of ROS and decreased expressions of NOX2 and NLRP1-related proteins in brain cortex and hippocampus tissues in SAMP8 mice. The findings suggest that Rg1 can alleviate aging-related neuronal damage, the mechanisms may be involved in reducing NOX2-mediated ROS generation and inhibiting NLRP1 inflammasome activation.

Glucocorticoids (GCs) have been increasingly reported to have adverse effects on aquatic organisms, but the lack of comprehensive analytical methods for a broad number of GCs has limited the effective management of pollution by these molecules in surface and coastal waters. In this study, we developed an original analytical method for simultaneously monitoring 25 natural GCs, and 43 synthetic GCs (4 hydrocortisone types, 6 acetonide types, 8 betamethasone types, 14 halogenated esters, and 11 labile prodrug esters) in water samples. Of the river samples investigated, 15 natural and 25 synthetic compounds were detected with the concentrations ranging from 0.13 ng/L (11-epitetrahydrocortisol) to 433 ng/L (cortisone) and from 0.05 (clobetasol) to 94 ng/L (prednisolone), respectively. Thirteen natural metabolites of cortisol (CRL) were first detected, and their concentrations were up to 36 times higher than that of CRL. Hydrocortisone-type GCs were the dominant synthetic compounds (≤154 ng/L), followed by halogenated esters (≤81 ng/L), acetonide type GCs (≤57 ng/L), betamethasone type GCs (≤32 ng/L), and labile prodrug esters (≤22 ng/L). Considering the relative potencies for detected GCs compared to dexamethasone, halogenated esters predominantly contributed to the GC activities in the samples. Notably, this is the first report of the halogenated esters 11-oxo fluticasone propionate (OFP) and cloticasone propionate (CTP) in environmental waters. Untreated wastewater is the main source of GCs in the studied waters, and the concentration ratios between natural and synthetic GCs can be used as potential indicators of sewage input. Because of the high detected concentrations and bioactivity potency of halogenated GCs, they are the main contributors to GC activities in the studied waters, and deserved more study in the future. Keywords: Glucocorticoids, River water, Effluent, Sewage, UPLC-MS/MS

The definition of air resistance is nonuniform when analyzing the bearing capacity, stiffness, and stability of an orifice throttling aerostatic restrictor. In this study, a capillary tube similar to the inlet section of an aerostatic restrictor is used as the research object, and the Bernoulli equation under adiabatic conditions is established. Through an experiment, the pressure and temperature of the capillary tube inlet and outlet and the flow through the capillary tube are measured. Based on the air resistance definition, the empirical formula of the coefficient k is obtained, and the theoretical air resistance of the capillary path is calculated. The relative error between the theoretical air resistance and experimental air resistance is kept within 10%. The comparison results verify the accuracy of the air resistance theory and provide a basis for the subsequent establishment of a universal definition of air resistance. Subsequently, air resistance can be used to design aerostatic bearings and help improve their characteristics.

Slide stability is key to the aerostatic guide in ultra-precise machines; thus, it has garnered plenty of attention. Macro-scale studies are commonplace, but micro- and nano-vibration issues require more attention. Microscope vibration is mainly caused by tiny changes in the fluid parameters of lubricating gas film, which is complex and has no verdict. In this case, slide-gas interaction should be considered. In this study, the widely used orifice-type restrictor was investigated for its nano-vibration performance. A Comsol finite-element-method fluid–structure interaction model was used to simulate and analyze an orifice-type restrictor, and orifice-restrictor vibration characteristics at the nanometer scale were inspected using a high-performance laser vibrometer. The results demonstrate that see-saw mode vibrations occur in the restrictors, growing stronger with increased air-supply pressure. The see-saw vibration’s axis is speculatively determined based on orifice and restrictor structures, and the vibration type is related to the number of orifices. The results also show that the vibration is random with natural frequencies at the kilohertz level. The newly provided research results are beneficial for better understanding the nano-vibrations of orifice-type restrictors.

Herein, a processing method is proposed for accurate microdisplacement measurements from a 2D Fabry–Perot (F-P) fringe pattern. The core of the processing algorithm uses the F-P interference imaging concentric ring pattern to accurately calculate the centre coordinates of the concentric ring. The influencing factors of measurement were analysed, and the basic idea of data processing was provided. In particular, the coordinate rotation by the 45-degree method (CR) was improved; consequently, the virtual pixel interval was reduced by half, and the calculation accuracy of the circle centre coordinate was improved. Experiments were conducted to analyse the influence of the subdivision and circle fitting methods. The results show that the proposed secondary coordinate rotation (SCR) by 45 degrees method can obtain higher accuracy of the centre coordinate than the CR method, and that the multichord averaging method (MCAM) is more suitable for calculation of the centre coordinate than the circular regression method (CRM). Displacement measurement experiments were performed. The results show that the standard experimental deviation of the centre of the circle is approximately 0.009 µm, and the extended uncertainty of the displacement measurement in the range of 5 mm is approximately 0.03 μm. The data processing method studied in this study can be widely used in the field of F-P interferometry.

In this work, a smartphone-based electrochemical detection system was designed and developed for rapid and real-time detection of dopamine (DA). The system included a screen-printed electrode (SPE) used as a sensor, a hand-held electrochemical potentiostat and a smart phone with a specially designed app. During the detection period, the SPEs modified with poly(3,4-ethylenedioxythiophene) (PEDOT), chitosan (CS) and graphene (G) were used to convert and amplify the electrochemical reaction signals. The electrochemical potentiostat was used to generate excitation electrical signals and collect the electrical signals converted from the sensor. The smartphone—connected to the detector via Bluetooth-was used to control the detector for tests, further process the uploaded data, and plot graphs in real time. Experimental results showed that the self-designed sensing system could be employed for highly selective detection of DA in the presence of interfering substances such as ascorbic acid (AA) and uric acid (UA). CV was carried out to characterize the electrochemical properties of the modified SPEs and the electrochemical behaviors of DA on the modified SPEs. Finally, according to the analysis of DPV responses of DA, the system could detect DA with a detection sensitivity of 0.52 ± 0.01 μA/μM and a limit of detection of 0.29 μM in the linear range of DA concentrations from 0.05 to 70 μM.

Tubeimoside-1 (TBMS1) is a triterpenoid saponin with potent anticancer properties. In this study, for the first, we examined the anti-proliferative effects of TBMS1 in human bladder cancer T24 cells and its ability to induce apoptosis and cell cycle arrest. Our results demonstrated that TBMS1 decreased the cell viability of bladder cancer T24 cells in a dose-dependent manner. Flow cytometric analysis showed that TBMS1 significantly triggered apoptosis in T24 cells and arrested cell cycle at G2/M phase in a dose-dependent manner. Further characterization demonstrated that TBMS1-induced apoptosis is associated with dissipation in mitochondrial membrane potential (ΔΨm), down-regulation of Bcl-2, and up-regulation of Bax and p21 in TBMS1-treated T24 cells. These in vitro results suggested that TBMS1 is an effective anti-bladder cancer natural compound that worth further mechanistic and therapeutic studies in human bladder cancer.

Accumulation of foam cells in the neointima represents a key event in atherosclerosis. We previously demonstrated that Tanshinone IIA (Tan), a lipophilic bioactive compound extracted from Salvia miltiorrhiza Bunge, inhibits experimental atherogenesis, yet the detailed mechanisms are not fully understood. In this study, we sought to explore the potential effects of Tan on lipid accumulation in macrophage foam cells and the underlying molecular mechanisms. Our data indicate that Tan treatment reduced the content of macrophages, cholesterol accumulation, and the development of atherosclerotic plaque in apolipoprotein E-deficient mice. In human macrophages, Tan ameliorated oxidized low density lipoporotein (oxLDL)-elicited foam cell formation by inhibiting oxLDL uptake and promoting cholesterol efflux. Mechanistically, Tan markedly reduced the expression of scavenger receptor class A and increased the expression of ATP-binding cassette transporter A1 (ABCA1) and ABCG1 in lipid-laden macrophages via activation of the extracellular signal-regulated kinase (ERK)/nuclear factor-erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway. Tan treatment induced the phosphorylation and nuclear translocation of Nrf2 and subsequently increased the expression of HO-1, and these effects were abolished by the specific ERK inhibitors, PD98059 and U0126. Moreover, HO-1 small interfering RNA or zinc protoporphyrin (a HO-1 inhibitor) abrogated Tan-mediated suppression of lipid accumulation in macrophages. Our current findings demonstrate that a novel HO-1-dependent mechanism is involved in the regulation of cholesterol balance by Tan.

Tubeimoside-1 (TBMS1) is a triterpenoid saponin with potent anticancer properties. In this study, for the first, we examined the anti-proliferative effects of TBMS1 in human bladder cancer T24 cells and its ability to induce apoptosis and cell cycle arrest. Our results demonstrated that TBMS1 decreased the cell viability of bladder cancer T24 cells in a dose-dependent manner. Flow cytometric analysis showed that TBMS1 significantly triggered apoptosis in T24 cells and arrested cell cycle at G2/M phase in a dose-dependent manner. Further characterization demonstrated that TBMS1-induced apoptosis is associated with dissipation in mitochondrial membrane potential (??m), down-regulation of Bcl-2, and up-regulation of Bax and p21 in TBMS1-treated T24 cells. These in vitro results suggested that TBMS1 is an effective anti-bladder cancer natural compound that worth further mechanistic and therapeutic studies in human bladder cancer.

ATP binding cassette transporter A1 (ABCA1) plays a key role in atherogenesis. Hydrogen sulfide (H2S), a gasotransmitter, has been reported to play an anti-atherosclerotic role. However, the underlying mechanisms are largely unknown. In this study we examined whether and how H2S regulates ABCA1 expression. The effect of H2S on ABCA1 expression and lipid metabolism were assessed in vitro by cultured human hepatoma cell line HepG2, and in vivo by ApoE−/− mice with a high-cholesterol diet. NaHS (an exogenous H2S donor) treatment significantly increased the expression of ABCA1, ApoA1, and ApoA2 and ameliorated intracellular lipid accumulation in HepG2 cells. Depletion of the endogenous H2S generator cystathionine γ-lyase (CSE) by small RNA interference (siRNA) significantly decreased the expression of ABCA1 and resulted in the accumulation of lipids in HepG2 cells. In vivo NaHS treatment significantly reduced the serum levels of total cholesterol (TC), triglycerides (TG), and low-density lipoproteins (LDL), diminished atherosclerotic plaque size, and increased hepatic ABCA1 expression in fat-fed ApoE−/− mice. Further study revealed that NaHS upregulated ABCA1 expression by promoting peroxisome proliferator-activated receptor α (PPARα) nuclear translocation. H2S up-regulates the expression of ABCA1 by promoting the nuclear translocation of PPARα, providing a fundamental mechanism for the anti-atherogenic activity of H2S. H2S may be a promising potential drug candidate for the treatment of atherosclerosis.

The accumulation of glomerular extracellular matrix (ECM) is one of the critical pathological characteristics of diabetic renal fibrosis. Fibronectin (FN) is an important constituent of ECM. Our previous studies indicate that the activation of the sphingosine kinase 1 (SphK1)-sphingosine 1- phosphate (S1P) signaling pathway plays a key regulatory role in FN production in glomerular mesangial cells (GMCs) under diabetic condition. Among the five S1P receptors, the activation of S1P2 receptor is the most abundant. Berberine (BBR) treatment also effectively inhibits SphK1 activity and S1P production in the kidneys of diabetic models, thus improving renal injury. Based on these data, we further explored whether BBR could prevent FN production in GMCs under diabetic condition via the S1P2 receptor. Here, we showed that BBR significantly down-regulated the expression of S1P2 receptor in diabetic rat kidneys and GMCs exposed to high glucose (HG) and simultaneously inhibited S1P2 receptor-mediated FN overproduction. Further, BBR also obviously suppressed the activation of NF-κB induced by HG, which was accompanied by reduced S1P2 receptor and FN expression. Taken together, our findings suggest that BBR reduces FN expression by acting on the S1P2 receptor in the mesangium under diabetic condition. The role of BBR in S1P2 receptor expression regulation could closely associate with its inhibitory effect on NF-κB activation.

Cerebral glucose metabolism is a reliable index of neural activity and may provide evidence for brain function in healthy adults. We studied the correlation between cerebral glucose metabolism and age under the resting-state in both sexes with position emission tomography. Statistical test of age effect on cerebral glucose metabolism was performed using the statistical parametric mapping software with a voxel-by-voxel approach (p=0.05 family wise error corrected, 100-voxel threshold). The subjects consisted of 108 females (mean ± S.D. = 45 ± 10 years) and 126 males (mean ± S.D. = 49 ± 11 years). We showed here that brain activity in the frontal and temporal lobes in both sexes decreased significantly with normal aging. The glucose metabolism in the caudate bilaterally showed a negative correlation with age in males, but not in females. Few regions in males were shown with an increased glucose metabolism with age. Although the mechanisms of brain aging are still unknown, a map of brain areas susceptible to age was described in this report.

BACKGROUND:Although increased levels of plasminogen activators have been found in psoriatic lesions, the role of plasmin converted from plasminogen by plasminogen activators in pathogenesis of psoriasis has not been investigated. METHODOLOGY/PRINCIPAL FINDINGS:Here we examined the contribution of plasmin to amplification of inflammation in patients with psoriasis. We found that plasminogen was diminished, but that the amount and activity of its converted product plasmin were markedly increased in psoriasis. Moreover, annexin II, a receptor for plasmin was dramatically increased in both dermis and epidermis in psoriasis. Plasmin at sites of inflammation was pro-inflammatory, eliciting production of inflammatory factors, including CC chemokine ligand 20 (CCL20) and interleukin-23 (IL-23), that was mediated by the nuclear factor-kappaB (NF-κB) signaling pathway and that had an essential role in the recruitment and activation of pathogenic C-C chemokine receptor type 6 (CCR6)+ T cells. Moreover, intradermal injection of plasmin or plasmin together with recombinant monocyte/macrophage chemotactic protein-1 (MCP-1) resulted in induction of psoriasiform skin inflammation around the injection sites with several aspects of human psoriasis in mice. CONCLUSIONS/SIGNIFICANCE:Plasmin converted from plasminogen by plasminogen activators plays an essential role in amplification of psoriasiform skin inflammation in mice, and targeting plasmin receptor--annexin II--may harbor therapeutic potential for the treatment of human psoriasis.

Malignant gliomas represent one of the most aggressive types of cancers and their recurrence is closely linked to acquired therapeutic resistance. A combination of chemotherapy is considered a promising therapeutic model in overcoming therapeutic resistance and enhancing treatment efficacy. Herein, we show by colony formation, Hochest 33342 and TUNEL staining, as well as by flow cytometric analysis, that LY294002, a specific phosphatidylinositide-3-kinase (PI3K) inhibitor, enhanced significantly the sensitization of a traditional cytotoxic chemotherapeutic agent, tamoxifen-induced apoptosis in C6 glioma cells. Activation of PI3K signaling pathway by IGF-1 protected U251 cells from apoptosis induced by combination treatment of LY294002 and tamoxifen. Interference of PI3K signaling pathway by PI3K subunit P85 siRNA enhanced the sensitization of U251 glioma cells to tamoxifen -induced apoptosis. By Western blotting, we found that combination treatment showed lower levels of phosphorylated Akt(Ser473) and GSK-3β(Ser9) than a single treatment of LY294002. Further, we showed a significant decrease of nuclear β-catenin by combination treatment. In response to the inhibition of β-catenin signaling, mRNA and protein levels of Survivin and the other three antiapoptotic genes Bcl-2, Bcl-xL, and Mcl-1 were significantly decreased by combination treatment. Our results indicated that the synergistic cytotoxic effect of LY294002 and tamoxifen is achieved by the inhibition of GSK-3β/β-catenin signaling pathway.