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Abstract Backgroud Intrauterine Adhesions (IUA) is a common gynecological disease which is seriously endangers the reproductive function of women without any ideal treatment. Some researchers found Menstrual Blood-derived Mesenchymal Stem Cells (MenSCs) can repair of damaged endometrium, however, has not been fully clarified. This study aims to evaluate the therapeutic effects of MenSCs in IUA and the repair mechanism in vivo. Methods This study is Laboratory-based study. To evaluate the therapeutic effects of MenSCs in IUA, We cultivated MenSCs, established mouse endometrial injury model, observed the uterine morphology and degree of endometrial fibrosis and compared the expression of CXC chemokine ligand-13 (CXCL13)、CXC chemokine receptor-5 (CXCR5)、Plasmin Activating Inhibitor-1(Pai-1), Transforming Growth Faction-β1(TGF- β1) and Matrix Metalloproteinase-9 (Mmp-9) among each groups. GraphPad Prism 8.0 was used for statistical processing. Data were expressed as mean ± SD. Statistical comparisons among groups were performed with one-way ANOVA. P

To examine the effects and mechanisms of Camellia petelotii Chi extract on the rat model of non-alcoholic fatty liver disease (NAFLD), a set of ten SD rats was randomly chosen as the blank group, while the remaining 50 rats were given a high-sugar, high-fat emulsion to develop the model of non-alcoholic fatty liver disease. After 14 days, the rats were separated into different groups based on their serum total cholesterol (TC) levels. These groups included the model group, the simvastatin group (8 mg/kg), and the Camellia petelotii Chi high, medium, and low dose groups (260, 130, 65 mg/kg). The medication was administered continuously for 6 weeks. Before the last administration, an oral glucose tolerance test (OGTT) was performed, and the area under the blood glucose curve (AUC) was calculated. Both serum and liver tissues were collected to examine the concentrations of total cholesterol (TC), triacylglycerol (TG), high-density lipoprotein (HDL-C), low-density lipoprotein (LDL-C), and free fatty acid (FFA). In addition, TC and TG were measured to evaluate the amount of lipids in the liver, while glutamic-pyruvic transaminase (ALT) and glutamic oxaloacetic transaminase (AST) were examined to assess liver function. The levels of malondialdehyde (MDA) was measured to evaluate the extent of lipid peroxidation in the liver, while the activity of superoxide dismutase (SOD) was also evaluated. Serum inflammatory factors interleukin 6 (IL-6), interleukin 8 (IL-8), and tumor necrosis factor (TNF-α) were determined in rats. Serum insulin (FINS) was measured and the insulin resistance index (HOMA-IR) was calculated. The HE staining technique was employed to examine the pathomorphological alterations in the liver and determine the non-alcoholic fatty liver disease activity score (NAS). The gene and protein expression of Toll-like receptor 4 (TLR-4) and nuclear factor κB (NF-κB) were determined in liver tissue. The results showed that compared with the model group, AUC, HOMA-IR and serum levels of FINS, TG, TC, LDL-C, FFA, ALT, AST, IL-6, IL-8, TNF were significantly lower (P

Abstract Aryl hydrocarbon receptor (AhR) plays an important role in inflammation and immunity as a new therapeutic target for infectious disease and sepsis. Punicalagin (PUN) is a Chinese herbal monomer extract of pomegranate peel that has beneficial anti-inflammatory, antioxidant and anti-infective effects. However, whether PUN is a ligand of AhR, its effect on AhR expression, and its signaling pathway remain poorly understood. In this study, we found that PUN was a unique polyphenolic compound that upregulated AhR expression at the transcriptional level, and regulated the AhR nongenomic pathway. AhR expression in lipopolysaccharide-induced macrophages was upregulated by PUN in vitro and in vivo in a time- and dose-dependent manner. Using specific inhibitors and siRNA, induction of AhR by PUN depended on sequential phosphorylation of 90-kDa ribosomal S6 kinase (p90RSK), which was activated by the mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) and phosphoinositide-dependent protein kinase (PDK)1 pathways. PUN promoted p90RSK-mediated activator protein-1 (AP-1) activation. AhR knockout or inhibitors reversed suppression of interleukin (IL)-6 and IL-1β expression by PUN. PUN decreased Listeria load and increased macrophage survival via AhR upregulation. In conclusion, we identified PUN as a novel selective AhR modulator involved in AhR expression via the MEK/ERK and PDK1 pathways targeting p90RSK/AP-1 in inflammatory macrophages, which inhibited macrophage inflammation and promoted bactericidal activity.

Abstract Malignant mesothelioma is a rare tumour caused by asbestos exposure that originates mainly from the pleural lining or the peritoneum. Treatment options are limited, and the prognosis is dismal. Although immune checkpoint blockade (ICB) can improve survival outcomes, the determinants of responsiveness remain elusive. Here, we report the outcomes of a multi-centre phase II clinical trial (MiST4, NCT03654833) evaluating atezolizumab and bevacizumab (AtzBev) in patients with relapsed mesothelioma. We also use tumour tissue and gut microbiome sequencing, as well as tumour spatial immunophenotyping to identify factors associated with treatment response. MIST4 met its primary endpoint with 50% 12-week disease control, and the treatment was tolerable. Aneuploidy, notably uniparental disomy (UPD), homologous recombination deficiency (HRD), epithelial-mesenchymal transition and inflammation with CD68+ monocytes were identified as tumour-intrinsic resistance factors. The log-ratio of gut-resident microbial genera positively correlated with radiological response to AtzBev and CD8+ T cell infiltration, but was inversely correlated with UPD, HRD and tumour infiltration by CD68+ monocytes. In summary, a model is proposed in which both intrinsic and extrinsic determinants in mesothelioma cooperate to modify the tumour microenvironment and confer clinical sensitivity to AtzBev. Gut microbiota represent a potentially modifiable factor with potential to improve immunotherapy outcomes for individuals with this cancer of unmet need.

Abstract Background Guidelines must be interpreted comprehensively and correctly to standardize the clinical process. However, this process is challenging and requires interpreters to have a medical background and qualifications. In this study, the accuracy of ChatGPT3.5 in answering clinical questions related to the 2019 guidelines for severe acute pancreatitis was evaluated. Methods and results An observational study was conducted using the 2019 guidelines for severe acute pancreatitis. The study compared the accuracy of ChatGPT3.5 in English versus Chinese and found that it was more accurate in English (71%) than in Chinese (59%) (P value: 0.203). Additionally, the study assessed the accuracy of ChatGPT3.5 in answering short-answer questions versus true/false questions and found that it was more accurate in answering short-answer questions (76%) than in answering true/false questions (60%) (P value: 0.405). Conclusions For clinicians managing severe acute pancreatitis, ChatGPT3.5 may have potential value. However, it should not be relied upon excessively for clinical decision making.

Abstract Neurons rely heavily on high mitochondrial metabolism to provide sufficient energy for proper development. However, it remains unclear how neurons maintain high oxidative phosphorylation (OXPHOS) during development. Mitophagy plays a pivotal role in maintaining mitochondrial quality and quantity. We herein describe that G protein-coupled receptor 50 (GPR50) is a novel mitophagy receptor, which harbors the LC3-interacting region (LIR) and is required in mitophagy under stress conditions. Although it does not localize in mitochondria under normal culturing conditions, GPR50 is recruited to the depolarized mitochondrial membrane upon mitophagy stress, which marks the mitochondrial portion and recruits the assembling autophagosomes, eventually facilitating the mitochondrial fragments to be engulfed by the autophagosomes. Mutations Δ502-505 and T532A attenuate GPR50-mediated mitophagy by disrupting the binding of GPR50 to LC3 and the mitochondrial recruitment of GPR50. Deficiency of GPR50 causes the accumulation of damaged mitochondria and disrupts OXPHOS, resulting in insufficient ATP production and excessive ROS generation, eventually impairing neuronal development. GPR50-deficient mice exhibit impaired social recognition, which is rescued by prenatal treatment with mitoQ, a mitochondrially antioxidant. The present study identifies GPR50 as a novel mitophagy receptor that is required to maintain mitochondrial OXPHOS in developing neurons.

Abstract This study spanned 6 years and 4 generations, involving the progressive crossbreeding of South African Kalahari Goat (SK) and Guizhou Black Goat (GB) over three generations, followed by cross fixation F3 with F1 in the fourth generation, accompanied by the use of molecular markers technology to select a high fertility population, resulting in the creation of a hybrid goat, BKF4 (11/16 SK lineage and 5/16 GB lineage). A comparative evaluation of the BKF4 hybrid breed and its parental breeds was conducted. Reproductive and production parameters of GB, SK, and BKF4 goat groups were monitored, including lambing rate (LR), survival rate (SR), daily weight gain at 3 months of age (DWG), and adult body weight (ABW) (n = 110, 106, 112 per group). In addition, dressing percentage (DP) (n = 12 per group) and analyses of amino acids (n = 8, 6, 10 per group) and fatty acids (n = 6 per group) were conducted to evaluate meat quality indicators. Results: (1) Reproductive and production performance: The index of LR reached 199%, significantly higher than GB and SK (p ≤ 0.001), with a SR of 95.0%, markedly higher than SK (p ≤ 0.001); DWG was 276.5 g, ABW reached 56.6 kg and with a dressing percentage (DP) of 54.5%, they are significantly surpassing GB (p ≤ 0.001). (2) Regarding meat quality: pH45-value and crude protein content (CP) increased, while intramuscular fat content increased compared to GB and ash content decreased. The amino acid composition was similar to GB, but the taste was more similar to SK. However, there were some negative impacts on fatty acid composition and functionality. (3) PCA analysis revealed that: BKF4 exhibited superior meat quality compared to GB and SK, influenced by two key factors contributing 83.49% and 16.51% to the explained variance, respectively. The key factors affecting meat quality include intramuscular fat (IMF), nutrient index (NI), PUFAs/MUFAs, n-6FAs, and drip loss (DL).

The importance of effective teacher-child interactions in preschool classrooms has been well documented; however, very few studies examined the difference between novice and experienced teachers. The aim of this study was to quantitatively compare the characteristics and patterns of teacher-child interactions during preschool picture book reading activities between novice and experienced teachers. Video observation data were collected from nine novice teachers and nine experienced teachers from a Chinese preschool, and were coded using the Flanders Interaction Analysis System. A total of 7,642 codes of experienced teachers and 6,444 codes of novice teachers were obtained. Aside from some commonalities, results indicated that there were several major differences between novice and experienced teachers. The indirect and positive influence on children, and the rate of positive influence to negative influence of experienced teachers were higher than that of novice teachers; the proportion of teacher talk, positive integration grid, steady-state grid, open question, and indirect response of novice teachers were higher than that of experienced teachers. The findings shed light on how novice and experienced teachers interact with their children, and how professional development supports should be delivered differently to novice and experienced teachers.

Alzheimer’s disease (AD) is an age-related neurodegenerative disorder. Transgenic and pharmacological AD models are extensively studied to understand AD mechanisms and drug discovery. However, they are time-consuming and relatively costly, which hinders the discovery of potential anti-AD therapeutics. Here, we established a new model of AD in larval zebrafish by co-treatment with aluminum chloride (AlCl3) and D-galactose (D-gal) for 72 h. In particular, exposure to 150 μM AlCl3 + 40 mg/mL D-gal, 200 μM AlCl3 + 30 mg/mL D-gal, or 200 μM AlCl3 + 40 mg/mL D-gal successfully induced AD-like symptoms and aging features. Co-treatment with AlCl3 and D-gal caused significant learning and memory deficits, as well as impaired response ability and locomotor capacity in the plus-maze and light/dark test. Moreover, increased acetylcholinesterase and β-galactosidase activities, β-amyloid 1–42 deposition, reduced telomerase activity, elevated interleukin 1 beta mRNA expression, and enhanced reactive oxygen species production were also observed. In conclusion, our zebrafish model is simple, rapid, effective and affordable, incorporating key features of AD and aging, thus may become a unique and powerful tool for high-throughput screening of anti-AD compounds in vivo.

Objective To investigate the mechanism of nerve growth factor β (NGF β) in diabetic peripheral neuropathy (DPN). Methods High glucose cell model was established and divided into control group, OE-NGFβ group and NC-NGFβ group. Diabetic neuropathy model was established and divided into rat control group, OE-NGFβ group and NC-NGFβ group. RT-qPCR and Western blot were used to detect the expression changes of insulin-like growth factor-1 (IGF-1), intercellular adhesion molecule-1 (ICAM-1), tumor necrosis factor-α (TNF-α), autophagy-related gene 12 (ATG12), microtubule-associated protein 1A/1B light chain 3B (LC3B) and P62 in cells and rat sciatic nerves. The levels of malondialdehyde (MDA), nitric oxide (NO), reactive oxygen species (ROS) and superoxide dismutase (SOD) in blood samples of DPN rats were detected by ELISA. Results Compared with control group,the mRNA and protein levels of IGF-1, ATG12, LC3B and P62 in the OE-NGFβ group were significantly increased(P

Abstract Background Remimazolam tosilate (RT) is a new, ultrashort-acting benzodiazepine. Here, we investigated the efficacy and safety of RT for general anesthesia in patients undergoing Laparoscopic Cholecystectomy (LC). Methods In this study, 122 patients undergoing laparoscopic cholecystectomy were randomly allocated to receive either remimazolam tosilate (Group RT) or propofol group (Group P). RT was administered as a slow bolus of 0.3 mg kg− 1 for induction, followed by 1.0–2.0 mg kg− 1 h− 1 for maintenance of general anesthesia. Propofol was started at 2 mg kg− 1 and followed by 4–10 mg kg− 1 h− 1 until the end of surgery. The primary outcome was the time to bispectral index (BIS) ≤ 60. The secondary outcome included the time to loss of consciousness (LoC), and the time to extubation. Adverse events were also assessed. Results A total of 112 patients were recruited for study participation. Among them, the time to BIS ≤ 60 in Group RT was longer than that in Group P (Group RT: 89.3 ± 10.7 s; Group P: 85.9 ± 9.7 s, P > 0.05). While the time to LoC comparing remimazolam and propofol showed no statistical significance (Group RT: 74.4 ± 10.3 s; Group P: 74.7 ± 9.3 s, P > 0.05). The time to extubation in Group RT was significantly longer than that in Group P (Group RT: 16.0 ± 2.6 min; Group P: 8.8 ± 4.3 min, P

Abstract Cancer cells are often addicted to serine synthesis to support growth. How serine synthesis is regulated in cancer is not well understood. We recently demonstrated protein arginine methyltransferase 1 (PRMT1) is upregulated in hepatocellular carcinoma (HCC) to methylate and activate phosphoglycerate dehydrogenase (PHGDH), thereby promoting serine synthesis. However, the mechanisms underlying PRMT1 upregulation and regulation of PRMT1-PHGDH axis remain unclear. Here, we show the E3 ubiquitin ligase F-box-only protein 7 (FBXO7) inhibits serine synthesis in HCC by binding PRMT1, inducing lysine 37 ubiquitination, and promoting proteosomal degradation of PRMT1. FBXO7-mediated PRMT1 downregulation cripples PHGDH arginine methylation and activation, resulting in impaired serine synthesis, accumulation of reactive oxygen species (ROS), and inhibition of HCC cell growth. Notably, FBXO7 is significantly downregulated in human HCC tissues, and inversely associated with PRMT1 protein and PHGDH methylation level. Overall, our study provides mechanistic insights into the regulation of cancer serine synthesis by FBXO7-PRMT1-PHGDH axis, and will facilitate the development of serine-targeting strategies for cancer therapy.

Abstract The diagnostic accuracy of clinically significant prostate cancer (csPCa) of Prostate Imaging Reporting and Data System version 2 (PI-RADSv2) is limited by subjectivity in result interpretation and the false positive results from certain similar anatomic structures. We aimed to establish a new model combining quantitative contrast-enhanced ultrasound, PI-RADSv2, clinical parameters to optimize the PI-RADSv2-based model. The analysis was conducted based on a data set of 151 patients from 2019 to 2022, multiple regression analysis showed that prostate specific antigen density, age, PI-RADSv2, quantitative parameters (rush time, wash-out area under the curve) were independent predictors. Based on these predictors, we established a new predictive model, the AUCs of the model were 0.910 and 0.879 in training and validation cohort, which were higher than those of PI-RADSv2-based model (0.865 and 0.821 in training and validation cohort). Net Reclassification Index analysis indicated that the new predictive model improved the classification of patients. Decision curve analysis showed that in most risk probabilities, the new predictive model improved the clinical utility of PI-RADSv2-based model. Generally, this new predictive model showed that quantitative parameters from contrast enhanced ultrasound could help to improve the diagnostic performance of PI-RADSv2 based model in detecting csPCa.

Abstract Metabolic syndrome (MetS) is closely related to cardiovascular and cerebrovascular diseases, and genetic predisposition is one of the main triggers for its development. To identify the susceptibility genes for MetS, we investigated the relationship between angiotensin-converting enzyme 2 (ACE2) single nucleotide polymorphisms (SNPs) and MetS in southern China. In total, 339 MetS patients and 398 non-MetS hospitalized patients were recruited. Four ACE2 polymorphisms (rs2074192, rs2106809, rs879922, and rs4646155) were genotyped using the polymerase chain reaction-ligase detection method and tested for their potential association with MetS and its related components. ACE2 rs2074192 and rs2106809 minor alleles conferred 2.485-fold and 3.313-fold greater risks of MetS in women. ACE2 rs2074192 and rs2106809 variants were risk factors for obesity, diabetes, and low–high-density lipoprotein cholesterolemia. However, in men, the ACE2 rs2074192 minor allele was associated with an approximately 0.525-fold reduction in MetS prevalence. Further comparing the components of MetS, ACE2 rs2074192 and rs2106809 variants reduced the risk of obesity and high triglyceride levels. In conclusion, ACE2 rs2074192 and rs2106809 SNPs were independently associated with MetS in a southern Chinese population and showed gender heterogeneity, which can be partially explained by obesity. Thus, these SNPs may be utilized as predictive biomarkers and molecular targets for MetS. A limitation of this study is that environmental and lifestyle differences, as well as genetic heterogeneity among different populations, were not considered in the analysis.

Abstract The coronavirus disease 2019 (COVID-19) pandemic, along with the implementation of public health and social measures (PHSMs), have markedly reshaped infectious disease transmission dynamics. We analysed the impact of PHSMs on 24 notifiable infectious diseases (NIDs) in the Chinese mainland, using time series models to forecast transmission trends without PHSMs or pandemic. Our findings revealed distinct seasonal patterns in NID incidence, with respiratory diseases showing the greatest response to PHSMs, while bloodborne and sexually transmitted diseases responded more moderately. 8 NIDs were identified as susceptible to PHSMs, including hand, foot, and mouth disease, dengue fever, rubella, scarlet fever, pertussis, mumps, malaria, and Japanese encephalitis. The termination of PHSMs did not cause NIDs resurgence immediately, except for pertussis, which experienced its highest peak in December 2023 since January 2008. Our findings highlight the varied impact of PHSMs on different NIDs and the importance of sustainable, long-term strategies, like vaccine development.

Background The circadian variation pattern of sudden cardiac arrest (SCA) occurred in Chinese community including both community healthcare centres and primary hospitals remains unknown. This study analysed the circadian variation of SCA in the Chinese community.Methods Data between 2018 and 2022 from the remote ECG diagnosis system of Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine were analysed to examine the circadian rhythm of SCA, stratified by initial shockable (ventricular tachycardia or ventricular fibrillation) versus non-shockable (asystole or pulseless electrical activity) rhythm.Results Among 10 210 cases of SCA, major cases (8736, 85.6%) were non-shockable and 1474 (14.4%) cases were shockable. The circadian rhythm of SCA was as follows: peak time was from 08:00 to 11:59 (30.1%), while deep valley was from 00:00 to 03:59 (7.5%). The proportions of events by non-shockable and shockable events were similar and both reached their peak from 08:00 to 11:59, with a percentage of 29.0% and 36.4%, respectively. Multivariable analysis showed that the relative risk of shockable compared with non-shockable arrests was lower between 00:00 and 03:59 (adjusted OR (aOR): 0.72, 95% CI: 0.54 to 0.97, p=0.028) and 04:00 to 07:59 (aOR: 0.60, 95% CI: 0.46 to 0.79, p

ABSTRACT Cordyceps militaris infects insects and forms sclerotia within the insect remains, establishing insect–microbe complexes. Here, C. militaris sclerotia samples from a single location in China over a 5-year period were subjected to high-throughput DNA sequencing, and the core microbes (which were stably enriched in the sclerotia over the 5 years) were identified. Next, seven bacterial strains were isolated from the C. militaris sclerotia, their biochemical characteristics were assessed, and they were co-cultured with C. militaris to study their effects on C. militaris metabolite production and biomass. Furthermore, the effects of NH4, NO3, and peptone media on C. militaris were compared. The results showed that Rhodococcus, Phyllobacterium, Pseudomonas, Achromobacter, Ensifer, Stenotrophomonas, Sphingobacterium, Variovorax, and Acinetobacter were the core microbes. Although co-culture of C. militaris with the seven bacterial strains isolated from the sclerotia did not directly increase the cordycepin level, they all had NO3 reduction ability, and four had urea decomposition ability. Meanwhile, C. militaris in NH4 medium had an increased cordycepin level compared to C. militaris in the other two media. From this, we inferred that bacteria in the sclerotia can convert NO3 to NH4, and then cordycepin is produced using NH4, which was confirmed by RNA-seq and real-time fluorescence quantitative PCR. Thus, bacteria in the sclerotia may indirectly affect the C. militaris metabolite production by regulating nitrogen metabolism. In summary, there are stable core microbes in the C. militaris sclerotia, and they may directly and indirectly affect the growth and metabolite production of C. militaris.IMPORTANCEThe model Cordyceps species Cordyceps militaris is rich in therapeutic compounds. It has recently been demonstrated that symbiotic microbes in sclerotia affect Cordyceps’ growth, development, and secondary metabolite production. In this study, core microbes were identified based on C. militaris sclerotia samples obtained from the same site over 5 years. Additionally, bacterial strains isolated from C. militaris sclerotia were found to affect metabolite production and nitrogen utilization, based on functional tests. Moreover, based on the bacterial nitrogen metabolism capacity in the sclerotia and its influence on C. militaris metabolite production, we deduced that bacteria in the sclerotia can indirectly affect C. militaris metabolite production by regulating nitrogen metabolism. This is the first report on how bacteria in the sclerotia affect C. militaris metabolite production from the perspective of the nitrogen cycle. The results increase our understanding of microbial functions in C. militaris sclerotia.

IntroductionThe rapid evolution of online health services (OHS) has significantly improved healthcare accessibility. However, the impact of air pollution on individuals’ willingness to engage with OHS remains underexplored in the existing literature. This study addresses this gap by investigating how air pollution threats influence the intention to use OHS, grounded in Protection Motivation Theory (PMT) and Rational Choice Theory (RCT).MethodsUsing cross-sectional survey data, a theoretical model was developed and tested to examine the relationships between threat appraisal, coping appraisal, perceived benefits, perceived costs, and OHS usage intentions.ResultsThe findings indicate that threat appraisal, coping appraisal, and perceived benefits positively affect the intention to use OHS, while perceived costs negatively impact usage intention. Additionally, age significantly moderates the relationship between coping appraisal and the intention to use OHS.DiscussionThis study extends the application of PMT and RCT in the context of OHS. It provides valuable insights into the factors influencing users’ intentions to utilize these services, with implications for improving OHS adoption in environments affected by air pollution.

Reactive Oxygen Species (ROS) refer to a variety of derivatives of molecular oxygen that play crucial roles in regulating a wide range of physiological and pathological processes. Excessive ROS levels can cause oxidative stress, leading to cellular damage and even cell demise. However, moderately elevated levels of ROS can mediate the oxidative post-translational modifications (oxPTMs) of redox-sensitive proteins, thereby affecting protein functions and regulating various cellular signaling pathways. Among the oxPTMs, ROS-induced reversible protein sulfenylation represents the initial form of cysteine oxidation for sensing redox signaling. In this review, we will summarize the discovery, chemical formation, and detection approaches of protein sulfenylation. In addition, we will highlight recent findings for the roles of protein sulfenylation in various diseases, including thrombotic disorders, diabetes, cardiovascular diseases, neurodegenerative diseases, and cancer.

The ATR-Chk1 pathway is essential in cellular responses to DNA damage and replication stress, whereas the role of long noncoding RNAs (lncRNAs) in regulating this pathway remains largely unknown. In this study, we identify an ATR and Chk1 interacting lncRNA (ACIL, also known as LRRC75A-AS1 or SNHG29), which promotes the phosphorylation of Chk1 by ATR upon DNA damages. High ACIL levels are associated with chemoresistance to DNA damaging agents and poor outcome of breast cancer patients. ACIL knockdown sensitizes breast cancer cells to DNA damaging drugs in vitro and in vivo. ACIL protects cancer cells against DNA damages by inducing cell cycle arrest, stabilizing replication forks and inhibiting unscheduled origin firing, thereby guarding against replication catastrophe and contributing to DNA damage repair. These findings demonstrate a lncRNA-dependent mechanism of activating the ATR-Chk1 pathway and highlight the potential of utilizing ACIL as a predictive biomarker for chemotherapy sensitivity, as well as targeting ACIL to reverse chemoresistance in breast cancer.

Podocytopathies encompass kidney diseases where direct or indirect podocyte injury leads to proteinuria or nephrotic syndrome. Although Semaphorin3A (Sema3A) is expressed in podocytes and tubular cells in adult mammalian kidneys and has a common effect on the progression of podocyte injury, its mechanism remains unclear. Previous studies have shown increased Sema3A expression in various glomerulopathies, indicating a gap in understanding its role. In this study, analysis of human data revealed a positive correlation between the levels of urinary Sema3A and Podocalyxin (PCX), suggesting a close relationship between Sema3A and podocyte loss. Furthermore, the impact of Adriamycin on podocytes was investigated. Adriamycin induced podocyte migration and apoptosis, along with an increase in Sema3A expression, all of which were ameliorated by the inhibition of Sema3A. Importantly, TRPC5 was found to increase the overexpression of Sema3A in podocytes. A TRPC5 inhibitor, AC1903, alleviated podocyte migration and apoptosis, inhibiting the formation of lamellar pseudopodia in the podocyte cytoskeleton by lowering the expression of Rac1. Furthermore, AC1903 relieved massive albuminuria and foot process effacement in the kidneys of Adriamycin-treated mice in vivo. In conclusion, our findings suggest that Sema3A may impact the cytoskeletal stability of podocytes through TRPC5 ion channels, mediated by Rac1, ultimately leading to foot process effacement. Notably, AC1903 demonstrates the potential to reverse Adriamycin-induced foot process fusion and urine protein. These results contribute to a deeper understanding of the mechanisms involved in podocytopathies and highlight the therapeutic potential of targeting the Sema3A-TRPC5 pathway.

BackgroundChina’s National Essential Medicines Policy (NEMP) has been implemented for over 15 years; yet empirical evidence on its long-term impacts is lacking, particularly in remote and rural regions. This study aims to assess the short-and long-term effects of NEMP on the drug availability, price, and usage in a deprived rural county in southwestern China.MethodsA quasi-experimental design was employed, featuring a single-group pre-and-post comparison. We gathered 74,436 procurement records spanning from 2009 to 2016 from the drug warehouses of local medical institutions. Pharmaceutical data were analyzed quarterly, considering various policy and therapeutic attributes. Fisher’s Drug Price Index (DPI-F) was calibrated for the retail and wholesale prices of a consistent collection of 405 medications. We conducted interrupted time-series analysis to examine the immediate and enduring impacts of NEMP’s initial (commencing in January 2011) and second (starting from December 2015) stages.ResultsAfter initiation of NEMP, the number of available essential medicines surged by 115 but subsequently faced a steady quarterly decline (−9.1) in township healthcare centers (THCs, primary care). Conversely, county hospitals (secondary care) initially saw a reduction of 40 in drug availability but later exhibited a steady increase (+4.2 per quarter) up to the second-stage NEMP. Regarding price, THCs encountered abrupt (−26.1%/−15.9% in retail/wholesale price) and sustained (−0.2%/−0.3% per quarter) price drops after NEMP. The immediate price change after NEMP in county hospitals were milder but significant in non-essential medicines, and long-term declines were also observed in all drugs. As for total sales, a significant long-term disparity emerged between THCs (+0.9% per quarter) and county hospitals (+3.3% per quarter). Following the second-stage NEMP, retail prices in county hospitals further decreased, although wholesale prices did not; however, following price upward trends were observed in both THCs and county hospitals. Lastly, the influences of NEMP varied across different therapeutical categories of medicines.ConclusionNEMP has successfully regulated drug prices in primary and secondary healthcare facilities in remote and rural areas, both short-term and long-term. However, a remarkable disparity in medicine availability and utilization was observed between different levels of facilities over time. Continuous monitoring is essential, with increased attention needed on the uneven impacts of the policy on diverse drugs, facilities, regions, and demographics.

Cancer is a serious public health problem worldwide. Traditional treatments, such as surgery, radiotherapy, chemotherapy, and immunotherapy, do not always yield satisfactory results; therefore, an efficient treatment for tumours is urgently needed. As a convenient and minimally invasive modality, focused ultrasound (FUS) has been used not only as a diagnostic tool but also as a therapeutic tool in an increasing number of studies. FUS can help treat malignant tumours by inducing apoptosis. This review describes the three apoptotic pathways, apoptotic cell clearance, and how FUS affects these three apoptotic pathways. This review also discusses the role of thermal and cavitation effects on apoptosis, including caspase activity, mitochondrial dysfunction, and Ca2+ elease. Finally, this article reviews various aspects of FUS combination therapy, including sensitization by radiotherapy and chemotherapy, gene expression upregulation, and the introduction of therapeutic gases, to provide new ideas for clinical tumour therapy.

Abstract Objective This survey aims to comprehensively understand occupational burnout among pre-hospital emergency medical personnel and explore associated risk factors. Methods A cross-sectional online survey using a census method was conducted between 15 July, 2023, and ends on 14 August, 2023, in Chengdu, SiChuan province, China. The questionnaire included general demographic information, the Maslach Burnout Inventory-General Survey (MBI-GS) with 15 items, and the Fatigue Scale-14 (FS-14) with 14 items. Univariate analysis was conducted on all variables, followed by multivariate logistic regression models to examine the associations between occupational burnout and the risk factors. Results A total of 2,299 participants,99.57% completed the survey effectively The participants were from 166 medical institutions in Chengdu, comprising 1,420 nurses (61.50%) and 889 clinical doctors (38.50%). A total of 33.36% participants experienced burnout, predominantly mild (30.27%), followed by moderate (2.78%) and severe (0.3%). Physicians, higher fatigue scores, age, work experience appeared to be related to burnout. Logistic regression models revealed that individuals aged over 50 were less prone to experience burnout compared to medical staff aged 18–30 (OR: 0.269, 95% CI: 0.115–0.627, p = 0.002). Physicians were more prone to experience burnout compared to nursing staff (OR: 0.690, 95% CI: 0.531–0.898, p = 0.006). Those with 0–5 years of experience were more prone to experience burnout compared to those with 6–10 years or over 15 years of experience (OR: 0.734, 95% CI: 0.547–0.986, p = 0.040; OR: 0.559, 95% CI: 0.339–0.924, p = 0.023). Additionally, for each 1-point increase in the fatigue score, the likelihood of burnout in medical staff increased by 1.367 times (OR: 1.367, 95% CI: 1.323–1.412, p

Abstract The progression of heart failure (HF) is complex and involves multiple regulatory pathways. Iron ions play a crucial supportive role as a cofactor for important proteins such as hemoglobin, myoglobin, oxidative respiratory chain, and DNA synthetase, in the myocardial energy metabolism process. In recent years, numerous studies have shown that HF is associated with iron dysmetabolism, and deficiencies in iron and overload of iron can both lead to the development of various myocarditis diseases, which ultimately progress to HF. Iron toxicity and iron metabolism may be key targets for the diagnosis, treatment, and prevention of HF. Some iron chelators (such as desferrioxamine), antioxidants (such as ascorbate), Fer-1, and molecules that regulate iron levels (such as lactoferrin) have been shown to be effective in treating HF and protecting the myocardium in multiple studies. Additionally, certain natural compounds can play a significant role by mediating the imbalance of iron-related signaling pathways and expression levels. Therefore, this review not only summarizes the basic processes of iron metabolism in the body and the mechanisms by which they play a role in HF, with the aim of providing new clues and considerations for the treatment of HF, but also summarizes recent studies on natural chemical components that involve ferroptosis and its role in HF pathology, as well as the mechanisms by which naturally occurring products regulate ferroptosis in HF, with the aim of providing reference information for the development of new ferroptosis inhibitors and lead compounds for the treatment of HF in the future.

To address the lack of theoretical guidance for sponge city construction (SCC) in China, this study introduces a method to evaluate the available water volume (AWV) in urban watersheds. This evaluation is based on the water balance relationship, water volume, and ecological water demand (EWD). The Xi'an urban area was selected as a case study due to its water shortage and flooding issues. Results show monthly surface and subsurface AWV ranging between 53.06 and 53.98 million m3 and between 8,701.89 and 8,898.14 million m3, respectively. By maximizing the potential for surface AWV, an annual water supply of 527.75 million m3 could be provided, surpassing the annual artificial water consumption of 394.20 million m3, effectively addressing water scarcity. During the rainy season, implementing measures such as employing permeable paving materials, establishing wetlands and rainwater gardens, and constructing lakes and reservoirs can mitigate flooding caused by rainfall exceeding 32.8 mm. While the subsurface space in Xi'an holds significant potential for subsurface AWV utilization, revitalizing the ecological environment of subsurface water is crucial. Overall, the AWV theoretical framework offers a comprehensive solution to water shortage and flooding issues in the Xi'an urban area, serving as a vital theory for SCC. HIGHLIGHTS Available water volume (AWV) is a novel index to guide sponge city construction.; Water volume refers to the maximum volume to store water resources.; EWD refers to the minimum water resources to meet the ecological environment.; AWV refers to the total dynamic water volume to store water and used by humans.; Water shortage problem in Xi'an urban area can be solved by using AWV.;

Abstract IgG4-related disease (IgG4-RD) has complex clinical manifestations ranging from fibrosis and inflammation to deregulated metabolism. The molecular mechanisms underpinning these phenotypes are unclear. In this study, by using IgG4-RD patient peripheral blood mononuclear cells (PBMCs), IgG4-RD cell lines and Usp25 knockout mice, we show that ubiquitin-specific protease 25 (USP25) engages in multiple pathways to regulate fibrotic and inflammatory pathways that are characteristic to IgG4-RD. Reduced USP25 expression in IgG4-RD leads to increased SMAD3 activation, which contributes to fibrosis and induces inflammation through the IL-1β inflammatory axis. Mechanistically, USP25 prevents ubiquitination of RAC1, thus, downregulation of USP25 leads to ubiquitination and degradation of RAC1. Decreased RAC1 levels result in reduced aldolase A release from the actin cytoskeleton, which then lowers glycolysis. The expression of LYN, a component of the B cell receptor signalosome is also reduced in USP25-deficient B cells, which might result in B cell activation deficiency. Altogether, our results indicate a potential anti-inflammatory and anti-fibrotic role for USP25 and make USP25 a promising diagnostic marker and potential therapeutic target in IgG4-RD.

Abstract Background Hemodialysis patients require a reasonable dietary intake to manage their disease progression effectively. However, there is limited research on these patients’ overall dietary knowledge, attitude, and practice (KAP) status. This study aimed to investigate the dietary KAP status and latent profiles in hemodialysis patients and identify sociodemographic and disease-related factors associated with these profiles and dietary practice. Methods A multicenter cross-sectional study involving 425 hemodialysis patients was conducted. A dietary KAP questionnaire in hemodialysis patients was used to evaluate the dietary KAP of the patients. A structural equation model was employed to analyze the correlations between dietary knowledge, attitude, and practice. Multiple linear regression analysis was used to identify factors associated with dietary practice scores. Latent profile analysis was conducted to determine the latent profiles of dietary KAP, and binary logistic regression was used to explore the sociodemographic and disease-related characteristics associated with each KAP profile in hemodialysis patients. Results The normalized average scores for dietary knowledge, attitude, and practice in hemodialysis patients were 0.58, 0.82, and 0.58, respectively. The structural equation model revealed significant positive correlations between dietary knowledge and attitude, and attitude and practice. Attitude played an indirect effect between knowledge and practice. Gender, cerebrovascular disease, and dietary attitude scores were identified as independent influencing factors for dietary practice scores. Two dietary KAP profiles were developed: a profile with general knowledge and attitude but low practice (40.2%) and a profile with general knowledge and attitude and high practice (59.8%). Binary logistic regression analysis indicated gender and monthly income per household significantly predicted membership in each KAP profile. Conclusions The dietary practice of hemodialysis patients requires improvement. It is necessary to develop more individualized dietary interventions for these patients. Further exploration is needed to understand the motivation of patients to change their dietary behavior.

Abstract Background Primary prostate cancer with metastasis has a poor prognosis, so assessing its risk of metastasis is essential. Methods This study combined comprehensive ultrasound features with tissue proteomic analysis to obtain biomarkers and practical diagnostic image features that signify prostate cancer metastasis. Results In this study, 17 ultrasound image features of benign prostatic hyperplasia (BPH), primary prostate cancer without metastasis (PPCWOM), and primary prostate cancer with metastasis (PPCWM) were comprehensively analyzed and combined with the corresponding tissue proteome data to perform weighted gene co-expression network analysis (WGCNA), which resulted in two modules highly correlated with the ultrasound phenotype. We screened proteins with temporal expression trends based on the progression of the disease from BPH to PPCWOM and ultimately to PPCWM from two modules and obtained a protein that can promote prostate cancer metastasis. Subsequently, four ultrasound image features significantly associated with the metastatic biomarker HNRNPC (Heterogeneous nuclear ribonucleoprotein C) were identified by analyzing the correlation between the protein and ultrasound image features. The biomarker HNRNPC showed a significant difference in the five-year survival rate of prostate cancer patients (p

Abstract Background Because of the progress on the diagnosis and treatment for patients with breast cancer (BC), the overall survival of the patients has been improved. However, a number of BC patients cannot benefit from the existing therapeutic strategies as the essential molecular events triggering the development of BC are not well understood. Previous studies have shown that abnormal expression of zinc finger proteins is involved in the development of various malignancies, whereas it remains largely unclear on their significance during the progression of BC. In this study, we aimed to explore the clinical relevance, cellular function and underlying mechanisms of zinc finger protein 468 (ZNF468) in BC. Methods The clinical relevance of ZNF468 and TFAM was analyzed based on TCGA database. Overexpression or knockdown of ZNF468 and TFAM were performed by transfecting the cells with overexpression plasmids and siRNAs, respectively. Overexpression and knockdown efficacy was checked by immunoblotting. CCK-8, colony formation, transwell and apoptosis experiments were conducted to check the cellular function of ZNF468 and TFAM. The content of mtDNA was measured by the indicated assay kit. The effects of cisplatin on BC cells were detected by CCK-8 and colony formation assays. The regulation of ZNF468 on TFAM was analyzed by RT-qPCR, immunoblotting, dual luciferase activity and ChIP-qPCR assays. Results ZNF468 was overexpressed in BC patients and inversely correlated with their prognosis. Based on overexpression and knockdown assays, we found that ectopic expression of ZNF468 was essential for the proliferation, growth and migration of BC cells. The expression of ZNF468 also negatively regulated the sensitivity of BC cells to the treatment of cisplatin. Mechanistically, ZNF468 potentiated the transcription activity of TFAM gene via direct binding on its promoter. Lastly, we demonstrated that ZNF468 up-regulation of TFAM was important for the growth, migration and cisplatin resistance in BC cells. Conclusion Our study indicates that ZNF468 promotes BC cell growth and migration via transcriptional activation of TFAM. ZNF468/TFAM axis can serve as the diagnostic and therapeutic target, as well as the predictor of cisplatin effectiveness in BC patients.

Objective To analyze the literature on artificial intelligence in forensic research from 2012 to 2022 in the Web of Science Core Collection Database, to explore research hotspots and developmental trends. Methods A total of 736 articles on artificial intelligence in forensic medicine in the Web of Science Core Collection Database from 2012 to 2022 were visualized and analyzed through the literature measuring tool CiteSpace. The authors, institution, country （region）, title, journal, keywords, cited references and other information of relevant literatures were analyzed. Results A total of 736 articles published in 220 journals by 355 authors from 289 institutions in 69 countries （regions） were identified, with the number of articles published showing an increasing trend year by year. Among them, the United States had the highest number of publications and China ranked the second. Academy of Forensic Science had the highest number of publications among the institutions. Forensic Science International, Journal of Forensic Sciences, International Journal of Legal Medicine ranked high in publication and citation frequency. Through the analysis of keywords, it was found that the research hotspots of artificial intelligence in the forensic field mainly focused on the use of artificial intelligence technology for sex and age estimation, cause of death analysis, postmortem interval estimation, individual identification and so on. Conclusion It is necessary to pay attention to international and institutional cooperation and to strengthen the cross-disciplinary research. Exploring the combination of advanced artificial intelligence technologies with forensic research will be a hotspot and direction for future research.

Abstract Background Dyslipidemia is a major risk factor for cardiovascular diseases, but its prevalence and determinants among sedentary occupational population are poorly understood. This study aimed to investigate the prevalence and associated factors for dyslipidemia among a sedentary occupational population in Shanghai, China. Methods We collected data from 35,950 sedentary occupational workers on their demographics, social, medical, and family history, lifestyle, anthropometry, and biochemistry. We used the 2016 Chinese guideline for the management of dyslipidemia in adults to define dyslipidemia and its subtypes. We performed multivariate logistic regression to examine the factors associated with dyslipidemia. Results The prevalence of dyslipidemia was 29.10%, with 15.86% for high triglycerides (TG), 6.43% for high total cholesterol (TC), 5.37% for high low-density lipoprotein cholesterol (LDL-C), and 14.68% for low high-density lipoprotein cholesterol (HDL-C). Men had a significantly higher prevalence of dyslipidemia than women (39.64% vs. 12.43%, P

Abstract Background Family doctor contract policy is now run by the State Council as an important move to promote the hierarchical medical system. Whether the family doctor contract policy achieves the initial government’s goal should be measured further from the perspective of patient visits between hospitals and community health centers, which are regarded as grass medical agencies. Methods The spatial feature measurement method is applied with ArcGIS 10.2 software to analyze the spatial aggregation effect of patient visits to hospitals or community health centers among 20 districts of one large city in China and analyze the family doctor contract policy published in those areas to compare the influence of visit tendencies. Results From year 2016-2020, visits to hospitals were in the high-high cluster, and the density was spatially overflow, while there was no such tendency in visits to community health centers. The analysis of different family doctor contract policy implementation times in 20 districts reflects that the family doctor contract policy has a very limited effect on the promotion of the hierarchical medical system, and the innovation of the family doctor contract policy needs to be considered. Conclusions A brief summary and potential implications. A multi-integrated medical system along with family doctor contract policy needs to be established, especially integrated in leadership and governance, financing, workforce, and service delivery between hospitals and community health centers, to promote the hierarchical medical system.

Abstract The complexity of the tumor microenvironment (TME) is a crucial factor in lung adenocarcinoma (LUAD) progression. To gain deeper insights into molecular mechanisms of LUAD, we perform an integrative single-cell RNA sequencing (scRNA-seq) data analysis of 377,574 cells from 117 LUAD patient samples. By linking scRNA-seq data with bulk gene expression data, we identify a cluster of prognostic-related UPP1high tumor cells. These cells, primarily situated at the invasive front of tumors, display a stronger association with the immunosuppressive components in the TME. Our cytokine array analysis reveals that the upregulation of UPP1 in tumor cells leads to the increased release of various immunosuppressive cytokines, with TGF-β1 being particularly prominent. Furthermore, this UPP1 upregulation also elevates the expression of PD-L1 through the PI3K/AKT/mTOR pathway, which contributes to the suppression of CD8 + T cells. Cytometry by time-of-flight (CyTOF) analysis provides additional evidence of the role of UPP1 in shaping the immunosuppressive nature of the TME. Using patient-derived organoids (PDOs), we discover that UPP1high tumors exhibit relatively increased sensitivity to Bosutinib and Dasatinib. Collectively, our study highlights the immunosuppressive role of UPP1 in LUAD, and these findings may provide insights into the molecular features of LUAD and facilitate the development of personalized treatment strategies.

Abstract Background Exposure to PM2.5 has been implicated in a range of detrimental health effects, particularly affecting the respiratory system. However, the precise underlying mechanisms remain elusive. Methods To address this objective, we collected ambient PM2.5 and administered intranasal challenges to mice, followed by single-cell RNA sequencing (scRNA-seq) to unravel the heterogeneity of neutrophils and unveil their gene expression profiles. Flow cytometry and immunofluorescence staining were subsequently conducted to validate the obtained results. Furthermore, we assessed the phagocytic potential of neutrophils upon PM2.5 exposure using gene analysis of phagocytosis signatures and bacterial uptake assays. Additionally, we utilized a mouse pneumonia model to evaluate the susceptibility of PM2.5-exposed mice to Pseudomonas aeruginosa infection. Results Our study revealed a significant increase in neutrophil recruitment within the lungs of PM2.5-exposed mice, with subclustering of neutrophils uncovering subsets with distinct gene expression profiles. Notably, exposure to PM2.5 was associated with an expansion of PD-L1high neutrophils, which exhibited impaired phagocytic function dependent upon PD-L1 expression. Furthermore, PM2.5 exposure was found to increase the susceptibility of mice to Pseudomonas aeruginosa, due in part to increased PD-L1 expression on neutrophils. Importantly, monoclonal antibody targeting of PD-L1 significantly reduced bacterial burden, dissemination, and lung inflammation in PM2.5-exposed mice upon Pseudomonas aeruginosa infection. Conclusions Our study suggests that PM2.5 exposure promotes expansion of PD-L1high neutrophils with impaired phagocytic function in mouse lungs, contributing to increased vulnerability to bacterial infection, and therefore targeting PD-L1 may be a therapeutic strategy for reducing the harmful effects of PM2.5 exposure on the immune system.