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Abstract Background The advancement of nanotechnology underscores the imperative need for establishing in silico predictive models to assess safety, particularly in the context of chronic respiratory afflictions such as lung fibrosis, a pathogenic transformation that is irreversible. While the compilation of predictive descriptors is pivotal for in silico model development, key features specifically tailored for predicting lung fibrosis remain elusive. This study aimed to uncover the essential predictive descriptors governing nanoparticle-induced pulmonary fibrosis. Methods We conducted a comprehensive analysis of the trajectory of metal oxide nanoparticles (MeONPs) within pulmonary systems. Two biological media (simulated lung fluid and phagolysosomal simulated fluid) and two cell lines (macrophages and epithelial cells) were meticulously chosen to scrutinize MeONP behaviors. Their interactions with MeONPs, also referred to as nano-bio interactions, can lead to alterations in the properties of the MeONPs as well as specific cellular responses. Physicochemical properties of MeONPs were assessed in biological media. The impact of MeONPs on cell membranes, lysosomes, mitochondria, and cytoplasmic components was evaluated using fluorescent probes, colorimetric enzyme substrates, and ELISA. The fibrogenic potential of MeONPs in mouse lungs was assessed by examining collagen deposition and growth factor release. Random forest classification was employed for analyzing in chemico, in vitro and in vivo data to identify predictive descriptors. Results The nano-bio interactions induced diverse changes in the 4 characteristics of MeONPs and had variable effects on the 14 cellular functions, which were quantitatively evaluated in chemico and in vitro. Among these 18 quantitative features, seven features were found to play key roles in predicting the pro-fibrogenic potential of MeONPs. Notably, IL-1β was identified as the most important feature, contributing 27.8% to the model’s prediction. Mitochondrial activity (specifically NADH levels) in macrophages followed closely with a contribution of 17.6%. The remaining five key features include TGF-β1 release and NADH levels in epithelial cells, dissolution in lysosomal simulated fluids, zeta potential, and the hydrodynamic size of MeONPs. Conclusions The pro-fibrogenic potential of MeONPs can be predicted by combination of key features at nano-bio interfaces, simulating their behavior and interactions within the lung environment. Among the 18 quantitative features, a combination of seven in chemico and in vitro descriptors could be leveraged to predict lung fibrosis in animals. Our findings offer crucial insights for developing in silico predictive models for nano-induced pulmonary fibrosis.

Abstract Hydrogels are currently widely used in regenerative medicine and wound repair due to their superior biocompatibility, reliable mechanical strength, and good morphological memory. We aimed to prepare a self-expanding hydrogel that can be used as a skin expander for the repair of large soft skin tissue defects. Self-expanding hydrogels were prepared by chemical cross-linking, which consisted of water-soluble chitosan (CS), acrylamide (AM), methylene bisacrylamide (NMBA), etc. Five groups of in vitro experiments, including (CS-AM) of 0% (pure AM group), 13.9%, 27.8%, 41.7%, and 55.6%, were conducted to determine mechanical properties, swelling properties, cytotoxicity, etc. In the rat model, both a tight skin area (neck) and a loose skin area (back) were selected for expansion with hydrogels. A total of 27.8% of the CS-AM samples expanded stably under the skin of the rats, achieving 370% expansion in the tight zone and 490% expansion in the flaccid zone. Subcutaneous histopathological examination suggested that the inflammation index of the pericolloid tissue was lower in the CS-AM group than in the pure AM group. Our results demonstrate that self-expanding CS-AM hydrogels have great potential for application as skin expanders. Graphical Abstract

Abstract Background LncRNAs play essential roles in multiple tumors. However, research on genome-wide lncRNA alterations and their functions in cervical cancer (CC) is limited. This study aims to explore key lncRNAs in CC progression and uncover the molecular mechanisms involved in the development of CC. Methods In this study, we analyzed 30 tissues from CC, cervical intraepithelial neoplasia (CIN), and normal (NOR) using transcriptome sequencing and weighted gene co-expression network analysis to establish gene modules related to the NOR-CIN-CC transition. Machine learning diagnostic models were employed to investigate the role of lncRNAs in this transition. Molecular biological experiments were conducted to elucidate the potential mechanisms of CARMN in CC, with a particular focus on its transcriptional and post-transcriptional regulation of abnormal expression in CC. Results CARMN was identified as a hub gene in two modules significantly associated with the NOR-CIN-CC transition. Analysis using ten machine learning models confirmed its critical role in this progression. The results of RNA-seq, qPCR and RNAScope performed in another cohort of 83 cervical tissues all showed that CARMN was significantly downregulated in CC. CARMN significantly enhanced the interaction between Keap1 and Nrf2, leading to increased ROS levels. The elevated ROS levels suppressed the Akt/mTOR signaling pathway, leading to autophagy arrest via autophagic flux blockade. Additionally, CARMN interacted with TFAP2α to repress MAPK13 transcription, further inhibiting the MAPK cascade. A promoter SNP (rs12517403) was found to increase CC risk (OR = 1.34, 95% CI = 1.11–1.61) and reduce CARMN expression by decreasing SP1 binding. Furthermore, the RNA binding proteins that could modulate CARMN RNA stability were also determined using RNA-pulldown assay. The results demonstrated that YBX1, a component of the coding region instability determinant (CRD)-mediated mRNA stabilization complex, promoted CARMN RNA stability. DHX9, another component of complex, acted as a scaffold to bridge YBX1 and CARMN. Conclusions CARMN exerts an anti-cancer effect in CC progression by inhibiting the Akt-mTOR and MAPK signaling pathways. rs12517403 and the YBX1/DHX9 complex are key mechanisms influencing its transcription and stability in CC cells. CARMN represents a promising biomarker for CC diagnosis and therapeutic target.

ObjectiveThe role of natural killer (NK) cells, which mediate innate immunity, in the immune reconstitution of people living with HIV (PLWH) remains unclear. Our previous research indicated that early activation of CD56dimCD16dim/- NK cells plays an important role in the recovery of CD4+ T cells in immunological non-responders (INRs) after ART. This study mainly focuses on the profiles of cell receptors and their relative ligands for NK cells and CD4+ T cells exhibited on INRs and immunological responders (IRs) in order to analyze the impact of differential immune status on immune reconstitution in PLWH receiving ART.MethodsThis study included 66 PLWH who had been on ART for 4 years, comprising 32 INRs and 34 IRs. Using flow cytometry, we examined the expression of cell receptors and ligands for NK cells and CD4+ T cells in PBMCs, as well as the differentiation of CD4+ T cells.ResultsThe expression of NKG2D ligands, including MICA/B and ULBP2-5, on CD4+ T cells in INRs is elevated prior to ART. Further research found that the expression of CD95 on MICA/B+CD4+ T cells and ULBP2-5+CD4+ T cells was higher in INRs before ART compared to IRs. Simultaneously, the percentages of death receptor CD95 expression on MICA/B+CD4+ T cells and on ULBP2-5+CD4+ T cells before ART were negatively correlated with CD4+ T-cell counts and ΔCD4. Among the CD4+ T-cell subsets, an imbalance persists in the CD4+ Tcm and CD4+ Temra subsets in both INRs and IRs, before or after ART. CD4+ T cells exhibit elevated levels of activation, proliferation, exhaustion, and apoptosis prior to ART initiation. However, CD4+ T-cell activation and proliferation normalize post-ART, while apoptosis and exhaustion levels remain significantly elevated. Regardless of ART, the anti-apoptotic capacity of CD4+ T cells in INRs is still lower than that of IRs and healthy controls (HCs). Before ART, the frequency of CD31 expression on naive CD4+ T cells in INRs is lower than that in IRs and HCs. Following ART, the amounts of CD31+ Tn from CD4+ T cells remain impaired in both INRs and IRs compared to HCs.ConclusionThe upregulation of related ligands for the NKG2D receptor on CD4+ T cells in INRs is associated with increased susceptibility of CD4+ T cells to NK cell-mediated killing. CD95 may plays an important role in poor recovery of CD4+ T cells co-expressing NKG2D-related ligands. The imbalance in CD4+ Tcm and CD4+ Temra subset homeostasis and impaired CD31 expression on naive CD4+ T cells in INRs are associated with poor immune reconstitution outcomes.

IntroductionPoa alpigena Lindm., a dominant forage grass on the Tibetan Plateau, plays a critical role in livestock production and grassland restoration. This study investigates the rhizospheric and non-rhizospheric soil microorganisms of Poa alpigena L. in the Ganzi River area of the Qinghai Lake basin using metagenomic sequencing to understand their diversity and potential ecological functions.MethodsSoil samples were collected from rhizospheric and non-rhizospheric areas of Poa alpigena L. using the S-type five-point sampling method. DNA was extracted, and metagenomic sequencing was performed using the BGISEQ-500 platform. Alpha and Beta diversity analyses were conducted, and LEfSe analysis was used to identify differentially abundant microbial taxa and metabolic pathways.ResultsA total of 5,681 microbial species across 1,606 genera, 521 families, 61 phyla, and 246 orders were identified. Non-rhizospheric soils exhibited higher species richness than rhizospheric soils. Proteobacteria was the most abundant phylum in both soil types. Rhizospheric soils showed significant enrichment in pathways related to antibiotic biosynthesis, carbon metabolism, and methane metabolism, while non-rhizospheric soils were enriched in quorum sensing and drug-metabolizing pathways.DiscussionThe findings highlight the selective influence of Poa alpigena L. on soil microbial communities and their potential role in mitigating methane emissions. The study provides a foundation for understanding the ecological functions of soil microorganisms in alpine meadows and supports sustainable grassland management practices.

BackgroundThis study examined the associations between health literacy and smoking behaviors among residents in Ningbo City, Zhejiang Province, China, investigating both the impact of health literacy on smoking prevalence and intensity, and its potential role in smoking cessation interventions.MethodsThis cross-sectional study analyzed data from 2,948 male participants in the 2023 Health Literacy and Tobacco Use Surveillance Survey. We applied logistic regression models and restricted cubic spline analyses to assess the association between health literacy and smoking behaviors, adjusting for demographic characteristics, socioeconomic factors, and self-reported health status.ResultsOur findings indicate that higher levels of health literacy are associated with significantly lower rates of smoking (OR = 0.643, 95%CI = 0.528, 0.783) and daily cigarette consumption (β = −1.938, 95%CI = −3.649, −0.228). Non-smokers with higher health literacy were more likely to discourage others from smoking (OR = 1.464, 95%CI = 1.096, 1.955), underscoring health literacy’s crucial role in smoking prevention and control. A nonlinear relationship between health literacy and smoking behavior was identified.ConclusionHealth literacy significantly influences smoking behavior, with higher literacy levels associated with reduced smoking prevalence and intensity. These findings support incorporating health literacy enhancement into comprehensive smoking cessation strategies.

Abstract Mitochondrial dysfunction is a key event driving the maladaptive repair of tubular epithelial cells during the transition from acute kidney injury to chronic kidney disease (CKD). Therefore, identifying potential targets involved in mitochondrial dysfunction in tubular epithelial cells is clinically important. Myeloid‐derived growth factor (MYDGF), a novel secreted protein, plays important roles in multiple cardiovascular diseases, but the function of MYDGF in tubular epithelial cells remains unknown. In the present study, it is found that MYDGF expression is significantly reduced in the cortex of the kidney, especially in the proximal tubules, from mice with CKD. Notably, lower expression of MYDGF is observed in tubules from patients with CKD and the level of MYDGF correlated with key factors related to kidney fibrosis and estimated glomerular filtration rate (eGFR) in patients with CKD. Tubule‐specific deletion of Mydgf exacerbates kidney injury in mice with CKD; however, Mydgf overexpression attenuates kidney fibrosis by remodeling mitochondrial homeostasis in tubular epithelial cells. Mechanistically, renal tubular MYDGF positively regulates the expression of isocitrate dehydrogenase 2 (IDH2), restores mitochondrial homeostasis, and slows CKD progression. Thus, this study indicates that MYDGF derived from tubules may be an effective therapeutic strategy for patients with CKD.

Abstract Background Stress-induced hyperglycemia (SIH) is associated with poor outcomes in cardiogenic shock (CS), and there have been inconsistent results among patients with or without diabetes mellitus (DM). The glycemic gap (GG) is derived by subtracting A1c-derived average glucose from blood glucose levels; it is a superior indicator of SIH. We aimed to explore the role of GG in the outcomes of patients with CS. Methods Data on patients diagnosed with CS were extracted from the MIMIC-IV v2.0 database to investigate the relationship between GG and 30-day mortality (Number of absolute GG subjects = 359; Number of relative GG subjects = 357). CS patients from the Second Affiliated Hospital of Wenzhou Medical University were enrolled to explore the correlation between GG and lactic acid (Number of absolute GG subjects = 252; Number of relative GG subjects = 251). Multivariate analysis, propensity score-matched (PSM) analysis, inverse probability treatment weighting (IPTW), and Pearson correlation analysis were applied. Results Absolute GG was associated with 30-day all-cause mortality in CS patients (HRadjusted: 1.779 95% CI: 1.137–2.783; HRPSM: 1.954 95% CI: 1.186–3.220; HRIPTW: 1.634 95% CI: 1.213–2.202). The higher the absolute GG level, the higher the lactic acid level (βadjusted: 1.448 95% CI: 0.474–2.423). A similar trend existed in relative GG (HRadjusted: 1.562 95% CI: 1.003–2.432; HRPSM: 1.790 95% CI: 1.127–2.845; HRIPTW: 1.740 95% CI: 1.287–2.352; βadjusted:1.294 95% CI: 0.369–2.219). Subgroup analysis showed that the relationship existed irrespective of DM. The area under the curve of GG combined with the Glasgow Coma Scale (GCS) for 30-day all-cause mortality was higher than that of GCS (absolute GG: 0.689 vs. 0.637; relative GG: 0.688 vs. 0.633). GG was positively related to the triglyceride-glucose index. Kaplan–Meier curves revealed that groups of higher GG with DM had the worst outcomes. The outcomes differed among races and GG levels (all P

Abstract Ferroptosis is a promising strategy for cancer therapy, with numerous inhibitors of its braking axes under investigation as potential drugs. However, few studies have explored the potential of activating the driving axes to induce ferroptosis. Herein, phosphatidylcholine peroxide decorating liposomes (LIPPCPO) are synthesized to induce ferroptosis by targeting divalent metal transporter 1 (DMT1). LIPPCPO is found to boost lysosomal Fe2+ efflux by inducing cysteinylation of lysosomal DMT1, resulting in glutathione peroxidase 4 (GPX4) suppression, glutathione depletion and ferroptosis in breast cancer cells and xenografts. Importantly, LIPPCPO induced ferroptotic cell death is independent of acquired resistance to radiation, chemotherapy, or targeted agents in 11 cancer cell lines. Furthermore, a strong synergistic ferroptosis effect is observed between LIPPCPO and an FDA-approved drug, artesunate, as well as X rays. The formula of LIPPCPO encapsulating artesunate significantly inhibits tumor growth and metastasis and improves the survival rate of breast cancer-bearing female mice. These findings provide a distinct strategy for inducing ferroptosis and highlight the potential of LIPPCPO as a vector to synergize the therapeutic effects of conventional ferroptosis inducers.

Abstract To explore the clinical characteristics of patients infected with SARS-CoV-2 nationwide, especially the effect factors of asymptomatic infection and disappearance of clinical symptoms. A total of 66,448 COVID-19 patients in China who have been diagnosed by nucleic acid test or rapid antigen test were surveyed online (December 24, 2022 to January 16, 2023). Our cross-sectional study used descriptive analyses and binary Logistics regression model to assess the correlation between the clinical characteristics and relative factors, including age, gender, pre-existing conditions, reinfection, vaccination and treatment. A total of 64,515 valid questionnaires were collected. Among included participants, 5969 of which were asymptomatic. The symptoms were mainly upper respiratory symptoms, including dry and itchy throat (64.16%), sore throat (59.95%), hoarseness (57.90%), nasal congestion (53.39%). In binary Logistics regression model, we found that male, no pre-existing conditions, reinfection and vaccination have positive correlations with the appearance of asymptomatic COVID-19 patients. In Cox proportional-hazards regression model, considering all clinical symptoms disappeared in 14 days as outcome, we found that ≤ 60 years old, male, no pre-existing conditions, vaccination and adopted treatment have positive correlations with rapid amelioration of clinical symptoms in COVID-19 patients. The clinical symptoms of the participants were mainly upper respiratory symptoms which were according with the infection of Omicron variant. Factors including age, gender, pre-existing conditions and reinfection could influence the clinical characteristics and prognosis of COVID-19 patients. Importantly, vaccination has positive significance for the prevention and treatment of COVID-19. Lastly, the use of Chinese medicine maybe beneficial to COVID-19 patients, however, reasonable guidance is necessary.

Abstract Safe and effective vaccines against COVID-19 for children and adolescents are needed. This international multicenter, randomized, double-blind, placebo-controlled, phase III clinical trial assessed the efficacy, immunogenicity, and safety of CoronaVac® in children and adolescents (NCT04992260). The study was carried out in Chile, South Africa, Malaysia, and the Philippines. The enrollment ran from September 10, 2021 to March 25, 2022. For efficacy assessment, the median follow-up duration from 14 days after the second dose was 169 days. A total of 11,349 subjects were enrolled. Two 3-μg injections of CoronaVac® or placebo were given 28 days apart. The primary endpoint was the efficacy of the CoronaVac®. The secondary endpoints were the immunogenicity and safety. The vaccine efficacy was 21.02% (95% CI: 1.65, 36.67). The level of neutralizing antibody in the vaccine group was significantly higher than that in the placebo group (GMT: 390.80 vs. 62.20, P

Abstract Objectives This study aimed to investigate the associations between changes in blood pressure (BP) and cerebral small vessel disease (CSVD). Methods This study included 401 participants in the magnetic resonance imaging (MRI) sub-study conducted between 2018 and 2020 as a part of the Multidomain Interventions to Delay Dementia and Disability in Rural China project. MRI markers of CSVD were assessed based on international criteria. Individualized linear regression models evaluated changes in BP by estimating the trend of blood pressure changes over time and fitting a straight line from 2014 to 2018. The data were analyzed using logistic and general linear regression models. Result The mean age of the participants was 64.48 ± 2.69 years, with 237 (59.1%) being females. Increases in systolic BP in later life were significantly associated with larger volumes of periventricular white matter hyperintensity (WMH), greater perivascular spaces in the basal ganglia (BG-PVS) burden, and the presence of deep lacunes and cerebral microbleeds. Additionally, increases in diastolic BP in later life were significantly associated with the presence of infratentorial and deep lacunes. Conclusions CSVDs are associated with increased exposure to elevated BP later in life.

Background Although tumor necrosis factor receptor 2 (TNFR2) has been recognized as an attractive next-generation candidate target for cancer immunotherapy, the factors that regulate the gene expression and their mechanistic effects on tumor-infiltrating regulatory T cells (Treg cells) remain poorly understood.Methods Single-cell RNA sequencing analysis was employed to analyze the phenotypic and functional differences between TNFR2+ Treg cells and TNFR2− Treg cells. Malignant pleural effusion (MPE) from humans and mouse was used to investigate the potential mechanisms by which lactate regulates TNFR2 expression.Results Treg cells with high TNFR2 expression exhibited elevated levels of immune checkpoint molecules. Additionally, the high expression of TNFR2 on Treg cells was positively correlated with a poor prognosis in MPE patients. Moreover, we revealed that lactate upregulated TNFR2 expression on Treg cells, thereby enhancing their immunosuppressive function in MPE. Mechanistically, lactate modulated the gene transcription of transcription factor nuclear factor-κB p65 (NF-κB p65) through histone H3K18 lactylation (H3K18la), subsequently upregulating the gene expression of TNFR2 and expediting the progression of MPE. Notably, lactate metabolism blockade combined with immune checkpoint blockade (ICB) therapy effectively enhanced the efficacy of ICB therapy, prolonged the survival time of MPE mice, and improved immunosuppression in the microenvironment of MPE.Conclusions The study explains the mechanism that regulates TNFR2 expression on Treg cells and its function in MPE progression, providing novel insights into the epigenetic regulation of tumor development and metabolic strategies for MPE treatment by targeting lactate metabolism in Treg cells.

The endemic status of goose parvovirus (GPV), H5 subtype avian influenza virus (AIV), and goose astrovirus (GoAstV) infections continues to devastate the poultry industry in China. Despite this, there exists a notable gap in the application of molecular diagnostic techniques. This investigation described the development of a multiplex qualitative polymerase chain reaction (qPCR) assay capable of concurrently detecting GPV, H5 AIV, and GoAstV, with no cross-reactivity observed with other avian viral pathogens. The assay exhibited a detection threshold of 10 copies/μL for both GPV and GoAstV, and 1 copy/μL for H5 AIV. The intra- and inter-assay coefficients of variation were < 3.0%, signifying high repeatability within and across assay batches. Utilizing this multiplex qPCR assay, a batch of 60 clinical samples was analyzed to assess its practical utility. The detected prevalence rates for GoAstV, GPV, and H5 AIV were 35.0% (21/60), 21.7% (13/60), and 15.0% (9/60), respectively. Concurrent infections were also identified, with rates for GPV + GoAstV, GPV + H5 AIV, GoAstV + H5 AIV, and GPV + GoAstV + H5 AIV being 6.7% (4/60), 3.3% (2/60), 3.3% (2/60), and 3.3% (2/60), respectively. The developed multiplex qPCR assay exhibited a diagnostic concordance rate equivalent to that of traditional PCR techniques. This novel assay serves as a rapid, efficient, specific, and sensitive tool for the detection of prevalent goose viruses, thereby enhancing disease management strategies and epidemiological monitoring efforts.

ObjectiveMental health has become a widely concerned topic worldwide. However, the impact and mechanism of positive activities on mental health still needed to be explored. This study aimed to apply the positive-activity model to investigate the effect of participation in positive activities on mental health and the mediating role of positive emotion.MethodsThis study used data from the 2021 China Comprehensive Social Survey (CGSS) and included 2,581 individuals. Ordinary Least Squares (OLS) and a three-step method was used for analysis.ResultsThe average of positive activities was 15.83. The positive activities affected positively mental health (β = 0.0132, p < 0.001). The positive emotion played a mediating role (β =0.2281, p < 0.001). The effect of positive activities on mental health was significant in older adults group (β = 0.024, p < 0.001), female (β = 0.015, p < 0.01) and male group (β = 0.01, p < 0.01), unmarried/divorced/widowed group (β = 0.024, p < 0.01), cohabitation/first marriage with spouse/remarriage with spouse/separation without divorce group (β = 0.010, p < 0.001), middle(β = 0.013, p < 0.05), and upper-middle-level SES group (β = 0.054, p < 0.001).ConclusionsWe concluded that the participation level of positive activities still needs to be improved and positive activities improve mental health through positive emotion, which implied that positive activities, as an easily implementable measure, should be greatly encouraged in mental health policies. And older adults, female, people without spouse, middle and upper-middle-income individuals need to be paid more attention.

Cyanobacterial blooms and aquatic macrophytes can affect the health, physiology, and behavior of freshwater fish. Changes in food intake can be a key indicator of stress in teleost fish, while changes in metabolite abundance in the gut can indicate a shift in metabolic priorities, including response to environmental stressors. Here, we exposed stone moroko (Pseudorasbora parva) to the cyanobacterium Microcystis aeruginosa and/or the macrophyte Ottelia acuminata and analyzed changes in fish health, appetite regulation, and intestinal metabolome after 96-h exposures. We found that O. acuminata treatment didn’t change the tested indicators, while exposure to M. aeruginosa increased concentrations of appetite-inhibiting factors, such as CART and GLP-1, and decreased concentrations of stimulatory factors like orexin. Exploration of the metabolome following exposure revealed that the appetite-inhibiting influence of M. aeruginosa was positively correlated with key metabolites of lipid, amino acid, and cholesterol metabolism, especially those associated with bile acid synthesis and secretion. Further, the presence of O. acuminata decreased the adverse effects of M. aeruginosa among neuro-endocrine regulatory factors, which could be explained by altered regulation of intestinal amino acid metabolites. The deeper mechanism by which O. acuminata moderates the harmful effects of M. aeruginosa remains to be identified.

Recently, the safety of anthraquinone (AQ) in Chinese tea has received much attention. This study determined the concentration of AQ in 1573 Chinese tea samples by gas chromatography-tandem mass spectrometry (GC-MS/MS). It was observed that the total detection rate of AQ was 60.97%, and the mean concentration was 0.0170 mg/kg. The concentration levels of AQ in tea varied by different types of tea, different packaging types, different sale spots and different tea-producing areas. The results of the deterministic assessment show that the health risks associated with daily exposure to AQ via tea consumption are low in different populations in China. For the general population, the mean daily exposure of AQ via tea consumption was (2.50 × 10−4) µg/kg body weight (BW), 0.0037% of the acceptable daily intake of AQ (6.8 µg/kg BW). In the different sex-age groups, the highest mean daily exposure of AQ via tea consumption was found in the male group aged ≥ 60 years, which was (2.84 × 10−4) µg/kg BW. The high consumer exposure (95th percentile, P95) was found in the female group aged ≥ 60 years, which was (9.36 × 10−4) µg/kg BW. Green tea is the main type of tea with AQ exposure by Chinese tea consumers.

Background This study aims to investigate the incidence and prognosis of malignancy in individuals with thrombospondin type-1 domain-containing 7A (THSD7A)-associated membranous nephropathy (MN).Methods First, we performed a systematic literature review of prevalence of malignancy in THSD7A-associated MN. Then, we conducted a retrospective analysis of 454 patients diagnosed with MN through renal biopsy at our hospital between January 2016 and December 2020. We assessed the presence of serum anti-THSD7A antibodies and performed immunohistochemical staining of renal tissue for THSD7A. Subsequently, we followed patients with THSD7A-associated MN for a minimum of 3–5 years, collecting their clinical, pathological characteristics, and prognosis. Additionally, we conducted a literature review on patients with THSD7A-associated MN in conjunction with malignancy.Results We identified a total of nine articles containing comprehensive data on THSD7A-associated MN and malignancy. Among 235 patients with THSD7A-positive MN, 36 individuals had concurrent malignancies, resulting in a malignancy prevalence of 13.3% (95% CI: 8.9–17.7%). In our center, we followed up with 15 patients diagnosed with THSD7A-associated MN and observed three cases of concomitant tumors: two cases of lung adenocarcinoma and one case of small cell lung cancer with multiple metastases. The prevalence of malignancy in our cohort was 20%. Notably, we detected positive THSD7A staining in both renal and lung cancer tissues in one patient with small cell lung cancer.Conclusions Patients with THSD7A-associated MN should undergo vigilant follow-up assessments, with a particular focus on actively seeking potential tumorigenic lesions to prevent misdiagnosis or oversight.

Background This retrospective study aims to investigate the prevalence and immunopathologic characteristics of seropositive and seronegative hepatitis B virus-associated membranous nephropathy (HBV-MN).Methods Clinicopathologic and serologic records of 420 patients with histologically confirmed HBV-MN between January 2014 and July 2021 were examined to determine the prevalence of seropositive and seronegative HBV-MN. Serum anti-PLA2R antibody testing was conducted on 280 patients with HBV-associated membranous nephropathy (HBV-MN) from August 2018 to July 2021. Immunopathologic characteristics of HBV-MN patients and anti-PLA2R antibody positivity were analyzed.Results Among 420 pathologically confirmed HBV-MN patients, 230 (54.8%) were seropositive for HBV. The seropositive group exhibited higher blood creatinine values and incidence of liver function abnormalities than the seronegative group (p

Background Renal insufficiency (RI) is a key factor affecting the prognosis of multiple myeloma (MM) patients. Because the benefit of daratumumab for treating MM patients with RI remains unclear, our objective was to evaluate the efficacy of daratumumab on MM patients with RI.Methods We conducted a systematic search of the PubMed, EMBASE, and Cochrane Library databases as of October 24, 2023. Two independent reviewers screened the article titles, abstracts, and full text to identify the randomized controlled trials (RCTs) meeting the inclusion and exclusion criteria. Meta-analyses were performed using RevMan version 5.4. Outcomes of interest were progression-free survival (PFS), overall survival (OS), complete response or better (≥CR), and minimal residual disease (MRD) negativity, all calculated as hazard ratios (HRs) or risk ratios (RRs) with 95% confidence intervals (CIs).Results A total of 10 RCTs with 5003 patients were included. Add-on daratumumab improved PFS and OS among newly diagnosed MM (NDMM) patients with RI (HR 0.48 [95% CI: 0.36, 0.64, I2 = 65%] and HR 0.63 [95% CI: 0.48, 0.82, I2 = 0%]) as well as relapsed/refractory MM (RRMM)-RI patients, compared with the control group (HR 0.46 [95% CI: 0.37, 0.58, I2 = 0%] and HR 0.68 [95% CI: 0.51, 0.92, I2 = 0%]). In terms of the renal status, the efficacy of add-on daratumumab for MMRI patients was similar to that for MM patients with normal renal function. A prolonged PFS benefit for add-on daratumumab treatment versus the control was evident across all RRMM-RI subgroups, and the benefits tended to increase with the follow-up time.Conclusions Our results indicate that MM patients with RI could benefit from a daratumumab-added regimen regardless of MM status. Additional high-quality RCTs are still warranted to confirm our findings.

ABSTRACT: Stress damage caused by early weaning and its possible mechanism have been studied mainly in young mammals, but rarely in altrices, especially in squabs. The study aimed to investigate the possible molecular mechanism of intestinal epithelial barrier damage caused by early weaning in squabs through determining the intestinal permeability, the ultrastructure of villous epithelium, the contents of ileal cytokines, and the protein relative expression of tight-junction proteins, TLRs and their mediated key factors in inflammatory signaling pathways. A total of 192 newly hatched squabs were randomly divided into 2 groups, 1 group was weaned and fed artificial pigeon milk from d 7, and the other group continued to be fed by the parent pigeons. The ileal mucosa and serum of 8 replicates were collected at 1, 4, 7, 10, and 14 d after weaning. The results indicated that early weaning could reduce the growth performance of squabs and damage the intestinal epithelial barrier, which is characterized by down-regulating the protein expression of claudin-1/3, up-regulating the protein expression of claudin-2, promoting the secretion of pro-inflammatory factors, inhibiting the secretion of anti-inflammatory factors, and increasing the permeability of the intestinal barrier. The specific mechanism of stress damage might be the activation of TLR2/4-MyD88-ERK/JNK inflammatory signaling pathway leading to the increase levels of IL-6 and TNF-α.

Cardiovascular diseases (CVDs) impose a significant burden worldwide. Despite the elucidation of the etiology and underlying molecular mechanisms of CVDs by numerous studies and recent discovery of effective drugs, their morbidity, disability, and mortality are still high. Therefore, precise risk stratification and effective targeted therapies for CVDs are warranted. Recent improvements in single-cell RNA sequencing and spatial transcriptomics have improved our understanding of the mechanisms and cells involved in cardiovascular phylogeny and CVDs. Single-cell RNA sequencing can facilitate the study of the human heart at remarkably high resolution and cellular and molecular heterogeneity. However, this technique does not provide spatial information, which is essential for understanding homeostasis and disease. Spatial transcriptomics can elucidate intracellular interactions, transcription factor distribution, cell spatial localization, and molecular profiles of mRNA and identify cell populations causing the disease and their underlying mechanisms, including cell crosstalk. Herein, we introduce the main methods of RNA-seq and spatial transcriptomics analysis and highlight the latest advances in cardiovascular research. We conclude that single-cell RNA sequencing interprets disease progression in multiple dimensions, levels, perspectives, and dynamics by combining spatial and temporal characterization of the clinical phenome with multidisciplinary techniques such as spatial transcriptomics. This aligns with the dynamic evolution of CVDs (e.g., “angina–myocardial infarction–heart failure” in coronary artery disease). The study of pathways for disease onset and mechanisms (e.g., age, sex, comorbidities) in different patient subgroups should improve disease diagnosis and risk stratification. This can facilitate precise individualized treatment of CVDs.

Objective: Emerging evidence highlights the pivotal roles of long non-coding RNAs (lncRNAs) in lipid metabolism. Apoprotein C3 (ApoC3) is a well-established therapeutic target for hypertriglyceridemia and exhibits a strong association with cardiovascular disease. However, the exact mechanisms via which the lncRNAs control ApoC3 expression remain unclear. Methods: We identified a novel long noncoding RNA (lncRNA), GM47544, within the ApoA1/C3/A4/A5 gene cluster. Subsequently, the effect of GM47544 on intracellular triglyceride metabolism was analyzed. The diet-induced mouse models of hyperlipidemia and atherosclerosis were established to explore the effect of GM47544 on dyslipidemia and plaque formation in vivo. The molecular mechanism was explored through RNA sequencing, immunoprecipitation, RNA pull-down assay, and RNA immunoprecipitation. Results: GM47544 was overexpressed under high-fat stimulation. GM47544 effectively improved hepatic steatosis, reduced blood lipid levels, and alleviated atherosclerosis in vitro and in vivo. Mechanistically, GM47544 directly bound to ApoC3 and facilitated the ubiquitination at lysine 79 in ApoC3, thereby facilitating ApoC3 degradation via the ubiquitin-proteasome pathway. Moreover, we identified AP006216.5 as the human GM47544 transcript, which fulfills a comparable function in human hepatocytes. Conclusions: The identification of GM47544 as a lncRNA modulator of ApoC3 reveals a novel mechanism of post-translational modification, with significant clinical implications for the treatment of hypertriglyceridemia and atherosclerosis.

The synergistic integration of tourism, the economy, and the ecological environment within a region is crucial for promoting its sustainable development. Tourism acts as a catalyst for green economic growth, yet varying levels of tourism development can intensify the strain on the ecological environment. Thus, achieving a Pareto optimal balance among the benefits of these three entities holds significant theoretical and practical relevance. This research utilizes statistical data spanning from 2000 to 2021 to devise a tourism-economy-ecological environment (TEE) indicator system for Xinjiang. The study employs a coupled coordination model to analyze the spatial and temporal coupling dynamics between subsystems and to classify the types of coupled coordination. The analysis also identifies obstacles that impede the degree of coordination. The findings indicate that during the period under investigation, the TEE system in Xinjiang experienced consistent growth. However, the tourism subsystem exhibited disparate development and pronounced resource monopolization, which stimulated the economic subsystem’s growth, albeit with noticeable developmental lags in the latter stages. Spatially, economic performance demonstrated a declining trend from core urban centers like Urumqi City and Karamay City towards peripheral areas. From an ecological perspective, the distribution of resources exhibited a heterogeneous “M-V-W” pattern, characterized by significant disparities in the availability of natural resources and the occurrence of localized ecological deterioration. There is a notable and increasing degree of coupled coordination in regional synergistic development, which is primarily manifested in the delayed development of tourism. The combined development of the three subsystems is influenced by some factors, including environmental pollution, resources, economic quality, and industrial structure. Soot emissions, green space per capita in parks, and sulfur dioxide emissions are identified as key constraints. This study provides theoretical backing and empirical evidence for economic growth, the optimization of industrial structure, and the preservation of the ecological environment in arid and semi-arid regions globally.

Abstract Background Process-based teaching is a new education model. SPARK case database is a free medical imaging case database. This manuscript aimed to explore the application of the process-based teaching based on SPARK case database in the practice teaching of radiology in the musculoskeletal system. Methods 117 third year medical students were included. They were divided into Group A, B, C and D according to the curriculum arrangement. Group A and B attended the experimental class at the same time, A was the experimental group, B was the control group. Group C and D attended experimental classes at the same time, C was the experimental group, D was the control group. The experimental group used SPARK case database, while the control group used traditional teaching model for learning. The four groups of students were respectively tested after the theoretical class, before the experimental class, after the experimental class, and one week after the experimental class to compare the results. Finally, all students used SPARK case database to study, and were tested one month after the experimental class to compare their differences. Results The scores after the theoretical class of Group A and B were (100.0 ± 25.4), (101.0 ± 23.8)(t=-0.160, P > 0.05), Group C and D were (94.7 ± 23.7), (92.1 ± 18.6)(t = 0.467, P > 0.05). The scores of Group A and B before and after the experimental class and one week after the experimental class were respectively (84.1 ± 17.4), (72.1 ± 21.3)(t = 2.363, P 0.05), (89.7 ± 24.3), (66.6 ± 23.2)(t = 3.706, P 0.05), and Group C and D were (95.7 ± 20.3), (91.7 ± 23.0)(t = 0.699, P > 0.05). Conclusions The process-based teaching based on SPARK case database could improve the radiology practice ability of the musculoskeletal system of students.

Abstract Severe acute pancreatitis (SAP) begins with premature activation of enzymes, promoted by the immune system, triggering a potential systemic inflammatory response that leads to organ failure with increased mortality and a bleak prognosis. Interleukin-22 (IL-22) is a cytokine that may have a significant role in SAP. IL-22, a member of the IL-10 cytokine family, has garnered growing interest owing to its potential tissue-protective properties. Recently, emerging research has revealed its specific effects on pancreatic diseases, particularly SAP. This paper provides a review of the latest knowledge on the role of IL-22 and its viability as a therapeutic target in SAP.

Abstract Background Neoadjuvant therapy followed by surgery has become the standard of care for locally advanced esophageal squamous cell carcinoma (ESCC) and accurate pathological response assessment is critical to assess the therapeutic efficacy. However, it can be laborious and inconsistency between different observers may occur. Hence, we aim to develop an interpretable deep-learning model for efficient pathological response assessment following neoadjuvant therapy in ESCC. Methods This retrospective study analyzed 337 ESCC resection specimens from 2020–2021 at the Pudong-Branch (Cohort 1) and 114 from 2021–2022 at the Puxi-Branch (External Cohort 2) of Fudan University Shanghai Cancer Center. Whole slide images (WSIs) from these two cohorts were generated using different scanning machines to test the ability of the model in handling color variations. Four pathologists independently assessed the pathological response. The senior pathologists annotated tumor beds and residual tumor percentages on WSIs to determine consensus labels. Furthermore, 1850 image patches were randomly extracted from Cohort 1 WSIs and binarily classified for tumor viability. A deep-learning model employing knowledge distillation was developed to automatically classify positive patches for each WSI and estimate the viable residual tumor percentages. Spatial heatmaps were output for model explanations and visualizations. Results The approach achieved high concordance with pathologist consensus, with an R^2 of 0.8437, a RAcc_0.1 of 0.7586, a RAcc_0.3 of 0.9885, which were comparable to two senior pathologists (R^2 of 0.9202/0.9619, RAcc_0.1 of 8506/0.9425, RAcc_0.3 of 1.000/1.000) and surpassing two junior pathologists (R^2 of 0.5592/0.5474, RAcc_0.1 of 0.5287/0.5287, RAcc_0.3 of 0.9080/0.9310). Visualizations enabled the localization of residual viable tumor to augment microscopic assessment. Conclusion This work illustrates deep learning's potential for assisting pathological response assessment. Spatial heatmaps and patch examples provide intuitive explanations of model predictions, engendering clinical trust and adoption (Code and data will be available at https://github.com/WinnieLaugh/ESCC_Percentage once the paper has been conditionally accepted). Integrating interpretable computational pathology could help enhance the efficiency and consistency of tumor response assessment and empower precise oncology treatment decisions.

Abstract Background Isatropolone A and C, produced by Streptomyces sp. CPCC 204095, belong to an unusual class of non-benzenoid aromatic compounds and contain a rare seven-membered ring structure. Isatropolone A exhibits potent activity against Leishmania donovani, comparable to the only oral drug miltefosine. However, its variably low productivity represents a limitation for this lead compound in the future development of new anti-leishmaniasis drugs to meet unmet clinical needs. Results Here we first elucidated the regulatory cascade of biosynthesis of isatropolones, which consists of two SARP family regulators, IsaF and IsaJ. Through a series of in vivo and in vitro experiments, IsaF was identified as a pathway-specific activator that orchestrates the transcription of the gene cluster essential for isatropolone biosynthesis. Interestingly, IsaJ was found to only upregulate the expression of the cytochrome P450 monooxygenase IsaS, which is crucial for the yield and proportion of isatropolone A and C. Through targeted gene deletions of isaJ or isaS, we effectively impeded the conversion of isatropolone A to C. Concurrently, the facilitation of isaF overexpression governed by selected promoters, prompted the comprehensive activation of the production of isatropolone A. Furthermore, meticulous optimization of the fermentation parameters was conducted. These strategies culminated in the attainment of an unprecedented maximum yield—980.8 mg/L of isatropolone A—achieved in small-scale solid-state fermentation utilizing the genetically modified strains, thereby establishing the highest reported titer to date. Conclusion In Streptomyces sp. CPCC 204095, the production of isatropolone A and C is modulated by the SARP regulators IsaF and IsaJ. IsaF serves as a master pathway-specific regulator for the production of isatropolones. IsaJ, on the other hand, only dictates the transcription of IsaS, the enzyme responsible for the conversion of isatropolone A and C. By engineering the expression of these pivotal genes, we have devised a strategy for genetic modification aimed at the selective and high-yield biosynthesis of isatropolone A. This study not only unveils the unique regulatory mechanisms governing isatropolone biosynthesis for the first time, but also establishes an essential engineering framework for the targeted high-level production of isatropolone A.

To improve the accuracy of the risk evaluation results of hazardous chemical road transportation systems, an accident risk evaluation model based on the combined weight-cloud model is proposed to address the problems of ambiguity and randomness in the risk factors for hazardous chemical road transportation accidents. First, incorporating the risk factor identification results, the risk evaluation index system for hazardous chemical road transportation accidents is established. On the basis of determining the subjective and objective weights of the indices by using the analytic hierarchy process and entropy weight method, the comprehensive weights of the evaluation indices are calculated by the linear weighting method. Then, the weighting results are combined with the cloud model to calculate the risk level of the evaluation indices at all levels and to output the results in the form of a risk cloud diagram to visually determine the risk level of hazardous chemical road transportation. Finally, the model is applied to evaluate the accident risk in an example. The results demonstrate that the model is both practical and applicable in the evaluation of the risk of hazardous chemical road transportation accidents. The evaluation results can provide a valuable reference for hazardous chemical road transportation enterprises to prevent accidents.

ABSTRACT Malaria infection remains a serious threat to human health worldwide. Rapid and accurate detection technology is crucial for preventing malaria transmission and minimizing damage. We aimed to establish and validate a new rapid molecular detection method for malaria, called EasyNAT Malaria Assay, targeting Plasmodium vivax, Plasmodium falciparum, Plasmodium ovale, and Plasmodium malariae. The analytical performance of EasyNAT Malaria Assay was determined using positive materials. We identified 42 clinical samples as malaria positive and 95 negative samples. Each sample was examined by four methods: light microscopy, rapid diagnostic test, EasyNAT Malaria Assay, and digital PCR. Diagnostic accuracy and clinical performance were evaluated. The limit of detection (LOD)95% of EasyNAT Malaria was consistently 40 parasites/mL. It specifically amplified Plasmodium and performed with reliable repeatability and reproducibility. In 137 clinical samples, EasyNAT Malaria detected four more positive samples than microscopic examination and two more positive samples than rapid diagnostic test (RDT). One clinical sample was positive only under digital PCR. However, no significant differences statistically in sensitivity or specificity were observed. Compared with microscopy, the total, positive, and negative concordance rates of EasyNAT were 97.08%, 100%, and 95.79%, respectively. Enhanced diagnostic accuracy of EasyNAT Malaria in patients who had taken anti-malarial medication before their clinical appointment was observed. The EasyNAT Malaria Assay has good detection efficiency for clinical samples, presents a promising molecular detection tool in clinical practice, and is particularly suitable for rapid screening of high-risk populations in the emergency room.IMPORTANCEThis study established and validated EasyNAT Malaria Assay as a promising molecular detection tool for malaria screening of high-risk populations in clinical practice. This novel isothermal amplification method may effectively facilitate the rapid diagnosis of malaria and prevent its transmission.

Background: Neuromuscular blocking agents (NMBAs) are primarily used during surgical procedures to facilitate endotracheal intubation and optimize surgical conditions. This study aimed to explore the adverse event signals of NMBAs, providing reference for clinical safety.Methods: This study collected reports of atracurium, cisatracurium, rocuronium, and vecuronium as primary suspect drugs in The US Food and Drug Administration Adverse Event Reporting System (FAERS) from the first quarter of 2004 to the third quarter of 2023. The adverse events (AEs) reported in the study were retrieved based on the Preferred Terms (PTs) of the Medical Dictionary for Regulatory Activities. In addition, we conducted disproportionality analysis on relevant reports using the reporting odds ratio (ROR) method and Bayesian confidence propagation neural network (BCPNN) method. A positive signal was generated when both algorithms show an association between the target drug and the AE.Results: A total of 11,518 NMBA-related AEs were reported in the FAERS database. The most AEs of rocuronium were collected. NMBA-related AEs involved 27 different system organs (SOCs), all of the four NMBAs had positive signals in “cardiac disorders,” “immune system disorders,” “respiratory, thoracic and mediastinal disorders” and “vascular disorders.” At the PTs level, a total of 523 effective AEs signals were obtained for the four NMBAs. AEs labled in the instructions such as anaphylaxis (include anaphylactic reaction and anaphylactic shock), bronchospasm, respiratory arrest and hypotension were detected positive signals among all NMBAs. In addition, we also found some new AEs, such as ventricular fibrillation for the four NMBAs, hyperglycaemia for atracurium, kounis syndrome and stress cardiomyopathy for rocuronium, hepatocellular injury for cisatracurium, hyperkalaemia for vecuronium. To further investigated the AEs associated with serious clinical outcomes, we found that cardiac arrest and anaphylaxis were the important risk factors for death due to NMBAs.Conclusion: NMBA-related AEs have a significant potential to cause clinically severe consequences. Our study provides valuable references for the safety profile of NMBAs, and considering the limitations of the FAERS database, further clinical data are needed to validate the findings of this study.

Mathematical modeling plays an important role in improving students’ interests and attitudes in reasoning, communicating and solving problems. In order to understand modeling in the popular mathematics textbooks for primary schools in China, this study developed a modeling framework for K-12 mathematics textbooks, and used content analysis method to analyze China’s current textbooks of primary mathematics in grades 3 to 6. The results showed that the samples follow a gradual development principle in terms of “content level,”“appearing location,” and “representation mode,” but the scientificity of model content level needs to be enhanced. In the four stages of modeling, the contents for cultivating students’ high-order thinking ability need to be further enriched. It is also suggested that more mathematical background knowledge should be covered in future textbook compilations.

Abstract Background Fluvoxamine is one of the selective serotonin reuptake inhibitors (SSRIs) that are regarded as the first-line drugs to manage mental disorders. It has been also recognized with the potential to treat inflammatory diseases and viral infection. However, the effect of fluvoxamine on autoimmune diseases, particularly type 1 diabetes (T1D) and the related cellular and molecular mechanisms, are yet to be addressed. Method Herein in this report, we treated NOD mice with fluvoxamine for 2 weeks starting from 10-week of age to dissect the impact of fluvoxamine on the prevention of type 1 diabetes. We compared the differences of immune cells between 12-week-old control and fluvoxamine-treated mice by flow cytometry analysis. To study the mechanism involved, we extensively examined the characteristics of CD4+ T cells with fluvoxamine stimulation using RNA-seq analysis, real-time PCR, Western blot, and seahorse assay. Furthermore, we investigated the relevance of our data to human autoimmune diabetes. Result Fluvoxamine not only delayed T1D onset, but also decreased T1D incidence. Moreover, fluvoxamine-treated NOD mice showed significantly attenuated insulitis coupled with well-preserved β cell function, and decreased Th1 and Th17 cells in the peripheral blood, pancreatic lymph nodes (PLNs), and spleen. Mechanistic studies revealed that fluvoxamine downregulated glycolytic process by inhibiting phosphatidylinositol 3-kinase (PI3K)-AKT signaling, by which it restrained effector T (Teff) cell differentiation and production of proinflammatory cytokines. Conclusion Collectively, our study supports that fluvoxamine could be a viable therapeutic drug against autoimmunity in T1D setting.

Abstract Background Gastric cancer at different locations has distinct prognoses and biological behaviors, but the specific mechanism is unclear. Methods Non-targeted metabolomics was performed to examine the differential metabolite phenotypes that may be associated with the effects of tumor location on the prognosis of gastric cancer. And silencing of the rate-limiting enzyme to evaluate the effect of abnormal changes in metabolic pathway on the functional biological assays of gastric cancer cells HGC-27 and MKN28. Results In a retrospective study of 94 gastric cancer patients, the average survival time of patients with gastric cancer in the middle third of the stomach was significantly lower than that of patients with gastric cancer in other locations (p

The study aimed to prepare complex gels of sonicated quinoa protein (QP) and polysaccharides, comparing the effects of different protein components and pH on gel properties. FTIR analysis demonstrated that the β-structure in protein at pH 7.0 was enhanced by ultrasonic treatment, which could promote the formation of a gel network. Moreover, XG-AG (gel prepared by xanthan gum and albumin) and XG-GG (gel prepared by xanthan gum and globulin) exhibited higher levels of disulfide bonds and free sulfhydryl groups in the gel, requiring more energy to break the intermolecular sulfide bonds during heating. Under the same heating conditions, the rheological properties and gel strength of XG-UQPG (gel prepared by xanthan gum and ultrasonically treated QP) were superior to those of XG-UGG (gel prepared by xanthan gum and ultrasonically treated globulin) and XG-UAG (gel prepared by xanthan gum and ultrasonically treated albumin). Additionally, XG-UGG (pH 7.0) demonstrated the highest water holding capacity (WHC) and oil holding capacity (OHC). This was attributed to the disulfide bonds created in the proteins by the ultrasound treatment, encouraging them to interact to form more uniform holes in gel that can hold more water/oil molecules. Conversely, at pH 4.5, the WHCs of the gels were reduced due to the presence of rougher protein structures. These findings shed light on the impact of protein composition on gel properties and offer insights into enhancing the quality of quinoa protein gel.

Pressure swing adsorption (PSA) technology is among the most efficient techniques for purifying and separating hydrogen. A layered adsorption bed composed of activated carbon and zeolite 5A for a gas mixture (H2: 56.4 mol%, CH4: 26.6 mol%, CO: 8.4 mol%, N2: 5.5 mol%, CO2: 3.1 mol%) PSA model was built. The simulation model was validated using breakthrough curves. Then, a six-step PSA cycle model was built, and the purification performance was studied. The Box–Behnken design (BBD) method was utilized in Design Expert software (version 10) to optimize the PSA purification performance. The independent optimization parameters included the adsorption time, the pressure equalization time, and the feed flow rate. Quadratic regression models can be derived to represent the responses of purity and productivity. To explore a better optimization solution, a novel optimization method using machine learning with a back propagation neural network (BPNN) was then proposed, and a kind of heuristic algorithm–genetic algorithm (GA) was introduced to enhance the architecture of the BPNN. The predicted outputs of hydrogen production using two kinds of models based on the BPNN–GA and the BBD method integrated with the BPNN–GA (BBD–BPNN–GA). The findings revealed that the BBD–BPNN–GA model exhibited a mean square error (MSE) of 0.0005, with its R–value correlation coefficient being much closer to 1, while the BPNN–GA model exhibited an MSE of 0.0035. This suggests that the BBD–BPNN–GA model has a better performance, as evidenced by the lower MSE and higher correlation coefficient compared to the BPNN–GA model.

Abstract In the last few decades, sulfonated carbon materials have garnered significant attention as Brønsted solid acid catalysts. The sulfonation process and catalytic activity of sulfonated biochar can be influenced by the aromaticity and degree of condensation exhibited by biochar. However, the relationships between the aromaticity, sulfonating ability, and resultant catalytic activity are not fully understood. In this study, biochar samples pyrolyzed at 300–650 °C exhibiting different aromaticity and degrees of condensation were sulfonated and employed as sulfonate-bearing solid catalysts for hydrolytically removing tylosin. They exhibited excellent hydrolytic performance and their kinetic constants were positively correlated with the total acidity and negatively correlated with their aromaticity. This study has uncovered the relationship between the structure, properties, sulfonating ability, and subsequent hydrolytic performance of biochar samples. It was observed that the aromaticity of biochar decreased as the pyrolysis temperature increased. Lower pyrolysis temperatures resulted in a reduced degree of condensation, smaller ring size, and an increased number of ring edge sites available for sulfonation, ultimately leading to enhanced catalytic performance. These findings provide valuable insights into the fundamental chemistry behind sulfonation upgrading of biochar, with the aim of developing functional catalysts for mitigating antibiotics in contaminated water. Graphical Abstract

Abstract SUMOylation is an evolutionary conserved regulatory mechanism, in which Ubc9 is the only E2 conjugating enzyme. Previous studies demonstrated that SUMOylation is involved in multiple biological processes, but its role in dendritic cells (DCs) remains to be fully addressed. Herein in this report, we found that DCs deficient in Ubc9 protected mice from dextran sulfate sodium (DSS)-induced colitis, as evidenced by the ameliorated weight loss, colon length, and disrupted colon structure. Mechanistically, Ubc9 mediated SUMOylation of RBPJ, by which it stabilized RBPJ from ubiquitin-mediated degradation to enhance its transcriptional activity, while Ciita, a critical transcription factor, is a direct target downstream of RBPJ, which forms an enhanceosome complex to transcribe the expression of MHC II genes. Therefore, loss of Ubc9 abolished RBPJ SUMOylation, which was coupled with reduced Ciita transcription, thereby attenuating the expression of MHC class II genes. As a consequence of defective MHC II expression, Ubc9 -/- DCs were featured by the impaired capability to process antigen and to prime effector CD4+ T cells, thereby protecting mice from DSS-induced colitis. Together, our results shed novel insight into the understanding of SUMOylation in the regulation of DC functions in pathological conditions.

Abstract Previous studies have demonstrated the rejuvenating and restorative actions of mesenchymal stem cells (MSCs) in multiple diseases, but their role in reversing chronic atrophic gastritis (CAG) is not well understood owing to their low efficiency in homing to the stomach. In this work, we investigated the therapeutic effect of umbilical cord-derived MSCs (UC-MSCs) on CAG by endoscopic submucosal injection and preliminarily explored possible mechanisms in vitro. MSCs and normal saline (NS) were injected into the submucosa of the stomach in randomly grouped CAG rabbits. Therapeutic effects on serum indices and histopathology of the gastric mucosa were analyzed in vivo at 30 and 60 days after MSCs injection. GES-1 cells were co-cultured with MSCs in vitro using a Transwell system and cell viability, proliferation, and migration ability were detected. Additionally, in view of the potential mechanisms, the relative protein expression levels of apoptosis, autophagy and inflammation in vitro were explored by Western Blotting. We found that submucosal injection of MSCs up-regulated serum indices (G-17, PGI and PGI/PGII) and alleviated histopathological damage to the gastric mucosa in CAG rabbits. Co-culture of GES-1 cells with MSCs improved cell viability, proliferation, and migration ability, while suppressing apoptosis. We also observed a reduction in the expression of apoptosis indicators, including Bax and cleaved caspase-3, in GES-1 cells after co-culture with MSCs in vitro. Our findings suggest that submucosal injection of MSCs is a promising approach for reversing CAG, and attenuating apoptosis plays a potential role in this process.

Post-translational modifications (PTM) are covalent modifications of proteins or peptides caused by proteolytic cleavage or the attachment of moieties to one or more amino acids. PTMs play essential roles in biological function and regulation and have been linked with several diseases. Modifications of protein acylation (Kac), a type of PTM, are known to induce epigenetic regulatory processes that promote various diseases. Thus, an increasing number of studies focusing on acylation modifications are being undertaken. Butyrylation (Kbu) is a new acylation process found in animals and plants. Kbu has been recently linked to the onset and progression of several diseases, such as cancer, cardiovascular diseases, diabetes, and vascular dementia. Moreover, the mode of action of certain drugs used in the treatment of lymphoma and colon cancer is based on the regulation of butyrylation levels, suggesting that butyrylation may play a therapeutic role in these diseases. In addition, butyrylation is also commonly involved in rice gene expression and thus plays an important role in the growth, development, and metabolism of rice. The tools and analytical methods that could be utilized for the prediction and detection of lysine butyrylation have also been investigated. This study reviews the potential role of histone Kbu, as well as the mechanisms underlying this process. It also summarizes various enzymes and analytical methods associated with Kbu, with the goal of providing new insights into the role of Kbu in gene regulation and diseases.

ObjectiveTo evaluate mutagenic and teratogenic effects of lanthanum nitrate for providing evidence to safe use of the rare earth element. MethodsThe mutagenicity of lanthanum nitrate was evaluated by micronucleus assay on mouse bone marrow cells, in vitro chromosome aberration test, and Salmonella typhimurium strains bacterial reverse mutation test and the teratogenic effect of lanthanum nitrate was assessed with teratogenicity test in rats. The micronucleus assay on mouse bone marrow cells was performed in three groups of ICR mice (10 in each group, half male and half female) administrated with lanthanum nitrate at concentrations (mg/kg·BW) of 875, 437.5, 218.75 for the male mice and 1015, 507.5, 253.75 for the female mice according to the median lethal dose (LD50) of lanthanum nitrate for the mice. The chromosome aberration test of mammalian cells in vitro was conducted on Chinese hamster lung (CHL) cells (with good growth during logarithmic division and inoculated into 25 mL cell culture bottle, 1 × 106 cells per bottle) treated with lanthanum nitrate at concentrations of 1 × 10 – 3, 1 × 10 – 4, 1 × 10 – 5 mol (without S9 mixture) and 5 × 10 – 3, 2.5 × 10 – 4,1.25 × 10 – 5 mol (with S9 mixture) based on the median inhibition concentration (IC50) of lanthanum nitrate on CHL cells. Five lanthanum nitrate dose groups (5, 1, 0.2, 0.04, 0.008 mg/dish, respectively) were set up to carry out Salmonella typhimurium (TA97, TA98, TA100, TA102, TA1535) strains bacterial reverse mutation test in the presence or absence of S9 metabolic activation system. In teratogenicity test on pregnant Sprague-Dawley (SD) rats (at least 15 in each group), three lanthanum nitrate dosages of (9, 36, 144 mg/kg·BW) were determined and the growth and implantation ability and the offspring rats′ weight and length, rate of skeletal malformation, rate of organ malformation and total rate of viscera malformation were oberserved. ResultsIn micronucleus assay, the micronucleus formation rates of bone marrow cells in each lanthanum nitrate dose group were similar with that of vehicle control group (P > 0.05) . In vitro chromosome aberration test, the rate of cells with chromosome aberration in 1 × 10 – 5 M lanthanum nitrate group significantly increased in the absence of S9 compared to that of the control group (χ2 = 12.109, P < 0.01); however, the proportion of cells with chromosome aberration was less than 5%, indicating a biological insignificance; in the presence of S9, there was no significant difference in chromosome aberration the between each lanthanum nitrate dose group and the control group (all P > 0.05). The results of Salmonella typhimurium strains bacterial reverse mutation test showed that there were no significant differences in the mutagenicity among lanthanum nitrate dose groups and the control group in both the presence and absence of S9 mixture. The results of teratogenic test showed that there were no significant differences in the growth and the implantation ability of pregnant rats among all dose groups and the vehicle group; lanthanum nitrate at concentration of 144 mg/kg BW inhibited fetal body weight and length significantly (both P < 0.05) and increased skeletal malformation of fetal rat compared with those of the vehicle group (χ2 = 9.939, P < 0.05). However, there was no significant difference in organ-specific and total visceral malformation among the dose groups (P > 0.05 for all). ConclusionsThe mutagenic effect of lanthanum nitrate was not observed under the conditions of this study and the study resulted in a no observable adverse effect level (NOAEL) of 36 mg/kg BW for lanthanum nitrate (15.38 mg/kg BW in terms of lanthanum).

Papillary thyroid carcinoma (PTC) is the most common endocrine malignancy, and its incidence has increased rapidly in recent years. The BRAF inhibitor vemurafenib is effective against BRAFV600E-positive PTC; however, acquired resistance to single agent therapy frequently leads to tumor recurrence and metastasis, underscoring the need to develop tailored treatment strategies. We previously showed that the oncogenic kinase PIM1 was associated with the malignant phenotype and prognosis of PTC. In this study, we showed that sustained expression of the PIM1 protein in PTC was affected by the BRAFV600E mutation. Based on this regulatory mechanism, we tested the synergistic effects of inhibitors of BRAF (BRAFi) and PIM1 in BRAFV600E-positive PTC cell lines and xenograft tumors. LC-MS metabolomics analyses suggested that BRAFi/PIMi therapy acted by restricting the amounts of critical amino acids and nucleotides required by cancer cells as well as modulating DNA methylation. This study elucidates the role of BRAFV600E in the regulation of PIM1 in PTC and demonstrates the synergistic effect of a novel combination, BRAFi/PIMi, for the treatment of PTC. This discovery, along with the pathways that may be involved in the powerful efficacy of BRAFi/PIMi strategy from the perspective of cell metabolism, provides insight into the molecular basis of PTC progression and offers new perspectives for BRAF-resistant PTC treatment.

Background: There is no standard consensus on the optimal number of cycles of neoadjuvant immunotherapy prior to surgery for patients with locoregionally advanced non-small cell lung cancer (NSCLC). We carried out a systematic review to evaluate the efficacy and safety of neoadjuvant immunotherapy with different treatment cycles in order to provide valuable information for clinical decision-making. Methods: PubMed, Embase, the Cochrane Library and ClinicalTrials.gov were systematically searched before May 2023. The included studies were categorized based on different treatment cycles of neoadjuvant immunotherapy to assess their respective efficacy and safety in patients with resectable NSCLC. Results: Incorporating data from 29 studies with 1331 patients, we found major pathological response rates of 43 % (95%CI, 34–52 %) with two cycles and 33 % (95%CI, 22–45 %) with three cycles of neoadjuvant immunotherapy. Radiological response rates were 39 % (95%CI, 28–50 %) and 56 % (95%CI, 44–68 %) for two and three cycles, respectively, with higher incidence rates of severe adverse events (SAEs) in the three-cycle group (32 %; 95%CI, 21–50 %). Despite similar rates of R0 resection between two and three cycles, the latter showed a slightly higher surgical delay rate (1 % vs. 7 %). Neoadjuvant treatment modes significantly affected outcomes, with the combination of immunotherapy and chemotherapy demonstrating superiority in improving pathological and radiological response rates, while the incidence of SAEs in patients receiving combination therapy remained within an acceptable range (23 %; 95%CI, 15–35 %). However, regardless of the treatment mode administered, an increase in the number of treatment cycles did not result in substantial improvement in pathological response rates. Conclusion: There are clear advantages of combining immunotherapy and chemotherapy in neoadjuvant settings. Increasing the number of cycles of neoadjuvant immunotherapy from two to three primarily may not substantially improve the overall efficacy, while increasing the risk of adverse events. Further analysis of the outcomes of four cycles of neoadjuvant immunotherapy is necessary.

BackgroundVaccine effectiveness against SARS-CoV-2 infection has been somewhat limited due to the widespread dissemination of the Omicron variant, its subvariants, and the immune response dynamics of the naturally infected with the virus.MethodsTwelve subjects between 3-17 years old (yo), vaccinated with two doses of CoronaVac®, were followed and diagnosed as breakthrough cases starting 14 days after receiving the second dose. Total IgGs against different SARS-CoV-2 proteins and the neutralizing capacity of these antibodies after infection were measured in plasma. The activation of CD4+ and CD8+ T cells was evaluated in peripheral blood mononuclear cells stimulated with peptides derived from the proteins from the wild-type (WT) virus and Omicron subvariants by flow cytometry, as well as different cytokines secretion by a Multiplex assay.Results2 to 8 weeks post-infection, compared to 4 weeks after 2nd dose of vaccine, there was a 146.5-fold increase in neutralizing antibody titers against Omicron and a 38.7-fold increase against WT SARS-CoV-2. Subjects showed an increase in total IgG levels against the S1, N, M, and NSP8 proteins of the WT virus. Activated CD4+ T cells showed a significant increase in response to the BA.2 subvariant (p

Background: Pandy's test is used to assess the globulin level in cerebrospinal fluid (CSF). As a semi-quantitative manual method, the practicality and clinical value of Pandy's test has been challenged. Objective: We tend to summarize the relationship between CSF total protein (CSF-TP) quantification and Pandy's results, providing a formula to estimate Pandy's results merely by CSF-TP value. Methods: This retrospective study involved 1090 cases hospitalized in Huashan Hospital during 1/1/2023 to 20/4/2023. All samples were divided into six group based on their Pandy's results. Their corresponding CSF-TP quantitative results were subsequently analyzed and summarized. Another 364 patients were also gathered for verification. Results: The turbidity of samples won't affect examiners'ocular inspection and interpretation of Pandy's tests in positive groups. The results of Pandy's tests can be deduced based on CSF-TP quantitative results according to following rules: CSF-TP quantitative results 0–614 mg/L for Pandy negative (−), 615–1322 mg/L for extremely weak positive (±), 1323–2953 mg/L for weak positive (1+), 2954–6561 mg/L for medium positive results (2+), 6562–13007 mg/L for strong positive results (3+) and CSF-TP results >13007 for strongest positive (4+). The quantitative range above was experimentally verified as effective and correct by calculating the agreement rate through another 364 samples and the R ratio of each Pandy group was greater than 90 %. Conclusion: There is an excellent correlation between CSF-TP and Pandy's test. Therefore, CSF-TP quantification test through PROT Slides can be used to infer the results of Pandy's test to accelerate the abolish of this traditional manual test.

Chlorocholine chloride (CCC) is a plant growth regulator used worldwide that is detectable in cereals, fruits and animal products. The health effects of CCC exposure have raised public concern. Our previous research showed that CCC exposure decreased testosterone synthesis in pubertal rats. However, little is known about whether and how pubertal CCC exposure impacts spermatogenesis. In this study, we used BALB/c mice and spermatogonia-derived GC-1 cells to examine CCC-induced spermatogenic dysfunction. In vivo, pubertal CCC exposure led to decreased testicular weight, decreased testicular germ cells and poor sperm quality. This effect worsened after cessation of CCC exposure for the next 30 days. RNA-seq and western blot analysis revealed that CCC induced aryl hydrocarbon receptor (AhR) signaling, endoplasmic reticulum stress (ERS) and ferritinophagy. Increased iron content and lipid peroxidation levels were also observed in CCC-treated testes. In vitro, it was identified that iron overload mediated by enhanced ferritinophagy occurred in CCC-treated GC-1 cells, which might be attributed to the PERK pathway in ERS. Further, for the first time, our study elucidated the involvement of AhR in CCC-induced iron overload, which aggravated testicular oxidative damage via lipid peroxidation. Considering the adverse impact of CCC exposure on rodents, supportive evidence from GC-1 cells, and the critical importance of spermatogenesis on male development, the effects of CCC on the male reproduction warrant increased attention.

Microcystins (MCs) are the most widespread cyanobacterial toxins in eutrophic water body. As high toxic intermediate metabolites, linearized MCs are further catalyzed by linearized microcystinase (MlrB) of Sphingopyxis sp. USTB-05. Here MlrB structure was studied by comprizing with a model representative of the penicillin-recognizing enzyme family via homology modeling. The key active sites of MlrB were predicted by molecular docking, and further verified by site-directed mutagenesis. A comprehensive enzymatic mechanism for linearized MCs biodegradation by MlrB was proposed: S77 transferred a proton to H307 to promote a nucleophilic attack on the peptide bond (Ala-Leu in MC-LR or Ala-Arg in MC-RR) of linearized MCs to form the amide intermediate. Then water was involved to break the peptide bond and produced the tetrapeptide as product. Meanwhile, four amino acid residues (K80, Y171, N173 and D245) acted synergistically to stabilize the substrate and intermediate transition states. This study firstly revealed the enzymatic mechanism of MlrB for biodegrading linearized MCs with both computer simulation and experimental verification.

Abstract The regulation of autoimmunity against pancreatic islet β cells for type 1 diabetes (T1D) onset is still unclear. NOD/ShiLtJ (NOD) mice are prone to the onset of autoimmune diabetes, but its congenic strain, ALR/Lt (ALR), is not. Here we show that dendritic cells (DC) in ALR mice have impaired migratory and T-cell priming capability. Genomic comparative analysis maps a 33-bp deletion in the ALR Myosin IXb (Myo9b) gene when compared with NOD genome; meanwhile, data from knock-in models show that this ALR Myo9b allele impairs phenotypic and functional maturation of DCs, and prevents the development and progression of spontaneous autoimmune diabetes in NOD mice. In parallel, while the ALR 33-bp deletion of Myo9b is not conserved in human, we find a MYO9B R133Q polymorphism associating with increased risk of T1D and enhanced DC function in patients with T1D. Our results thus hint that alterations in Myo9b may contribute to altered DC function and autoimmune diabetes onset.