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Abstract Protein-bound uremic toxins (PBUTs) are the main cause of uremia, but traditional hemodialysis is ineffective in removing them because of their strong ability to bind to human serum albumin (HSA), highlighting the need for new treatments. In this study, first, structure-based docking was used to screen a diverse library of 200,376 virtual compounds against the active sites I and II. After two rounds of docking screening, 3944 candidate molecules were obtained. Second, 23 candidate molecules were obtained after ADMET prediction and toxicity analysis. Five candidate molecules were finally obtained after visual analysis and MM-PBSA calculations. We subsequently assessed their competitive displacement efficiency through a microdialysis experiment, and the results revealed that ZINC000008791789, ZINC000012297018, and ZINC000012296493 are promising binding competitors for PBUTs, as they have higher dialysis efficiency than the optimal displacer LA, approximately double the dialysis efficiency. The other two molecules, ZINC000031161007 and ZINC000004090361, although less efficient than LA, still outperformed the control group. Notably, four of them shared the same molecular scaffold, and three of them contained a flavonoid group. These findings provide a foundation for the development of more effective PBUT binding competitors, potentially benefiting uremia patients in the future.

Background: Pulmonary hypertension (PH) represents a progressive condition characterized by the remodeling of pulmonary arteries, ultimately culminating in right heart failure and increased mortality rates. Substantial evidence has elucidated the pivotal role of perivascular inflammatory factors and immune dysregulation in the pathogenesis of PH. Chemokines, a class of small secreted proteins, exert precise control over immune cell recruitment and functionality, particularly with respect to their migration to sites of inflammation. Consequently, chemokines emerge as critical drivers facilitating immune cell infiltration into the pulmonary tissue during inflammatory responses. This review comprehensively examines the significant contributions of CC chemokines in the maintenance of immune cell homeostasis and their pivotal role in regulating inflammatory responses. The central focus of this discussion is directed towards elucidating the precise immunoregulatory actions of CC chemokines concerning various immune cell types, including neutrophils, monocytes, macrophages, lymphocytes, dendritic cells, mast cells, eosinophils, and basophils, particularly in the context of pH processes. Furthermore, this paper delves into an exploration of the underlying pathogenic mechanisms that underpin the development of PH. Specifically, it investigates processes such as cellular pyroptosis, examines the intricate crosstalk between bone morphogenetic protein receptor type 2 (BMPR2) mutations and the immune response, and sheds light on key signaling pathways involved in the inflammatory response. These aspects are deemed critical in enhancing our understanding of the complex pathophysiology of PH. Moreover, this review provides a comprehensive synthesis of findings from experimental investigations targeting immune cells and CC chemokines. Aim of review: In summary, the inquiry into the inflammatory responses mediated by CC chemokines and their corresponding receptors, and their potential in modulating immune reactions, holds promise as a prospective avenue for addressing PH. The potential inhibition of CC chemokines and their receptors stands as a viable strategy to attenuate the inflammatory cascade and ameliorate the pathological manifestations of PH. Nonetheless, it is essential to acknowledge the current state of clinical trials and the ensuing progress, which regrettably appears to be less than encouraging. Substantial hurdles exist in the successful translation of research findings into clinical applications. The intention is that such emphasis could potentially foster the advancement of potent therapeutic agents presently in the process of clinical evaluation. This, in turn, may further bolster the potential for effective management of PH.

Void drift between subchannels in a rod bundle is a crucial phenomenon affecting the calculation accuracy of thermal-hydraulic parameters in SMRs. It holds significant importance in enhancing the precision of safety analysis for SMRs. Existing research on experiment and model of void drift between rod bundle subchannels is relatively rare, and the accuracy of model calculations requires improvement. In this study, experiments on gas-liquid two-phase non-equilibrium flow were conducted to measure the redistribution of two-phase flow induced by void drift in a 1 × 2 rod bundle. The experiment results indicated that in bubby flow regime with void fraction less than 0.3, the void diffusion coefficient showed little variation with changes in void fraction. However, in slug flow and annular flow regimes with void fraction exceeding 0.3, the void diffusion coefficient significantly increased with an increase in void fraction. Furthermore, a new void drift model was developed and validated based on a subchannel code. The overall predicted uncertainty for the outlet void fraction in the rod bundle benchmark was less than 13%.

Objective Admission hyperglycaemia is recognized as a contributor to poor outcomes in patients with cardiovascular and cerebrovascular diseases. This study aimed to evaluate the association between admission hyperglycaemia and in-hospital mortality in patients with hypertension and acute aortic dissection (AAD). Methods Patients diagnosed with hypertension and AAD between 1 January 2010 and 1 March 2023 were enrolled into this retrospective observational study, and divided into two groups based on admission blood glucose levels (BGA): normoglycemia (BGA 6.1 mmol/L. Stratified analysis and sensitivity analysis confirmed the robustness of this relationship. Conclusion Admission hyperglycaemia correlated with an elevated risk of in-hospital mortality in patients with hypertension and AAD, particularly BGA > 6.1 mmol/L, indicating that BGA level may be useful in identifying patients who are at an elevated risk of all-cause mortality.

Millet is one of the major coarse grain crops in China. Its geographical origin and Fusarium fungal contamination with ergosterol and deoxynivalenol have a direct impact on food quality, so the rapid prediction of the geographical origins and fungal toxin contamination is essential for protecting market fairness and consumer rights. In this study, 600 millet samples were collected from twelve production areas in China, and traditional algorithms such as random forest (RF) and support vector machine (SVM) were selected to compare with the deep learning models for the prediction of millet geographical origin and toxin content. This paper firstly develops a deep learning model (wavelet transformation-attention mechanism long short-term memory, WT-ALSTM) by combining hyperspectral imaging to achieve the best prediction effect, the wavelet transformation algorithm effectively eliminates noise in the spectral data, while the attention mechanism module improves the interpretability of the prediction model by selecting spectral feature bands. The integrated model (WT-ALSTM) based on selected feature bands achieves optimal prediction of millet origin, with its accuracy exceeding 99% on both the training and prediction datasets. Meanwhile, it achieves optimal prediction of ergosterol and deoxynivalenol content, with the coefficient of determination values exceeding 0.95 and residual predictive deviation values reaching 3.58 and 3.38 respectively, demonstrating excellent model performance. The above results suggest that the combination of hyperspectral imaging with a deep learning model has great potential for rapid quality assessment of millet. This study provides new technical references for developing portable and rapid hyperspectral imaging inspection technology for on-site assessment of agricultural product quality in the future.

Abstract Background Aldosterone plays important parts in development of cardio-metabolic diseases as end product of renin-angiotensin-aldosterone system. However, factors elevating circulating aldosterone are not clear, and lifestyle-related factors are suggested to be involved, whereas less studied. Therefore, we aimed to explore the association of lifestyle factors with plasma aldosterone concentration (PAC) in community population. Methods In this cross-sectional study, we recruited participants using multistage random sampling from Emin China in 2019, and collected data and fasting blood samples. The considered lifestyle factors included obesity parameters (neck circumference, abdominal circumference), alcohol consumption, blood pressure (BP), physical activity, sleep duration, sleep quality, mental state (depression and anxiety), fasting blood glucose (FBG), and lipid profiles (total cholesterol and triglyceride). PAC was measured using radioimmunoassay. We performed sex-stratified linear and logistic regressions to explore associated factors of PAC. Component analysis was further performed to identify the main factors affecting PAC. Results Twenty-seven thousand four hundred thirty-six participants with 47.1% men were included. Obesity parameters (neck circumference, abdominal circumference), glucose metabolism (FBG), psychological status (anxiety status in men and women, depression status in men), BP, liver function (in men), lipid metabolism (TC and TG in men), sleep parameters (sleep quality in women), and renal function (in women) are the main factors associated with elevated PAC. Conclusion lower physical activity, alcohol consumption, higher BP, fat accumulation, dyslipidemia, higher fasting blood glucose, and presence of depression and anxiety were the main factors associated with eleveated PAC.

Abstract. Chimeric antigen receptor T (CAR-T) cell therapy achieved advanced progress in the treatment of hematological tumors. However, the application of CAR-T cell therapy for solid tumors still faces many challenges. Competition with tumor cells for metabolic resources in an already nutrient-poor tumor microenvironment is a major contributing cause to CAR-T cell therapy’s low effectiveness. Abnormal metabolic processes are now acknowledged to shape the tumor microenvironment, which is characterized by increased interstitial fluid pressure, low pH level, hypoxia, accumulation of immunosuppressive metabolites, and mitochondrial dysfunction. These factors are important contributors to restriction of T cell proliferation, cytokine release, and suppression of tumor cell-killing ability. This review provides an overview of how different metabolites regulate T cell activity, analyzes the current dilemmas, and proposes key strategies to reestablish the CAR-T cell therapy’s effectiveness through targeting metabolism, with the aim of providing new strategies to surmount the obstacle in the way of solid tumor CAR-T cell treatment.

Urban Air Mobility (UAM) is poised to revolutionize transportation, necessitating an assessment of public acceptance before broad commercial adoption. This study presents the Urban Air Mobility Acceptance Model (UAM-AM), which draws from the Technology Acceptance Model (TAM) and underscores the crucial role of initial trust, technology belief and perceived risk. The UAM-AM is validated using Structural Equation Modeling (SEM) based on 544 questionnaires for the first time in China. The findings highlight the significant impact of perceived ease of use and perceived usefulness on acceptance, uncovering a complex interplay with the intention to utilize UAM services. Notably, initial trust emerges as a foundational factor, influencing attitudes directly or indirectly through perceived ease of use and perceived usefulness. Moreover, the research identifies technology belief and perceived risk as fundamental drivers of initial trust. Examination of demographic segments reveals a heightened technology belief among individuals with backgrounds in science, indicative of a more favorable attitude towards UAM adoption. In closing, the paper presents recommendations for policymakers, service providers, and eVTOL manufacturers to formulate effective strategies that promote public acceptance during the initial phases of UAM deployment.

ABSTRACTInfluenza D virus (IDV) plays an important role in the bovine respiratory disease (BRD) complex. Its potential for the zoonotic transmission is of particular concern. In China, IDV has previously been identified in agricultural animals by molecular surveys with no live virus isolates reported. In this study, live IDVs were successfully isolated from cattle in China, which prompted us to further investigate the national prevalence, antigenic property, and infection biology of the virus. IDV RNA was detected in 11.1% (51/460) of cattle throughout the country in 2022–2023. Moreover, we conducted the first IDV serosurveillance in China, revealing a high seroprevalence (91.4%, 393/430) of IDV in cattle during the 2022–2023 winter season. Notably, all the 16 provinces from which cattle originated possessed seropositive animals, and 3 of them displayed the 100% IDV-seropositivity rate. In contrast, a very low seroprevalence of IDV was observed in pigs (3%, 3/100) and goats (1%, 1/100) during the same period of investigation. Furthermore, besides D/Yama2019 lineage-like IDVs, we discovered the D/660 lineage-like IDV in Chinese cattle, which has not been detected to date in Asia. Finally, the Chinese IDVs replicated robustly in diverse cell lines but less efficiently in the swine cell line. Considering the nationwide distribution, high seroprevalence, and appreciably genetic diversity, further studies are required to fully evaluate the risk of Chinese IDVs for both animal and human health in China, which can be evidently facilitated by IDV isolates reported in this study.

BackgroundThe stress hyperglycemia ratio (SHR) has emerged as a potential prognostic indicator for various critical illnesses. However, its role in determining outcomes in patients with atrial fibrillation (AF) within the intensive care unit (ICU) remains unclear. This study aimed to elucidate the association between SHR and all-cause mortality in this clinical setting.MethodsWe conducted a retrospective cohort study utilizing data from a large, retrospective database. Critically ill patients with documented AF were stratified based on quartiles of SHR. The primary outcome was 365-day all-cause mortality, with secondary outcomes including 90-day and 28-day mortality. COX proportional hazards models adjusted for confounders and Kaplan-Meier curve analyses were used to explore the relationship between SHR and mortality.Results2,679 patients with critical AF were enrolled in the final study. Among the patients studied, those in the highest SHR quartiles exhibited an increased risk of 365-day all-cause mortality (HR:1.32, 95%CI=1.06-1.65). Notably, in subgroup analyses, the prognostic value of SHR was particularly pronounced in patients with hypertension. Sensitivity analyses confirmed the persistence of these findings after excluding cohorts with malignant tumors, and heart failure.ConclusionsOur research discerns a positive association between SHR and all-cause mortality in critically ill patients with AF, highlighting the significance of acute glycemic dysregulation on patient outcomes. Longer follow-up is still needed in the future to study the association between SHR and all-cause mortality in critically ill patients with AF.

ObjectiveTo evaluate and summarize the best evidence for nutritional support in patients receiving radiotherapy for nasopharyngeal carcinoma and to offer guidance for clinical practice.BackgroundPatients with nasopharyngeal carcinoma undergoing radiotherapy often experience a high prevalence of malnutrition, and there is a lack of compiled guideline recommendations, which complicates the provision of a reference for clinical nursing.MethodsA systematic literature search revealed the best evidence of nutritional support for nasopharyngeal carcinoma patients undergoing radiotherapy. Included in the review were various types of literature, such as clinical guidelines, expert consensus, systematic evaluations, meta-analyses, evidence summaries, and original studies. The evidence was graded according to the Australian Joanna Briggs Institute Centre for Evidence-Based Health Care Evidence Pre-Grading System (2016 version). Data were gathered from a range of sources, including BMJ Best Practice, the Scottish Intercollegiate Guidelines Network, the Cochrane Library, Embase, PubMed, Web of Science, CINAL, CNKI, the WanFang database, SinoMed, the Yi Maitong Guidelines Network, Dingxiangyuan, the Chinese Nutrition Society, the European Society for Clinical Nutrition and Metabolism website, and the American Society for Parenteral and Enteral Nutrition website. The search spanned from January 2013 to 2023.ResultsA comprehensive review identified a total of 3,207 articles, comprising six guidelines, eight expert consensus articles, four systematic evaluations, five randomized controlled trials, two cohort trials, and two observational studies. From these articles, we synthesized 63 pieces of evidence spanning six domains: nutritional risk screening and assessment, nutrient requirements, nutritional support, management of nutritional symptoms, functional exercise, and nutritional monitoring and follow-up.ConclusionA total of lines of evidence supporting nutritional support for nasopharyngeal carcinoma patients receiving radiotherapy were summarized. However, the evidence should be combined with the actual clinical situation, and it should be validated in the future by combining large-sample and multicenter studies to provide a more scientific and beneficial nutritional support program for nasopharyngeal carcinoma patients receiving radiotherapy.

BackgroundAlthough diabetic retinopathy (DR) is closely related to dietary patterns and oxidative stress, there is little research on the relationship between the compound dietary antioxidant index (CDAI) and DR. This study aims to fill this gap by analyzing data from the National Health and Nutrition Examination Survey (NHANES) to explore the association between CDAI and DR in patients with type 2 diabetes, in order to provide a basis for dietary guidance to prevent DR.MethodsData for this study was obtained from NHANES conducted between 1999 and 2020. Information regarding dietary intake was collected through 24 h dietary recall interviews. Multivariate logistic regression analyses and restricted cubic splines (RCS) were employed to explore the association between CDAI and DR. Furthermore, subgroup analyses were conducted to further examine the relationship.ResultsIn this study, a total of 2,158 participants were included, with a mean age of 58.87 years. After adjusting for all potential confounding factors, multivariate logistic regression analyses consistently demonstrated a negative correlation between CDAI and DR (OR = 0.94, 95%CI: 0.90–0.98, p = 0.007). Specifically, individuals in the highest quartile of CDAI had a significantly reduced risk of DR compared to those in the lowest quartile (OR = 0.51, 95%CI: 0.34–0.75, p

Abstract Background According to the studies, more than 80% of pediatric patients with cancer can achieve a survival rate greater than 5 years; however, long‐term chemotherapy and/or radiation therapy may seriously affect their reproductive ability. Fertility preservation in adolescents with cancer in China was initiated late, and related research is lacking. Analyze data to understand the current situation and implement measures to improve current practices. Methods From 2011 to 2020, data on 275 male adolescents with cancer whose age ranged from 0 to 19 years old were collected from 16 human sperm banks for this retrospective study. Methods include comparing the basic situation of male adolescents with cancer, the distribution of cancer types, and semen quality to analyze the status of fertility preservation. Results The mean age was 17.39 ± 1.46 years, with 13 cases (4.7%) aged 13–14 years and 262 cases (95.3%) aged 15–19 years. Basic diagnoses included leukemia (55 patients), lymphomas (76), germ cell and gonadal tumors (65), epithelial tumors (37), soft tissue sarcomas (14), osteosarcoma (7), brain tumors (5), and other cancers (16). There are differences in tumor types in different age stages and regions. The tumor type often affects semen quality, while age affects semen volume. Significant differences were found in sperm concentration and progressive motility before and after treatment (p

BackgroundIncreased levels of serum Klotho have been associated with a reduced risk of several cardiovascular diseases (CVD). However, limited studies exist on the association between serum Klotho and mortality in patients with CVD.MethodsWe collected data from CVD patients in the National Health and Nutrition Examination Survey (NHANES) spanning 2007 to 2016. We linked NHANES data with the National Death Index to determine the survival status of participants. Univariate and multivariable Cox regression models were used to investigate the relationship between serum Klotho levels and mortality in CVD patients. The relationship between serum Klotho quartiles and mortality in CVD patients was visualized using Kaplan-Meier (KM) curves and restricted cubic spine. Finally, subgroup analyses were used to examine the association between serum Klotho and all-cause mortality in different populations.Results1905 patients with CVD were finally enrolled in our study with a mean follow-up of 7.1 years. The average age of the participants was 63.4 years, with 58.40% being male. KM showed that lower Klotho levels were associated with lower survival rates. After adjusting for potential confounders, patients with higher serum Klotho levels had lower all-cause mortality (Q1: 1.00, Q2: 0.58 (0.42–0.80), Q3: 0.69 (0.47–1.01), and Q4:0.64 (0.45–0.92). However, the relationship between serum Klotho levels and cardiovascular mortality was not statistically significant. Dose-response analysis shows a U-shaped relationship between serum Klotho levels and all-cause mortality in patients with CVD (P nonlinear=0.002). Subgroup analysis indicated that participants with a history of hypertension had a higher risk of all-cause mortality in serum Klotho Q4 compared to Q1 (P trend

Metal ions play an essential role in regulating the functions of immune cells by transmitting intracellular and extracellular signals in tumor microenvironment (TME). Among these immune cells, we focused on the impact of metal ions on T cells because they can recognize and kill cancer cells and play an important role in immune-based cancer treatment. Metal ions are often used in nanomedicines for tumor immunotherapy. In this review, we discuss seven metal ions related to anti-tumor immunity, elucidate their roles in immunotherapy, and provide novel insights into tumor immunotherapy and clinical applications.

This study investigates the effect of tectochrysin, a flavonoid found in plants and fruits in ovarian cancer. We employed in vitro assays to assess the impact of tectochrysin in ovarian cancer cells. The study evaluated cell viability, colony and spheroid formation, cell invasion, migration and protein levels of CDK1 and Cyclin B1. Tectochrysin inhibited cell viability in ovarian cancer cell lines while showing lower toxicity towards normal ovarian cells. It reduced colony, spheroid formation, invasion and migration and increased cisplatin sensitivity. In vivo, tectochrysin inhibited tumor growth and enhanced cisplatin sensitivity. The overexpression of CDK1 promoted ovarian cancer progression while tectochrysin inhibited this through CDK1/Cyclin B1. Tectochrysin demonstrates anti-cancer effects in ovarian cancer by selectively targeting cancer cells, enhancing cisplatin sensitivity via CDK1/Cyclin B1 pathway. These findings suggest that tectochrysin could be a synergistic agent for ovarian cancer treatment, meriting further clinical investigation.

Abstract Chronic obstructive pulmonary disease (COPD) is a heterogeneous lung disease and a major health burden worldwide. Extracellular vesicles (EVs) are nanosized vesicles which possess a lipid bilayer structure that are secreted by various cells. They contain a variety of bioactive substances, which can regulate various physiological and pathological processes and are closely related to the development of diseases. Recently, EVs have emerged as a novel tool for intercellular crosstalk, which plays an essential role in COPD development. This paper reviews the role of EVs in the development of COPD and their potential clinical value, in order to provide a reference for further research on COPD.

Abstract Background MRI-based tumor shrinkage patterns (TSP) after neoadjuvant therapy (NAT) have been associated with pathological response. However, the understanding of TSP after early NAT remains limited. We aimed to analyze the relationship between TSP after early NAT and pathological response after therapy in different molecular subtypes. Methods We prospectively enrolled participants with invasive ductal breast cancers who received NAT and performed pretreatment DCE-MRI from September 2020 to August 2022. Early-stage MRIs were performed after the first (1st-MRI) and/or second (2nd-MRI) cycle of NAT. Tumor shrinkage patterns were categorized into four groups: concentric shrinkage, diffuse decrease (DD), decrease of intensity only (DIO), and stable disease (SD). Logistic regression analysis was performed to identify independent variables associated with pathologic complete response (pCR), and stratified analysis according to tumor hormone receptor (HR)/human epidermal growth factor receptor 2 (HER2) disease subtype. Results 344 participants (mean age: 50 years, 113/345 [33%] pCR) with 345 tumors (1 bilateral) had evaluable 1st-MRI or 2nd-MRI to comprise the primary analysis cohort, of which 244 participants with 245 tumors had evaluable 1st-MRI (82/245 [33%] pCR) and 206 participants with 207 tumors had evaluable 2nd-MRI (69/207 [33%] pCR) to comprise the 1st- and 2nd-timepoint subgroup analysis cohorts, respectively. In the primary analysis, multivariate analysis showed that early DD pattern (OR = 12.08; 95% CI 3.34–43.75; p

Abstract Background This study aimed to explore the knowledge, attitude, and practice (KAP) toward exercise therapy of patients with major depressive disorder (MDD). Methods This cross-sectional study was conducted at the First Hospital of Shanxi Medical University between April and October 2023 in patients with MDD. A self-designed questionnaire was used to evaluate the KAP (Cronbach’s α = 0.787). The minimum-maximum scores were 2–23 for knowledge, 11–55 for attitude, and 7–35 for practice. Results A total of 494 valid questionnaires were analyzed. The mean KAP dimension scores were 15.39 ± 3.34/23 (66.91%), 36.54 ± 19.33/55 (66.44%), and 19.33 ± 5.22/35 (55.23%), indicating poor knowledge, negative attitude, and weak practice. Multivariable logistic regression analysis showed that female (OR = 0.613, 95%CI: 0.376-1.000, P = 0.050), urban residence (OR = 0.443, 95%CI: 0.259–0.758, P = 0.003), suburban residence (OR = 0.047, 95%CI: 0.016–0.138, P

Abstract Objective We aimed to reveal the role of structural and functional alterations of cingulate gyrus in early cognitive impairment in Type 2 diabetes mellitus (T2DM) patients. Methods Fifty‐six T2DM patients and 60 healthy controls (HCs) underwent a neuropsychological assessment and sagittal three‐dimensional T1‐weighted and resting‐state functional MRI. Differences in the cortical thickness of the cingulate cortex and the functional connectivity (FC) of the nine subregions of the cingulate gyrus and the whole brain were compared between T2DM patients and HCs. Correlation analysis was performed between cortex thickness and FC and the participants' clinical/cognitive variables. Results The cortical thickness of the cingulate gyrus was not significantly different between T2DM patients and HCs. However, the T2DM patients showed significantly lower FC between the pregenual ACC (pACC) and the bilateral hippocampus, significantly higher FC between the pACC and bilateral lateral prefrontal cortex (LPFC) and left precentral gyrus, and significantly lower FC between the retrosplenial cortex (RSC) and right cerebellar Crus I. The FC between the pACC and the left hippocampus was negatively correlated with the FC between the pACC and LPFC (r = −0.306, p = 0.022). Interpretation The pACC and the RSC show dysfunctional connectivity before the appearance of structural abnormalities in T2DM patients. Abnormal FC of the pACC with the bilateral hippocampus and LPFC may imply a neural compensatory mechanism for memory function. These findings provide valuable information and new directions for possible interventions for the T2DM‐related cognitive impairment.

AbstractContext Paeoniflorin (PF) contributes to improving coronary artery disease (CAD).Objective This study clarified the efficiency of PF in CAD and the molecular mechanism.Materials and methods Human coronary artery endothelial cells (HCAECs) were treated with oxidized low-density lipoprotein (ox-LDL; 20, 40, 80 and 160 μg/mL) and PF (0.05, 0.1 0.2 and 0.4 mM). To study cell phenotypes, HCAECs were treated with 80 μg/mL ox-LDL with or without 0.1 mM PF for 24 h, and cell viability and apoptosis were evaluated using the methyl thiazolyl tetrazolium (MTT) assay and flow cytometry, respectively. In addition, inflammatory cytokines levels were measured by enzyme-linked immunosorbent assay (ELISA). Western blot evaluated the Wnt/β-catenin pathway-related factors.Results ox-LDL and PF (0.2 and 0.4 mM) suppressed cell viability in a dose-dependent manner. The IC50 value of PF was 722.9 nM. PF facilitated cell viability (115.76%), inhibited apoptosis (46.28%), reduced IL-6 (63.43%) and IL-8 (66.70%) levels and increased IL-10 levels (181.15%) of ox-LDL-treated HCAECs. Additionally, PF inactivated the Wnt/β-catenin pathway, and XAV939 treatment further promoted cell viability (120.54%), suppressed apoptosis (56.92%), reduced the levels of IL-6 (76.16%) and IL-8 (86.82%) and increased the IL-10 levels (120.22%) of ox-LDL-induced HCAECs after PF treatment. Moreover, PF alleviated plaque lesions of the aorta and aorta root and serum lipid of ApoE−/− mice with a high-fat diet.Discussion and conclusions This study first revealed that PF inhibited ox-LDL-induced HCAECs apoptosis and inflammation via the Wnt/β-catenin pathway and alleviated CAD, suggesting the potential of PF as a drug for CAD treatment.

ObjectiveThe coronavirus disease 2019 (COVID-19) spread rapidly and claimed millions of lives worldwide. Acute respiratory distress syndrome (ARDS) is the major cause of COVID-19-associated deaths. Due to the limitations of current drugs, developing effective therapeutic options that can be used rapidly and safely in clinics for treating severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infections is necessary. This study aims to investigate the effects of two food-extracted immunomodulatory agents, ajoene-enriched garlic extract (AGE) and cruciferous vegetables-extracted sulforaphane (SFN), on anti-inflammatory and immune responses in a SARS-CoV-2 acute lung injury mouse model.MethodsIn this study, we established a mouse model to mimic the SARS-CoV-2 infection acute lung injury model via intratracheal injection of polyinosinic:polycytidylic acid (poly[I:C]) and SARS-CoV-2 recombinant spike protein (SP). After the different agents treatment, lung sections, bronchoalveolar lavage fluid (BALF) and fresh faeces were harvested. Then, H&E staining was used to examine symptoms of interstitial pneumonia. Flow cytometry was used to examine the change of immune cell populations. Multiplex cytokines assay was used to examine the inflammatory cytokines.16S rDNA high-throughput sequencing was used to examine the change of gut microbiome.ResultsOur results showed that AGE and SFN significantly suppressed the symptoms of interstitial pneumonia, effectively inhibited the production of inflammatory cytokines, decreased the percentage of inflammatory cell populations, and elevated T cell populations in the mouse model. Furthermore, we also observed that the gut microbiome of genus Paramuribaculum were enriched in the AGE-treated group.ConclusionHere, for the first time, we observed that these two novel, safe, and relatively inexpensive immunomodulatory agents exhibited the same effects on anti-inflammatory and immune responses as neutralizing monoclonal antibodies (mAbs) against interleukin 6 receptor (IL-6R), which have been suggested for treating COVID-19 patients. Our results revealed the therapeutic ability of these two immunomodulatory agents in a mouse model of SARS-CoV-2 acute lung injury by promoting anti-inflammatory and immune responses. These results suggest that AGE and SFN are promising candidates for the COVID-19 treatment.

Summary: Tumors are intricate and heterogeneous systems characterized by mosaic cancer cell populations with diverse expression profiles. Leveraging single-cell technologies, we employed the Scissor algorithm to delineate an epithelial subpopulation associated with the aggressive phenotype in esophageal squamous cell carcinoma (ESCC). This identified subpopulation exhibited elevated expression of genes involved in critical pathways, such as epithelial-mesenchymal transition and PI3K-Akt. Key signature genes within this subpopulation, namely CAV1, COL3A1, COL6A1, POSTN, and TAGLN, demonstrated significant upregulation concomitant with both tumorigenesis and tumor progression across independent single-cell datasets. Furthermore, we selected 1,450 expression quantitative trait loci of the top 62 signature genes of this cell subpopulation to investigate their potential in predicting ESCC risk. The results showed that the POSTN loci were predominantly associated with ESCC susceptibility. Through functional annotation and replication analyses, we identified that the rs1028728 in the POSTN promoter was significantly associated with increased ESCC risk in 7,049 ESCC cases and 8,063 controls (odds ratio = 1.29, 95% confidence interval: 1.18–1.42, p = 4.03 × 10−8). Subsequent biochemical experiments showed that the rs1028728[T] allele enhanced POSTN expression by affecting the binding of PRRX1 in the POSTN promoter. In summary, our meticulous single-cell analysis delineates an invasive epithelial subpopulation in ESCC, with POSTN emerging as an important marker for the aggressive phenotype. These findings offer more insights into potential strategies for the prevention and intervention of ESCC, enriching our understanding of this complex cancer landscape.

Abstract Background T cell factor‐1 (TCF‐1) + stem‐like tumor‐infiltrating lymphocytes (stem‐like TILs) are important memory cells in the tumor microenvironment. However, their relationship with clinicopathological features, CD8+ TIL densities, immune checkpoint inhibitors (ICs), and prognostic values remain unknown for lung adenocarcinomas (LUADs). In this study, we aimed to characterize TCF‐1+ TILs and their prognostic significance in patients with surgically resected LUADs. Methods Expression of TCF‐1, CD8, and ICs including programmed death‐1 (PD‐1), lymphocyte activating‐3 (LAG‐3), and T cell immunoglobulin and mucin‐domain containing‐3 (TIM‐3) in TILs were estimated using immunohistochemistry of resected LUADs. The association between TCF‐1 expressions and clinicopathological characteristics of patient prognoses were analyzed. Results Positive TCF‐1 expression significantly correlated with advanced pathological stage, tumor grade, CD8+ TILs density, TIM‐3 expression, LAG‐3 expression, and PD‐1 expression. TCF‐1 positivity was significantly associated with a better recurrence‐free survival (RFS), and overall survival (OS). Subgroup analysis revealed that the TCF‐1+/CD8+ group had the best RFS and OS, while the TCF‐1‐/CD8‐ group had the worst RFS and OS. Similarly, patients with TCF‐1 + PD‐1‐ had the best prognoses and patients with TCF‐1‐PD‐1+ had the worst prognoses. Conclusion TCF‐1 had relatively high positive expression and special clinicopathological features in patients with LUAD. TCF‐1+ TILs were related to CD8 density, TIM‐3 expression, LAG‐3 expression, and PD‐1 expression, and were associated with better prognoses in LUAD patients. A combination of TCF‐1 and CD8 densities or PD‐1 expression further stratified patients into different groups with distinct prognoses.

Abstract Cardiovascular diseases (CVDs) continue to exert a significant impact on global mortality rates, encompassing conditions like pulmonary arterial hypertension (PAH), atherosclerosis (AS), and myocardial infarction (MI). Oxidative stress (OS) plays a crucial role in the pathogenesis and advancement of CVDs, highlighting its significance as a contributing factor. Maintaining an equilibrium between reactive oxygen species (ROS) and antioxidant systems not only aids in mitigating oxidative stress but also confers protective benefits on cardiac health. Herbal monomers can inhibit OS in CVDs by activating multiple signaling pathways, such as increasing the activity of endogenous antioxidant systems and decreasing the level of ROS expression. Given the actions of herbal monomers to significantly protect the normal function of the heart and reduce the damage caused by OS to the organism. Hence, it is imperative to recognize the significance of herbal monomers as prospective therapeutic interventions for mitigating oxidative damage in CVDs. This paper aims to comprehensively review the origins and mechanisms underlying OS, elucidate the intricate association between CVDs and OS, and explore the therapeutic potential of antioxidant treatment utilizing herbal monomers. Furthermore, particular emphasis will be placed on examining the cardioprotective effects of herbal monomers by evaluating their impact on cardiac signaling pathways subsequent to treatment. Graphical Abstract

The biological mechanism of action of platelet-rich plasma (PRP) in the treatment of temporomandibular joint (TMJ) osteoarthritis remains unclear. This study explored the mechanisms underlying interleukin (IL)-1β-induced inflammation and investigated the effect of PRP on TMJ condylar chondrocytes. Primary chondrocytes were isolated from the TMJ condyle of 4-week-old rats, and differentially expressed genes among three treatment groups (phosphate-buffered saline [control], IL-1β, and IL-1β + PRP) were identified using RNA-seq and characterized using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes path-enrichment analyses. IL-1β caused inflammatory injury to chondrocytes by upregulating the TNF, NF-κB, and IL-17 signaling pathways and downregulating the MAPK and PI3K/Akt signaling pathways. PRP activated the MAPK and PI3K/Akt signaling pathways, exerting a protective effect on IL-1β-induced chondrocytes. PRP also activated the TNF and IL-17 signaling pathways, producing an inflammatory effect. Additionally, PRP increased the mRNA expression of the matrix catabolism-related genes Mmp3, Mmp9, and Mmp13; the proliferative markers Mki67 and PCNA; and the anti-apoptotic genes of the Bcl-2 family (Bcl2a1 and Bok), while reducing the expression of the pro-apoptotic genes Casp4 and Casp12. The findings suggest that the protective effect of PRP on IL-1β-induced chondrocyte injury is mainly achieved via MAPK-PI3K/Akt signaling, increasing cell proliferation and inhibiting cell apoptosis.

Animal experiments have played a significant role in advancing scientific knowledge and enhancing people's quality of life. In order to better understand the opinions and knowledge of veterinary students in the domain of laboratory animal welfare and to explore and advance the teaching methods used in animal ethics education, a questionnaire was designed and used to conduct a survey among undergraduate and postgraduate students majoring in veterinary medicine. The survey encompassed various topics, such as students' level of knowledge about animal welfare, their perspectives on laboratory animals, their proficiency with animal experiments, and their opinions on teaching methods and content. The respondents were a total of 150 undergraduate students and 148 graduate students. The survey results indicated that most students expressed a strong sense of responsibility for the safeguarding of the welfare of experimental animals. However, there were a few students who lacked compassion for animals. Additionally, there was a general lack of basic theoretical knowledge of animal ethics and an inadequate grasp of experimental techniques among current students. Furthermore, most of the participants expressed a strong sense of responsibility to advocate for animal welfare. Although a substantial number of students were unaware of the existence of agencies for the supervision of work involving laboratory animals, they supported teaching and supervision in the domain of animal welfare and were open to various teaching methods and topics of content. In conclusion, targeted training and education regarding laboratory animal welfare and ethics should be conducted in the future to address the specific needs of students. This study provides a foundation for future animal welfare education and will help to improve the professional skills and humanistic qualities of veterinary students.

ObjectiveThe purpose of this study is to examine the moderating role of self-efficacy among rural elderly individuals in northern Sichuan Province in the relationship between certain sociodemographic variables and nutritional literacy.MethodsConvenience sampling was used to select 264 elderly individuals aged 60 and above from rural communities in Cangxi County, Guangyuan City, Yilong County, Nanchong City, and Bazhou District, Bazhong City, Sichuan Province. A self-designed questionnaire, including sociodemographic variables, the General Self-Efficacy Scale (GSES), and the Nutrition Literacy Questionnaire for the Elderly (NLQ-E), was administered through face-to-face interviews using a paper-based version. The relationships between sociodemographic variables, self-efficacy, and nutritional literacy in the elderly were analyzed using SPSS 26.0 and the Process plugin to examine the relationships between variables and to test for moderation effects.Results(1) There were significant differences in nutrition literacy scores among elderly people of different ages, genders, marital statuses, educational levels, personal monthly living expenses, dental conditions, and number of chronic diseases (p

ABSTRACT Staphylococcus aureus is an important human pathogen that often leads to hospital-acquired and community-acquired infections. The appearance of methicillin-resistant S. aureus (MRSA) has made the treatment extremely challenging. There is an urgent need to develop new antimicrobial agents to combat MRSA infections. In this study, through high-throughput screening, we found that tafenoquine (TAF), an antimalarial agent, exhibited antimicrobial efficacy against MRSA and its highly resistant phenotypes of biofilm and persister cells. No resistant mutation emerged by consecutive sub-minimal inhibitory concentration of TAF induction. Mechanistic studies by fluorescent probes of SYTOX Green/DiSC3(5), molecular dynamic simulations, electron microscopy, and proteomic analysis revealed that TAF exerts antimicrobial activity mainly through selective bacterial cell membrane disruption. In addition, TAF exhibited an effective antimicrobial effect in a subcutaneous abscess model in vivo with a good toxicity profile. In conclusion, TAF may have the potential to be developed as a new antimicrobial agent to treat refractory MRSA infections.IMPORTANCEThis study represents the first investigation into the antimicrobial effect of TAF against S. aureus and its potential mechanisms. Our data highlighted the effects of TAF against MRSA planktonic cells, biofilms, and persister cells, which is conducive to broadening the application of TAF. Through mechanistic studies, we revealed that TAF targets bacterial cell membranes. In addition, the in vivo experiments in mice demonstrated the safety and antimicrobial efficacy of TAF, suggesting that TAF could be a potential antibacterial drug candidate for the treatment of infections caused by multiple drug-resistant S. aureus.

Abstract Stroke has caused tremendous social stress worldwide, yet despite decades of research and development of new stroke drugs, most have failed and rt-PA (Recombinant tissue plasminogen activator) is still the accepted treatment for ischemic stroke. the complexity of the stroke mechanism has led to unsatisfactory efficacy of most drugs in clinical trials, indicating that there are still many gaps in our understanding of stroke. Pyroptosis is a programmed cell death (PCD) with inflammatory properties and are thought to be closely associated with stroke. Pyroptosis is regulated by the GSDMD of the gasdermin family, which when cleaved by Caspase-1/Caspase-11 into N-GSDMD with pore-forming activity can bind to the plasma membrane to form small 10–20 nm pores, which would allow the release of inflammatory factors IL-18 and IL-1β before cell rupture, greatly exacerbating the inflammatory response. The pyroptosis occurs mainly in the border zone of cerebral infarction, and glial cells, neuronal cells and brain microvascular endothelial cells (BMECs) all undergo pyroptosis after stroke, which largely exacerbates the breakdown of the blood-brain barrier (BBB) and thus aggravates brain injury. Therefore, pyroptosis may be a good direction for the treatment of stroke. In this review, we focus on the latest mechanisms of action of pyroptosis and the process by which pyroptosis regulates stroke development. We also suggest potential therapeutic stroke drugs that target the pyroptosis pathway, providing additional therapeutic strategies for the clinical management of stroke. The role of pyroptosis after stroke. After stroke, microglia first rush to the damaged area and polarize into M1 and M2 types. Under the influence of various stimuli, microglia undergo pyroptosis, release pro-inflammatory factors, and are converted to the M1 type; astrocytes and neuronal cells also undergo pyroptosis under the stimulation of various pro-inflammatory factors, leading to astrocyte death due to increased osmotic pressure in the membrane, resulting in water absorption and swelling until rupture. BMECs, the main structural component of the BBB, also undergo pyroptosis when stimulated by pro-inflammatory factors released from microglia and astrocytes, leading to the destruction of the structural integrity of the BBB, ultimately causing more severe brain damage. In addition, GSDMD in neutrophils mainly mediate the release of NETs rather than pyroptosis, which also aggravates brain injury. IL-10=interleukin-10; TGF-β = transforming growth factor-β; IL-18=interleukin-18; IL-1β = interleukin-1β; TNF-α = tumor necrosis factor-α; iNOS=induced nitrogen monoxide synthase; MMPs=Matrix metalloproteinases; GSDMD = gasdermin D; BMECs=brain microvascular endothelial cells; BBB = blood-brain barrier.

Abstract Myeloid-derived suppressor cells (MDSCs) were found to gradually accumulate in the orthotopic esophageal cancer mouse model during tumor progression. Although the roles of MDSCs in promoting tumor growth and inhibiting immune response have been extensively explored, currently, there are still no effective means for targeting MDSCs clinically. The deficiency of specific markers of MDSCs was responsible for the limited strategy to eliminating in clinic. This study identified that GPR84 was exclusively overexpressed on MDSCs. It was further found that GPR84 was prominently expressed on MDSCs in clinical samples and tumor mouse models, which drives the immunosuppression on CD8+T cells by inhibiting PD-L1 degradation in lysosomes. Furthermore, G-CSF and GM-CSF were found to induce GPR84 expression through the STAT3/C/EBPβ signaling pathway. In addition, GPR84+MDSCs and PD-L1+MDSCs were highly accumulated in anti-PD-1 therapy-resistant patients with esophageal cancer, and high GPR84 signature risk was verified as a negative factor for the overall survival of patients with anti-PD-1 treatment. Finally, GPR84 antagonism combined with an anti-PD-1 antibody enhanced the antitumor responses. Therefore, targeting GPR84 enhanced anti-PD-1 efficacy in esophageal cancer and other malignant tumors. This combination therapy has the potential for tumor therapy in clinics.

Abstract Background There is a lack of consensus regarding the best treatment option, including physical exercise, available for temporomandibular degenerative joint disease (DJD) that affect the older patients. Herein, we aimed to study and compare the efficacy of a combined approach using injection and home physical exercise with physical therapy alone as well as explored an optimal treatment strategy for older patients with DJD. Methods We included 213 older patients with DJD treated at our medical centre from June 2020 to June 2021, 64 of whom were selected for analysis. Of these 64 patients, 32 received injections combined with home physical exercise, and the other 32 received physical therapy alone. Propensity score matching was used to ensure that the two groups did not differ significantly in categorical and continuous variables. Measurements included pain intensity, maximum mouth opening, joint crepitus, jaw functional limitation scale (JFLS) scores, treatment times, and treatment durations. Improvement in each measurement was compared between the two groups 2, 4, and 12 weeks after the treatment commenced, as were the final treatment times and durations. Results Pain intensity, maximum mouth opening, and JFLS scores in the two groups improved 2, 4, and 12 weeks after treatment (all p

Dye/salt separation has gained increasing attention in recent years, prompting the quest to find cost-effective and environmentally friendly raw materials for synthesizing high performance nanofiltration (NF) membrane for effective dye/salt separation. Herein, a high-performance loose-structured NF membrane was fabricated via a simple vacuum filtration method using a green nanomaterial, 2,2,6,6-tetramethylpiperidine-1-oxide radical (TEMPO)-oxidized cellulose nanofiber (TOCNF), by sequentially filtrating larger-sized and finer-sized TOCNFs on a microporous substrate, followed by crosslinking with trimesoyl chloride. The resulting TCM membrane possessed a separating layer composed entirely of pure TOCNF, eliminating the need for other polymer or nanomaterial additives. TCM membranes exhibit high performance and effective dye/salt selectivity. Scanning Electron Microscope (SEM) analysis shows that the TCM membrane with the Fine-TOCNF layer has a tight layered structure. Further characterizations via Fourier transform infrared spectroscopy (FTIR) and X-ray diffraction (XRD) confirmed the presence of functional groups and chemical bonds of the crosslinked membrane. Notably, the optimized TCM-5 membrane exhibits a rejection rate of over 99% for various dyes (Congo red and orange yellow) and 14.2% for NaCl, showcasing a potential candidate for efficient dye wastewater treatment.

The increasing use of underwater vehicles facilitates deep-sea exploration at a wide range of depths and spatial scales. In this paper, we make an initial attempt to develop online computing strategies to identify seafloor categories and predict biogeographic patterns with a deep learning-based architecture, DenseNet, integrated with joint morphological cues, with the expectation of potentially developing its embedded smart capacities. We utilized high-resolution multibeam bathymetric measurements derived from MBES and denoted a collection of joint morphological cues to help with semantic mapping and localization. We systematically strengthened dominant feature propagation and promoted feature reuse via DenseNet by applying the channel attention module and spatial pyramid pooling. From our experiment results, the seafloor classification accuracy reached up to 89.87%, 82.01%, and 73.52% on average in terms of PA, MPA, and MIoU metrics, achieving comparable performances with the state-of-the-art deep learning frameworks. We made a preliminary study on potential biogeographic distribution statistics, which allowed us to delicately distinguish the functionality of probable submarine benthic habitats. This study demonstrates the premise of using underwater vehicles through unbiased means or pre-programmed path planning to quantify and estimate seafloor categories and the exhibited fine-scale biogeographic patterns.

Abstract Pulmonary hypertension (PH) was a cardiovascular disease with high morbidity and mortality. PH was a chronic disease with complicated pathogenesis and uncontrollable factors. PH was divided into five groups according to its pathogenesis and clinical manifestations. Although the treatment and diagnosis of PH has made great progress in the past ten years. However, the diagnosis and prognosis of the PAH had a great contrast, which was not conducive to the diagnosis and treatment of PH. If not treated properly, it will lead to right ventricular failure or even death. Therefore, it was necessary to explore the pathogenesis of PH. The problem we urgently need to solve was to find and develop drugs for the treatment of PH. We reviewed the PH articles in the past 10 years or so as well as systematically summarized the recent advance. We summarized the latest research on the key regulatory factors (pyroptosis, apoptosis, necroptosis, ferroptosis, and endoplasmic reticulum stress) involved in PH. To provide theoretical basis and basis for finding new therapeutic targets and research directions of PH.

Abstract Background The objective of this paper is to explore the value of a delta-radiomic model of the axillary lymph node (ALN) using dynamic contrast-enhanced (DCE) MRI for early prediction of the axillary pathological complete response (pCR) of breast cancer patients after neoadjuvant chemotherapy (NAC). Methods A total of 120 patients with ALN-positive breast cancer who underwent breast MRI before and after the first cycle of NAC between October 2018 and May 2021 were prospectively included in this study. Patients were divided into a training (n = 84) and validation (n = 36) cohort based on the temporal order of their treatments. Radiomic features were extracted from the largest slice of targeted ALN on DCE-MRI at pretreatment and after one cycle of NAC, and their changes (delta-) were calculated and recorded. Logistic regression was then applied to build radiomic models using the pretreatment (pre-), first-cycle(1st-), and changes (delta-) radiomic features separately. A clinical model was also built and combined with the radiomic models. The models were evaluated by discrimination, calibration, and clinical application and compared using DeLong test. Results Among the three radiomic models, the ALN delta-radiomic model performed the best with AUCs of 0.851 (95% CI: 0.770–0.932) and 0.822 (95% CI: 0.685–0.958) in the training and validation cohorts, respectively. The clinical model yielded moderate AUCs of 0.742 (95% CI: 0.637–0.846) and 0.723 (95% CI: 0.550–0.896), respectively. After combining clinical features to the delta-radiomics model, the efficacy of the combined model (AUC = 0.932) in the training cohort was significantly higher than that of both the delta-radiomic model (Delong p = 0.017) and the clinical model (Delong p

ABSTRACTUnder the strategic background of regional coordinated development, the County to District can remove administrative barriers and reduce local protection. Based on the matching data of Chinese A-share listed companies from 2000 to 2018 and the County to District Reforms, this paper empirically explores the influence of County to District Reforms on earnings management. We find the County to District Reform can effectively reduce earnings management, especially in areas with high local protection. Further mechanism analysis shows the County to District Reforms reduce local protection by increasing credit availability for enterprises, and ultimately restrain earnings management. Additional analysis shows the County to District Reforms increase the bank loans of enterprises in areas with higher local protection. This paper deepens the understanding of the County to District Reforms and enriches the literature on how government actions can affect corporate governance.

Key points Benzoxaborole Compound Tavaborole was discovered against E. coli by using HTS. Tavaborole showed synergistic efficacy with aminoglycosides in vitro and in vivo. The main mechanism of synergy was promoting protein mistranslation mutually.

Key points Ceritinib showed fierce lethality to the planktonic and persistent S. aureus. Ceritinib were highly effective in MRSA biofilm eradication and inhibition. The bactericidal mechanisms of ceritinib were showed by membrane breaking and ROS activation.

Summary: This study identifies interleukin-6 (IL-6)-independent phosphorylation of STAT3 Y705 at the early stage of infection with several viruses, including influenza A virus (IAV). Such activation of STAT3 is dependent on the retinoic acid-induced gene I/mitochondrial antiviral-signaling protein/spleen tyrosine kinase (RIG-I/MAVS/Syk) axis and critical for antiviral immunity. We generate STAT3Y705F/+ knockin mice that display a remarkably suppressed antiviral response to IAV infection, as evidenced by impaired expression of several antiviral genes, severe lung tissue injury, and poor survival compared with wild-type animals. Mechanistically, STAT3 Y705 phosphorylation restrains IAV pathogenesis by repressing excessive production of interferons (IFNs). Blocking phosphorylation significantly augments the expression of type I and III IFNs, potentiating the virulence of IAV in mice. Importantly, knockout of IFNAR1 or IFNLR1 in STAT3Y705F/+ mice protects the animals from lung injury and reduces viral load. The results indicate that activation of STAT3 by Y705 phosphorylation is vital for establishment of effective antiviral immunity by suppressing excessive IFN signaling induced by viral infection.

ABSTRACT The increasing occurrence of extensively drug-resistant and pan-drug-resistant K. pneumoniae has posed a serious threat to global public health. Therefore, new antimicrobial strategies are urgently needed to combat these resistant K. pneumoniae-related infections. Drug repurposing and combination are two effective strategies to solve this problem. By a high-throughput screening assay of FDA-approved drugs, we found that the potential small molecule 9-aminoacridine (9-AA) could be used as an antimicrobial alone or synergistically with rifampin (RIF) against extensively/pan-drug-resistant K. pneumoniae. In addition, 9-AA could overcome the shortcomings of RIF by reducing the occurrence of resistance. Mechanistic studies revealed that 9-AA interacted with bacterial DNA and disrupted the proton motive force in K. pneumoniae. Through liposomeization and combination with RIF, the cytotoxicity of 9-AA was significantly reduced without affecting its antimicrobial activity. In addition, we demonstrated the in vivo antimicrobial activity of 9-AA combined with RIF without detectable toxicity. In summary, 9-AA has the potential to be an antimicrobial agent or a RIF adjuvant for the treatment of multidrug-resistant K. pneumoniae infections. IMPORTANCE Klebsiella pneumoniae is a leading cause of clinically acquired infections. The increasing occurrence of drug-resistant K. pneumoniae has posed a serious threat to global public health. We found that the potential small molecule 9-AA could be used as an antimicrobial alone or synergistically with RIF against drug-resistant K. pneumoniae in vitro and with low resistance occurrence. The combination of 9-AA or 9-AA liposomes with RIF possesses effective antimicrobial activity in vivo without detected toxicity. 9-AA exerted its antimicrobial activity by interacting with specific bacterial DNA and disrupting the proton motive force in K. pneumoniae. In summary, we found that 9-AA has the potential to be developed as a new antibacterial agent and adjuvant for RIF. Therefore, our study can reduce the risk of antimicrobial resistance and provide an option for the exploitation of new clinical drugs and a theoretical basis for the research on a new antimicrobial agent.

Mesenchymal stromal cells (MSCs) derived from human embryonic stem cells (hESCs) are a desirable cell source for cell therapy owing to their capacity to be produced stably and homogeneously in large quantities. However, a scalable culture system for hPSC-derived MSCs is urgently needed to meet the cell quantity and quality requirements of practical clinical applications. In this study, we developed a new microcarrier with hyaluronic acid (HA) as the core material, which allowed scalable serum-free suspension culture of hESC-derived MSCs (IMRCs). We used optimal microcarriers with a coating collagen concentration of 100 ​μg/mL or concave-structured surface (cHAMCs) for IMRC amplification in a stirred bioreactor, expanding IMRCs within six days with the highest yield of over one million cells per milliliter. In addition, the harvested cells exhibited high viability, immunomodulatory and regenerative therapeutic promise comparable to monolayer cultured MSCs while showing more increased secretion of extracellular matrix (ECM), particularly collagen-related proteins. In summary, we have established a scalable culture system for hESC-MSCs, providing novel approaches for future cell therapies.

The fouling of separation membranes has consistently been a primary factor contributing to the decline in membrane performance. Enhancing the surface hydrophilicity of the membrane proves to be an effective strategy in mitigating membrane fouling in water treatment processes. Zwitterionic polymers (containing an equimolar number of homogeneously distributed anionic and cationic groups on the polymer chains) have been used extensively as one of the best antifouling materials for surface modification. The conventional application of zwitterionic compounds as surface modifiers is intricate and inefficient, adding complexity and length to the membrane preparation process, particularly on an industrial scale. To overcome these limitations, zwitterionic polymer, directly used as a main material, is an effective method. In this work, a novel zwitterionic polymer (TB)—zwitterionic Tröger’s base (ZTB)—was synthesized by quaternizing Tröger’s base (TB) with 1,3-propane sultone. The obtained ZTB is blended with TB to fabricate microfiltration (MF) membranes via the vapor-induced phase separation (VIPS) process, offering a strategic solution for separating emulsified oily wastewater. Atomic force microscopy (AFM), scanning electron microscopy (SEM), water contact angle, and zeta potential measurements were employed to characterize the surface of ZTB/TB blended membranes, assessing surface morphology, charge, and hydrophilic/hydrophobic properties. The impact of varying ZTB levels on membrane surface morphology, hydrophilicity, water flux, and rejection were investigated. The results showed that an increase in ZTB content improved hydrophilicity and surface roughness, consequently enhancing water permeability. Due to the attraction of water vapor, the enrichment of zwitterionic segments was enriched, and a stable hydration layer was formed on the membrane surface. The hydration layer formed by zwitterions endowed the membrane with good antifouling properties. The proposed mechanism elucidates the membrane’s proficiency in demulsification and the reduction in irreversible fouling through the synergistic regulation of surface charge and hydrophilicity, facilitated by electrostatic repulsion and the formation of a hydration layer. The ZTB/TB blended membranes demonstrated superior efficiency in oil–water separation, achieving a maximum flux of 1897.63 LMH bar−1 and an oil rejection rate as high as 99% in the oil–water emulsion separation process. This study reveals the migration behavior of the zwitterionic polymer in the membrane during the VIPS process. It enhances our comprehension of the antifouling mechanism of zwitterionic membranes and provides guidance for designing novel materials for antifouling membranes.

【Objective】The study was conducted to explore the effects of microplastics and polycyclic aromatic hydrocarbons(PAHs) on microbial community structure, biological functions and metabolic pathways in agricultural soil so as to provide a theoretical basis for ecological risk assessment and remediation of combined microplastics-PAHs pollution.【Method】Polyvinyl chloride(PVC) and pyrene(PY) were selected as the representatives of microplastics and PAHs, respectively. The responses of abundance, composition and function of microbial communities in agricultural soil to the combined pollution of PVC-PY were studied by using metagenomic techniques and PICRUSt function prediction.【Result】Modifications of soil microbial community structure were found with the addition of PVC and PY. The relative abundance of Acidobacteria, Betaproteobacteria, Gemmatimonas, Nitrososphaera and Burkholderia were decreased in the presence of PVC-PY. Addition of PVC-PY improved the relative abundance of Sphingomonas, Nocardioides, Lysobacter, Marmoricola, Streptomyces, Mycobacterium, Sphingopyxis, Sphingobium, Novosphingobium and Luteimonas. According to the analysis of GO function, KEGG metabolic pathway and CAZy enzyme function, PVC-PY showed positive effects on the development, reproduction and self-regulation of soil microorganisms, and then accelerated the metabolic process of bacteria flora and the transport/excretion process of harmful products.【Conclusion】The addition of PVC-PY induced the changes in the structure and function of soil microbial communities, which increased their antioxidant capacity. Thus, the soil microbes had better adaptability to polluted environment.

There has been an explosion in the prevalence of methicillin-resistant Staphylococcus aureus (MRSA) because of the indiscriminate use of antibiotics. In this study, we repurposed hexestrol (HXS) as an antibacterial agent to fight planktonic and biofilm-related MRSA infections. HXS is a nonsteroidal synthetic estrogen that targets estrogen receptors (ERα and ERβ) and has been used as a hormonal antineoplastic agent. In our work, the minimum inhibitory concentrations (MICs) were determined using the antimicrobial susceptibility of MSSA and MRSA strains. Anti-biofilm activity was evaluated using biofilm inhibition and eradication assays. Biofilm-related genes were analyzed with or without HXS treatment using RTqPCR analysis of S. aureus. HXS was tested using the checkerboard dilution assay to identify antibiotics that may have synergistic effects. Measurement of ATP and detection of ATPase allowed the determination of bacterial energy metabolism. As shown in the results, HXS showed effective antimicrobial activity against S. aureus, including both type strains and clinical isolations, with MICs of 16 µg/mL. Sub-HXS strongly inhibited the adhesion of S. aureus. The content of extracellular polymeric substances (EPS) and the relative transcription levels of eno, sacC, clfA, pls and fnbpB were reduced after HXS treatment. HXS showed antibacterial effects against S. aureus and synergistic activity with aminoglycosides by directly interfering with cellular energy metabolism. HXS inhibits adhesion and biofilm formation and eradicates biofilms formed by MRSA by reducing the expression of related genes. Furthermore, HXS increases the susceptibility of aminoglycosides against MRSA. In conclusion, HXS is a repurposed drug that may be a promising therapeutic option for MRSA infection.

Abstract Background Spindle and kinetochore‑associated complex subunit 3 (SKA3) has recently been considered a key regulator of carcinogenesis. However, the connection between SKA3 and immune cell infiltration remains unknown. Methods The current study investigated the expression mode, prognostic effect, and functional role of SKA3 in different tumors, particularly bladder cancer using numerous databases, comprising TIMER, GEPIA, HPA, UALCAN, PrognoScan, and Kaplan–Meier Plotter. Differentially expressed gene and enrichment analyses were implemented on SKA3 using R packages "edgR" and "clusterProfiler". Immunohistochemistry was further used to validate the expression of SKA3 gene in bladder cancer. Following that, the relevance of SKA3 expression to immune infiltration level in bladder cancer was evaluated using TIMER. Results Overall, the level of SKA3 expression in tumor tissue significantly increased than in normal tissue. In bladder cancer and other tumors, patients with high SKA3 expression levels had worse overall survival (OS) (p = 0.016), disease-specific survival (DSS) (p = 0.00004), and disease-free survival (DFS) (p = 0.032). Additionally, the major molecular functions for SKA3 included nuclear division, mitotic nuclear division, mitotic sister chromatid segregation, humoral immune response, and cell chemotaxis. Additionally, SKA3 expression was found to be positively associated with enhanced M2 macrophage and T helper (Th) 2 cell infiltration in bladder cancer. Conclusions Our study implies that SKA3 contributes to M2 macrophage and Th2 cell polarization by acting as an oncogene in bladder cancer. SKA3 might be a novel biomarker for evaluating prognosis and immune infiltration in bladder cancer.

Abstract Background Epitranscriptomics studies have contributed greatly to the development of research on human cancers. In recent years, N6-methyladenosine (m6A), an RNA modification on the N-6 position of adenosine, has been found to play a potential role in epigenetic regulation. Therefore, we aimed to evaluate the regulation of cancer progression properties by m6A. Results We found that m6A demethylase fat mass and obesity-associated protein (FTO) was highly expressed in esophageal cancer (EC) stem-like cells, and that its level was also substantially increased in EC tissues, which was closely correlated with a poor prognosis in EC patients. FTO knockdown significantly inhibited the proliferation, invasion, stemness, and tumorigenicity of EC cells, whereas FTO overexpression promoted these characteristics. Furthermore, integrated transcriptome and meRIP-seq analyses revealed that HSD17B11 may be a target gene regulated by FTO. Moreover, FTO promoted the formation of lipid droplets in EC cells by enhancing HSD17B11 expression. Furthermore, depleting YTHDF1 increased the protein level of HSD17B11. Conclusions These data indicate that FTO may rely on the reading protein YTHDF1 to affect the translation pathway of the HSD17B11 gene to regulate the formation of lipid droplets in EC cells, thereby promoting the development of EC. The understanding of the role of epitranscriptomics in the development of EC will lay a theoretical foundation for seeking new anticancer therapies.

The plerocercoid of Spirometra mansoni can parasitize both human and animals, resulting in sparganosis. Lactate dehydrogenase (LDH) is an important enzyme in parasites. However, our knowledge of the LDH family in S. mansoni is still inadequate. This work identified 19 new LDH members in S. mansoni. Clustering analysis demonstrated that all SmLDHs were divided into two main groups, which is consistent with the patterns of conserved motif organization. According to RT-qPCR, 2 LDHs were highly expressed in the plerocercoid stage and 17 LDHs were highly expressed in the adult stage. The evolutionary tree showed a high level of diversity of both cestode and trematode LDHs. SmLDHs contained both conserved family members and members in the process of further diversification. rSmLDH has a NAD-binding domain and a substrate-binding domain. The protein was immunolocalized in the epidermis of the pleroceroid and in the tegument, uterus and egg shell of adult worms. The optimum activity for rSmLDH in the pyruvate reduction reaction was found to be pH 4.5 and 37 °C. In the oxidation reaction, optimal values for pH and temperature were 9.0 and 30 °C, respectively. Gossypol was found to be the most powerful inhibitor in both reduction and oxidation reactions. The results provide a basis for the further study of the biological roles of LDHs in S. mansoni and other LDH-containing taxa.

Abstract Background Sleep disordered breathing (SDB) plays a significant role in both sleep quality and cognition and whether it has an impact on the relationship between above two factors remains to be clear. The study aimed to explore the association between sleep quality and cognitive performance in general population by considering influence of sleep disordered breathing (SDB). Methods In this cross-sectional study, we enrolled subjects aged ≥ 18 years using a multi-stage random sampling method. Cognitive status was assessed using Mini Mental State Examination (MMSE) questionnaire, sleep quality using Pittsburgh Sleep Quality Index (PSQI) and SDB was assessed using No-SAS scale, respectively. Multi-variable logistic regression was applied to examine the association of sleep quality and cognitive performance. Subgroup analyses were performed in different age groups, and in those with and without SDB. Results Finally, 30,872 participants aged 47.5 ± 13.8 years with 53.5% women were enrolled, of whom 32.4% had poor sleep quality and 18.6% had low cognitive performance. Compared with good sleepers, subjects with poor sleep quality exhibited significantly higher presence of low cognitive performance (23.7% vs 16.2%, P