Search

Background: Osteoarthritis (OA) presents a formidable challenge, characterized by as-yet-unclear mechanical intricacies within cartilage and the dysregulation of bone homeostasis. Our preliminary data revealed the encouraging potential of a Sargassum polysaccharide (SP), in promoting chondrogenesis. The aim of our study is to comprehensively assess the therapeutic effects of SP on OA models and further elucidate its potential mechanism. Methods: The protective effects of SP were initially evaluated in an inflammation-induced human chondrocyte (C28) cell model. CCK-8 assays, Alcian blue staining, RT-qPCR and Western blotting were used to verify the chondrogenesis of SP in vitro. To assess the efficacy of SP in vivo, surgically induced medial meniscus destabilization (DMM) OA rats underwent an 8-week SP treatment. The therapeutic effects of SP in OA rats were comprehensively evaluated using X-ray imaging, micro-computed tomography (μ-CT), histopathological analysis, as well as immunohistochemical and immunofluorescent staining. Following these assessments, we delved into the potential signaling pathways of SP in inflammatory chondrocytes utilizing RNA-seq analysis. Validation of these findings was conducted through RT-qPCR and western blotting techniques. Results: SP significantly enhance the viability of C28 chondrocytes, and increased the secretion of acidic glycoproteins. Moreover, SP stimulated the expression of chondrogenic genes (Aggrecan, Sox9, Col2a1) and facilitated the synthesis of Collagen II protein in C28 inflammatory chondrocytes. In vivo experiments revealed that SP markedly ameliorated knee joint stenosis, alleviated bone and cartilage injuries, and reduced the histopathological scores in the OA rats. μ-CT analysis confirmed that SP lessened bone impairments in the medial femoral condyle and the subchondral bone of the tibial plateau, significantly improving the microarchitectural parameters of the subchondral bone. Histopathological analyses indicated that SP notably enhanced cartilage quality on the surface of the tibial plateau, leading to increased cartilage thickness and area. Immunohistochemistry staining and immunofluorescence staining corroborated these findings by showing a significant promotion of Collagen II expression in OA joints treated with SP. RNA-seq analysis suggest that SP's effects were mediated through the regulation of the ITGβ1-PI3K-AKT signaling axis, thereby stimulating chondrogenesis. Verification through RT-qPCR and Western blot analyses confirmed that SP significantly upregulated the expression of ITGβ1, p110δ, AKT1, ACAN, and Col2a1. Notably, knock-down of ITGβ1 using siRNA in C28 chondrocytes inhibited the expression of ITGβ1, p110δ, AKT1, and ACAN. However, these inhibitory effects were not completely reversed by supplemental SP intervention. Conclusions: In summary, our findings reveal that SP significantly enhances chondrogenesis both in vitro and in vivo, alleviating OA progression both in bone and cartilage. The observed beneficial effects are intricately linked to the activation of the ITGβ1-PI3K-AKT signaling axis. The translational potential of this article: Our research marks the first instance unveiling the advantageous effects and underlying mechanisms of SP in OA treatment. With its clinical prospects, SP presents compelling new evidence for the advancement of a next-generation polysaccharide drug for OA therapy.

With the development of nanomedicine, nanomaterials have been widely used, offering specific drug delivery to target sites, minimal side effects, and significant therapeutic effects. The kidneys have filtration and reabsorption functions, with various potential target cell types and a complex structural environment, making the strategies for kidney function protection and recovery after injury complex. This also lays the foundation for the application of nanomedicine in kidney diseases. Currently, evidence in preclinical and clinical settings supports the feasibility of targeted therapy for kidney diseases using drug delivery based on nanomaterials. The prerequisite for nanomedicine in treating kidney diseases is the use of carriers with good biocompatibility, including nanoparticles, hydrogels, liposomes, micelles, dendrimer polymers, adenoviruses, lysozymes, and elastin-like polypeptides. These carriers have precise renal uptake, longer half-life, and targeted organ distribution, protecting and improving the efficacy of the drugs they carry. Additionally, attention should also be paid to the toxicity and solubility of the carriers. While the carriers mentioned above have been used in preclinical studies for targeted therapy of kidney diseases both in vivo and in vitro, extensive clinical trials are still needed to ensure the short-term and long-term effects of nano drugs in the human body. This review will discuss the advantages and limitations of nanoscale drug carrier materials in treating kidney diseases, provide a more comprehensive catalog of nanocarrier materials, and offer prospects for their drug-loading efficacy and clinical applications.

Background:. Pancreatic fistula after distal pancreatectomy is a common and potentially lethal complication. The optimal closure method for the pancreatic remnant during minimally invasive distal pancreatectomy (MDP) remains unclear. Methods:. Data of consecutive patients who underwent MDP in our institution between July 2018 and June 2021 were collected. The outcomes of MDP with stapler and hand-sewn closure were compared. The primary outcome was clinically relevant postoperative pancreatic fistula (CR-POPF) per the International Study Group of Pancreatic Surgery definition. Results:. Of the 384 patients (stapler closure, 339; hand-sewn closure, 45) enrolled, 249 developed CR-POPF (grades B and C: 242 and 7 patients, respectively). The rates of grade B and grade C POPF in the stapler group were similar to the corresponding rates in the hand-sewn group (64.6% and 1.5% vs 51.1% and 4.4%, P = .078 and P = .223, respectively). No differences between the stapler and hand-sewn groups were observed regarding the median operation time (207 vs 222 minutes, P = .139), incidence of major complications (16.5% vs 20.0%, P = .559), and mortality (0.2% vs 0%, P = 1.000). The independent risk factors of CR-POPF were abdominal abscess, prolonged operation time, and transection site (P = .004, .006, and .001, respectively). Conclusion:. The incidence and severity of CR-POPF by stapler closure of the pancreatic stump were comparable to those associated with hand-sewn closure in MDP in this retrospective cohort. Randomized controlled trials are needed to verify this finding.

Abstract Background Omicron variants are currently the predominant circulating lineage worldwide and most cases are mild or asymptomatic. The Omicron variant is characterized by high transmissibility and immune evasion. Early identification of Omicron cases in clinical settings is crucial for controlling its spread. Previous studies have indicated that changes in hematological parameters can be used to predict the severity of coronavirus disease 2019 (COVID-19). However, the role of hematological parameters in non-severe and asymptomatic cases remains unknown. This study aimed to investigate the role of hematological parameters in non-severe and asymptomatic Omicron variant infections. Methods Hematological parameters and results were analyzed and compared in symptomatic (n = 356) and asymptomatic (n = 171) groups respectively, and between these two groups with positive COVID-19 tests. The utility of hematological parameters for predicting positive COVID-19 tests was analyzed using receiver operating characteristic curves. Results Individuals with non-severe cases exhibited decreased levels of platelets, lymphocytes, eosinophils, basophils, lymphocytes (%), eosinophils (%), and basophils (%), while exhibiting elevated counts of monocytes, neutrophils (%), monocytes (%), neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio (PLR), and C-reactive protein (CRP) when compared to suspected cases or asymptomatic carriers. In asymptomatic patients, positive carriers had lower leukocyte, neutrophil, and lymphocyte counts but higher monocyte, monocyte (%), PLR, and CRP levels than negative carriers. Basophil counts combined with lymphocytes or the PLR demonstrated a more significant predictive value in screening non-severe cases earlier compared to other parameters. The combined assessment of the monocyte (%) and the PLR had the highest area under the curve for diagnosing asymptomatic carriers. Conclusions Circulating basophils, alone or in combination with other hematological parameters, may be used as efficient biomarkers for early screening of non-severe Omicron cases.

Abstract Coupling the Si-based anodes with nickel-rich LiNixMnyCo1−x−yO2 cathodes (x ≥ 0.8) in the energy-dense cell prototype suffers from the mechanical instability of the Li-Si alloys, cathode collapse upon the high-voltage cycling, as well as the severe leakage current at elevated temperatures. More seriously, the cathode-to-anode cross-talk effect of transitional metal aggravates the depletion of the active Li reservoir. To reconcile the cation utilization degree, stress dissipation, and extreme temperature tolerance of the Si-based anode||NMC prototype, we propose a gel polymer electrolyte to reinforce the mechanical integrity of Si anode and chelate with the transitional cations towards the stabilized interfacial property. As coupling the conformal gel polymer electrolyte encapsulation with the spatial arranged Si anode and NMC811 cathode, the 2.7 Ah pouch-format cell could achieve the high energy density of 325.9 Wh kg−1 (based on the whole pouch cell), 88.7% capacity retention for 2000 cycles, self-extinguish property as well as a wide temperature tolerance. Therefore, this proposed polymerization strategy provides a leap toward the secured Li batteries.

Abstract Background the mortality associated with severe malaria due to Plasmodiun falciparum remains high despite improvements in malaria management. Case prensentation: this case series aims to describe the efficacy and safety of the exchange transfusion combined with artesunate (ET-AS) regimen in severe P. falciparum malaria. Eight patients diagnosed with severe P. falciparum malaria were included. All patients underwent ET using the COBE Spectra system. The aimed for a post-exchange hematocrit of 30%. Half the estimated blood volume was removed and replaced using fresh frozen plasma. The regimen was well-tolerated without complications. The parasite clearance time ranged from 1 ~ 5 days. Five patients with cerebral malaria exhibited full improved consciousness within 3 days, while patient2 with hemolysis improved on day 2. Liver function improved within 1 ~ 6 days, and patient 1 and patient 6 showed improvements renal function on days 18 and 19, respectively. The length of intensive care unit stay range from 2 ~ 10 days, and all patients treated with ET-AS remained in the hospital for 3 ~ 19 days. Conclusions: these preliminary results suggest that ET-AS regimens are a safe and effective therapy for severe P. falciparum malaria and can benefit patients in clinical settings.

Abstract To define the characteristics of fundus manifestations in patients after SARS-CoV-2 infection with multimodal imaging techniques. This is a retrospective multicenter and multimodal imaging study including 90 patients. All patients with a visual complaint occurring immediately after SARS-CoV-2 infection were referred to six clinics between December 2022 and February 2023. Demographic information and the temporal relationship between SARS-CoV-2 infection and visual symptoms were documented. The characteristics of the fundus lesions were evaluated using multimodal imaging. Ninety patients from six hospitals were included in this study, including 24 males (26.67%) and 66 (73.33%) females. Seventy-eight patients (86.66%) (146 eyes) were diagnosed with Acute Macular Neuroretinopathy (AMN). The AMN patients were primarily young women (67.95%). Sixty-eight patients (87.18%) had AMN in both eyes. Thirty-eight eyes (24.36%) included Purtscher or Purtscher-like lesions. optical coherence tomography and infrared retinal photographs can show AMN lesions well. Eleven cases were diagnosed with simple Purtscher or Purtscher-like retinopathy (2 cases, 2.22%), Vogt‒Koyanagi‒Harada (VKH) syndrome or VKH-like uveitis (3 cases, 3.33%), multiple evanescent white-dot syndrome (MEWDS) (2 cases, 2.22%), and rhino-orbital-cerebral mucormycosis (ROCM) (5 cases, 5.56%). After SARS-CoV-2 infection, diversified fundus lesions were evident in patients with visual complaints. In this report, AMN was the dominant manifestation, followed by Purtscher or Purtscher-like retinopathy, MEWDS, VKH-like uveitis, and ROCM.

Abstract Dilated cardiomyopathy (DCM) is a common cause of heart failure, thromboembolism, arrhythmias, and sudden cardiac death. The quality of life and long-term survival rates of patients with dilated DCM have greatly improved in recent decades. Nevertheless, the clinical prognosis for DCM patients remains unfavorable. The primary driving factors underlying the pathogenesis of DCM remain incompletely understood. The present study aimed to identify driving factors underlying the pathogenesis of DCM from the perspective of gene regulatory networks. Single-cell RNA sequencing data and bulk RNA data were obtained from the Gene Expression Omnibus (GEO) database. Differential gene analysis, single-cell genomics analysis, and functional enrichment analysis were conducted using R software. The construction of Gene Regulatory Networks was performed using Python. We used the pySCENIC method to analyze the single-cell data and identified 401 regulons. Through variance decomposition, we selected 19 regulons that showed significant responsiveness to DCM. Next, we employed the ssGSEA method to assess regulons in two bulk RNA datasets. Significant statistical differences were observed in 9 and 13 regulons in each dataset. By intersecting these differentiated regulons and identifying shared targets that appeared at least twice, we successfully pinpointed three differentially expressed targets across both datasets. In this study, we assessed and identified 19 gene regulatory networks that were responsive to the disease. Furthermore, we validated these networks using two bulk RNA datasets of DCM. The elucidation of dysregulated regulons and targets (CDKN1A, SAT1, ZFP36) enhances the molecular understanding of DCM, aiding in the development of tailored therapies for patients.

Abstract OPFRs are emerging environmental pollutants with reproductive and endocrine toxicity. This study aimed to examine the association between environmental exposure to OPFRs during early pregnancy and GDM. This nested case–control study was based on a birth cohort that was constructed at a maternal and child health hospital, including 74 cases of GDM among 512 pregnant women. The OPFRs, including TBP, TBEP, TCEP, TDCPP, TMCP, TOCP, and TPHP during 10–14 weeks of pregnancy were determined using GC–MS. The association between the OPFRs and GDM was assessed using WQS and BKMR models. The levels of OPFRs were significantly elevated in GDM patients (60) compared with the controls (90). The WQS analysis showed that mixtures of the OPFRs were significantly associated with GDM (OR 1.370, 95% CI 1.036–1.810, P = 0.027), and TBP, TPHP, and TMCP were the major contributors to the mixed exposure effect. In the BKMR model, individual exposure to TBP, TPHP, and TMCP, and the interaction of TMCP with TBP and TPHP were significantly associated with GDM. Environmental exposure to OPFRs is positively associated with GDM. These findings provide evidence for the adverse effects of OPFR exposure on the health of pregnant women.

Abstract Background Non-small cell lung cancer (NSCLC) is a prevalent and heterogeneous disease with significant genomic variations between the early and advanced stages. The identification of key genes and pathways driving NSCLC tumor progression is critical for improving the diagnosis and treatment outcomes of this disease. Methods In this study, we conducted single-cell transcriptome analysis on 93,406 cells from 22 NSCLC patients to characterize malignant NSCLC cancer cells. Utilizing cNMF, we classified these cells into distinct modules, thus identifying the diverse molecular profiles within NSCLC. Through pseudotime analysis, we delineated temporal gene expression changes during NSCLC evolution, thus demonstrating genes associated with disease progression. Using the XGBoost model, we assessed the significance of these genes in the pseudotime trajectory. Our findings were validated by using transcriptome sequencing data from The Cancer Genome Atlas (TCGA), supplemented via LASSO regression to refine the selection of characteristic genes. Subsequently, we established a risk score model based on these genes, thus providing a potential tool for cancer risk assessment and personalized treatment strategies. Results We used cNMF to classify malignant NSCLC cells into three functional modules, including the metabolic reprogramming module, cell cycle module, and cell stemness module, which can be used for the functional classification of malignant tumor cells in NSCLC. These findings also indicate that metabolism, the cell cycle, and tumor stemness play important driving roles in the malignant evolution of NSCLC. We integrated cNMF and XGBoost to select marker genes that are indicative of both early and advanced NSCLC stages. The expression of genes such as CHCHD2, GAPDH, and CD24 was strongly correlated with the malignant evolution of NSCLC at the single-cell data level. These genes have been validated via histological data. The risk score model that we established (represented by eight genes) was ultimately validated with GEO data. Conclusion In summary, our study contributes to the identification of temporal heterogeneous biomarkers in NSCLC, thus offering insights into disease progression mechanisms and potential therapeutic targets. The developed workflow demonstrates promise for future applications in clinical practice.

AIM: To investigate ocular surface disorders and tear function changes in patients with acne vulgaris and explore the potential relationship between acne vulgaris and dry eye. METHODS: This cross-sectional study included right eyes of 53 patients with acne vulgaris and 54 healthy controls. The participants completed the Ocular Surface Disease Index (OSDI) questionnaire. The following ocular surface-related parameters were measured: tear meniscus height (TMH), noninvasive tear breakup time (NIBUT), Schirmer I test (SIT), lipid layer thickness (LLT) score of the tear film, meibum score, meibomian gland orifice obstruction score, the ratio of meibomian gland loss, conjunctival hyperemia score, and corneal fluorescein staining (CFS) score. RESULTS: The stability of the tear film decreased in acne vulgaris patients. In the acne group, the TMH and NIBUT were lower, whereas the OSDI, meibum score, meibomian gland orifice obstruction score, ratio of meibomian gland loss, and conjunctival hyperemia score were higher compared with controls (P0.05). In two dry eye groups, the TMH, NIBUT, and LLT score were lower in the acne with dry eye (acne-DE) group, and the meibum score, meibomian gland orifice obstruction score, ratio of meibomian gland loss and conjunctival hyperemia score in the acne-DE group were higher (P0.05). CONCLUSION: Patients with moderate-to-severe acne vulgaris are more likely to experience dry eye than those without acne vulgaris. Reduced tear film stability and meibomian gland structure dysfunction are more pronounced in patients with moderate-to-severe acne and dry eye.

Abstract Background Breast cancer is a serious threat to women’s health with high morbidity and mortality. The development of more effective therapies for the treatment of breast cancer is strongly warranted. Growing evidence suggests that targeting glucose metabolism may be a promising cancer treatment strategy. We previously identified a new glyceraldehyde-3-phosphate dehydrogenase (GAPDH) inhibitor, DC-5163, which shows great potential in inhibiting tumor growth. Here, we evaluated the anticancer potential of DC-5163 in breast cancer cells. Methods The effects of DC-5163 on breast cancer cells were investigated in vitro and in vivo. Seahorse, glucose uptake, lactate production, and cellular ATP content assays were performed to examine the impact of DC-5163 on cellular glycolysis. Cell viability, colony-forming ability, cell cycle, and apoptosis were assessed by CCK8 assay, colony formation assay, flow cytometry, and immunoblotting respectively. The anticancer activity of DC-5163 in vivo was evaluated in a mouse breast cancer xenograft model. Results DC-5163 suppressed aerobic glycolysis and reduced energy supply of breast cancer cells, thereby inhibiting breast cancer cell growth, inducing cell cycle arrest in the G0/G1 phase, and increasing apoptosis. The therapeutic efficacy was assessed using a breast cancer xenograft mouse model. DC-5163 treatment markedly suppressed tumor growth in vivo without inducing evident systemic toxicity. Micro-PET/CT scans revealed a notable reduction in tumor 18F-FDG and 18F-FLT uptake in the DC-5163 treatment group compared to the DMSO control group. Conclusions Our results suggest that DC-5163 is a promising GAPDH inhibitor for suppressing breast cancer growth without obvious side effects. 18F-FDG and 18F-FLT PET/CT can noninvasively assess the levels of glycolysis and proliferation in tumors following treatment with DC-5163.

Abstract Background There is little literature on the use of temporary pacemakers in children with fulminant myocarditis. Therefore, we summarized the use of temporary cardiac pacemakers in children with fulminant myocarditis in our hospital. Methods The clinical data of children with fulminant myocarditis treated with temporary pacemakers in Wuhan Children’s Hospital from January 2017 to May 2022 were retrospectively analyzed. Results A total of 6 children were enrolled in the study, including 4 boys and 2 girls, with a median age of 50 months and a median weight of 15 kg. The average time from admission to pacemaker placement was 2.75 ± 0.4 h. The electrocardiogram showed that all 6 children had third-degree atrioventricular block (III°AVB). The initial pacing voltage, the sensory sensitivity of the ventricle and the pacing frequency were set to 5–10 mV, 5 V and 100–120 bpm respectively. The sinus rhythm was recovered in 5 patients within 61 h (17–134) h, and the median time of using temporary pacemaker was 132 h (63–445) h. One of the children had persistent III°AVB after the temporary pacemaker. With parental consent, the child was fitted with a permanent pacemaker on the 12th day of his illness. Conclusions When fulminant myocarditis leads to severe bradycardia or atrioventricular block in children, temporary pacemakers have the characteristics of high safety to improve the heart function.

Abstract Background CAR-T cell therapy represents a novel approach for the treatment of hematologic malignancies and solid tumors. However, its implementation is accompanied by the emergence of potentially life-threatening adverse events known as cytokine release syndrome (CRS). Given the escalating number of patients undergoing CAR-T therapy, there is an urgent need to develop predictive models for severe CRS occurrence to prevent it in advance. Currently, all existing models are based on decision trees whose accuracy is far from meeting our expectations, and there is a lack of deep learning models to predict the occurrence of severe CRS more accurately. Results We propose PrCRS, a deep learning prediction model based on U-net and Transformer. Given the limited data available for CAR-T patients, we employ transfer learning using data from COVID-19 patients. The comprehensive evaluation demonstrates the superiority of the PrCRS model over other state-of-the-art methods for predicting CRS occurrence. We propose six models to forecast the probability of severe CRS for patients with one, two, and three days in advance. Additionally, we present a strategy to convert the model's output into actual probabilities of severe CRS and provide corresponding predictions. Conclusions Based on our findings, PrCRS effectively predicts both the likelihood and timing of severe CRS in patients, thereby facilitating expedited and precise patient assessment, thus making a significant contribution to medical research. There is little research on applying deep learning algorithms to predict CRS, and our study fills this gap. This makes our research more novel and significant. Our code is publicly available at https://github.com/wzy38828201/PrCRS . The website of our prediction platform is: http://prediction.unicar-therapy.com/index-en.html .

Abstract Background To investigate the clinical effects of double-dose (4 mg) aflibercept treatment in neovascular age-related macular degeneration (nAMD), compared with the standard-dose (2 mg) treatment. Methods A total of 108 eyes from 97 patients with nAMD and received intravitreal aflibercept 2 mg and/or 4 mg treatment were retrospectively reviewed. The changes of central macular thickness (CMT)/ pigmental epithelium detachment height and the recurrence rate of exudation during the 12-month follow-up were compared between the 2 mg group and the 4 mg group. Self-control comparisons (2 mg switch to 4 mg) were also made between two regimens. Results Compared with the 2 mg group, tendencies of lower intraretinal fluid incidence and more CMT reduction were observed in the 4 mg group. The later one was also observed when eyes switching from 2 mg to 4 mg regimen. The median remission interval was 5 months in the 4 mg group, 2 months longer than the 3 months in the 2 mg group (P = 0.452). Injections needed in the 4 mg group were 3.644 ± 1.670, less than the 4.286 ± 2.334 injections in the 2 mg group within 12 months as well (P = 0.151). However, no associated vision benefits were gained from the double-douse regimen. No markedly increased-intraocular pressure events, or other adverse events were found in two groups. Conclusions Compared to the aflibercept 2 mg treatment in nAMD, tendencies of anatomic gains and relieving treatment burden were brought by the aflibercept 4 mg treatment. This study may have additional importance, given the further application of high-dose aflibercept in real-world settings.

Abstract The study of progressive failure of reservoir rocks is very important for the stability analysis of ultra-deep boreholes. The progressive failure can be characterized by the crack initiation stress (CI), crack damage stress (CD) and peak stress (Peak), which is controlled by the evolution of cracks in rock and is significantly affected by confining pressure. To explore the effect of high confining pressure and initial crack on the progressive failure, the initial crack density of 121 sedimentary rock samples was characterized by acoustic waves, and the progressive failure under different confining pressures was analyzed. Experiments show that the ratios of CI to Peak (CI/Peak) and CD to Peak (CD/Peak) increase significantly with confining pressure, which is agreement with the existing conclusion from low confining pressure (0–52 MPa), but those decrease for high confining pressure (68–85 MPa) above critical point of sandstone. The CI/Peak and CD/Peak decrease with increase of initial crack density, which is sensitive to confining pressure but independent of rock type and grain size. The CD of sandstone is pertinent to the friction coefficient of cracks. These results laid a foundation for analyzing the evolution mechanism of wellbore damage and predicting the timing of wellbore instability in ultra-deep wells.

Abstract Objective Diabetic patients are often comorbid with dyslipidemia, however, the relationship between high-density lipoprotein cholesterol(HDL-C) and diabetic retinopathy (DR) in the adult diabetic population remains to be fully elucidated.The aim of this study is to evaluate the associations between HDL-C and DR in the United States adults with diabetes. Methods A total of 1708 participants from the National Health and Nutrition Examination Survey (NHANES) 2005–2008 were enrolled in the present study. Fundus images of all study subjects were captured and evaluated using a digital camera and an ophthalmic digital imaging system, and the diagnosis of DR was made by the severity scale of the Early Treatment Diabetic Retinopathy Study (ETDRS).Roche Diagnostics were used to measure serum HDL-C concentration. The relationship of DR with HDL-C was investigated using multivariable logistic regression. The potential non-line correlation was explored with smooth curve fitting approach. Results The fully-adjusted model showed that HDL-C positively correlated with DR(OR:1.69, 95%CI: 1.25–2.31).However, an inverted U-shaped association between them was observed by applying the smooth curve fitted method. The inflection point of HDL-C(1.99mmol/l) was calculated by utilizing the two-piecewise logistic regression model. In the subgroup analysis, the inverted U-shaped nonlinear correlation between HDL-C and DR was also found in female, Non-Hispanic White, and lower age groups. Conclusion Our study revealed an inverted U-shaped positive relationship between HDL-C and DR.The findings may provide us with a more comprehensive understanding of the association between HDL-C and DR.

Abstract Background Body mass index (BMI) and lipid disorders are both known to be strongly associated with the development of diabetes, however, the indirect effect of lipid parameters in the BMI-related diabetes risk is currently unknown. This study aimed to investigate the mediating role of lipid parameters in the association of BMI with diabetes risk. Methods We assessed the association of diabetes risk with BMI, as well as lipid parameters including high-density lipoprotein cholesterol(HDL-C), low-density lipoprotein cholesterol(LDL-CF and LDL-CS), triglycerides(TG), total cholesterol(TC), remnant cholesterol(RC), non-HDL-C, and combined indices of lipid parameters with HDL-C (RC/HDL-C ratio, TG/HDL-C ratio, TC/HDL-C ratio, non-HDL/HDL-C ratio, LDL/HDL-C ratio) using data from 15,453 subjects in the NAGALA project. Mediation models were used to explore the mediating role of lipid parameters in the association of BMI with diabetes risk, and mediation percentages were calculated for quantifying the strength of the indirect effects. Finally, receiver operating characteristic curve (ROC) analysis was used to compare the accuracy of BMI and BMI combined with lipid parameters in predicting incident diabetes. Results Multivariate regression models, adjusted for confounding factors, demonstrated robust associations of lipid parameters, BMI, with diabetes risk, with the exception of TC, LDL-CF, LDL-CS, and non-HDL-C. Mediation analysis showed that lipid parameters except TC, LDL-CF, LDL-CS, and Non-HDL-C were involved in and mediated the association of BMI with diabetes risk, with the largest mediation percentage being the RC/HDL-C ratio, which was as high as 40%; it is worth mentioning that HDL-C and HDL-C-related lipid ratio parameters also play an important mediating role in the association between BMI and diabetes, with the mediator proportion being greater than 30%. Finally, based on the ROC results, we found that the prediction performance of all lipid parameters in the current study except TC was significantly improved when combined with BMI. Conclusion Our fresh findings suggested that lipid parameters partially mediated the association of BMI with diabetes risk; this result indicated that in the context of diabetes risk screening and disease management, it is important to not only monitor BMI but also pay attention to lipid parameters, particularly HDL-C and HDL-C-related lipid ratio parameters.

Abstract Cholesterol metabolism reprogramming is one of the significant characteristics of hepatocellular carcinoma (HCC). Cholesterol increases the risk of epithelial–mesenchymal transition (EMT) in cancer. Sterol O-acyltransferases 1 (SOAT1) maintains the cholesterol homeostasis. However, the exact mechanistic contribution of SOAT1 to EMT in HCC remains unclear. Here we demonstrated that SOAT1 positively related to poor prognosis of HCC, EMT markers and promoted cell migration and invasion in vitro, which was mediated by the increased cholesterol in plasmalemma and cholesterol esters accumulation. Furthermore, we reported that SOAT1 disrupted cholesterol metabolism homeostasis to accelerate tumorigenesis and development in HCC xenograft and NAFLD-HCC. Also, we detected that nootkatone, a sesquiterpene ketone, inhibited EMT by targeting SOAT1 in vitro and in vivo. Collectively, our finding indicated that SOAT1 promotes EMT and contributes to hepatocarcinogenesis by increasing cholesterol esterification, which is suppressed efficiently by nootkatone. This study demonstrated that SOAT1 is a potential biomarker and therapeutic target in NAFLD-HCC and SOAT1-targeting inhibitors are expected to be the potential new therapeutic treatment for HCC.

Abstract Ambient air temperature is a key factor affecting human health. Female reproductive disorders are representative health risk events under low temperature. However, the mechanism involving in cold-induced female reproductive disorders remains largely unknown. Female mice were intermittently exposed to cold conditions (4 °C) to address the health risk of low temperature on female reproductive system. Primary granulosa cells (GCs) were prepared and cultured under low temperature (35 °C) or exposed to β3-adrenoreceptor agonist, isoproterenol, to mimic the condition of cold exposure. Western-blot, RT-PCR, co-IP, ELISA, pharmacological inhibition or siRNA-mediated knockdown of target gene were performed to investigate the possible role of hormones, gap conjunction proteins, and ER stress sensor protein in regulating female reproductive disorders under cold exposure. Cold exposure induced estrous cycle disorder and follicular dysplasia in female mice, accompanying with abnormal upregulation of progesterone and its synthetic rate-limiting enzyme, StAR, in the ovarian granulosa cells. Under the same conditions, an increase in connexin 43 (CX43) expressions in the GCs was also observed, which contributed to elevated progesterone levels in the ovary. Moreover, ER stress sensor protein, PERK, was activated in the ovarian GCs after cold exposure, leading to the upregulation of downstream NRF2-dependent CX43 transcription and aberrant increase in progesterone synthesis. Most importantly, blocking PERK expression in vivo significantly inhibited NRF2/CX43/StAR/progesterone pathway activation in the ovary and efficiently rescued the prolongation of estrous cycle and the increase in follicular atresia of the female mice induced by cold stress. We have elucidated the mechanism of ovarian PERK/NRF2/CX43/StAR/progesterone pathway activation in mediating female reproductive disorder under cold exposure. Targeting PERK might be helpful for maintaining female reproductive health under cold conditions.

Abstract Background Cancer stem cells (CSCs) and long non-coding RNAs (lncRNAs) are known to play a crucial role in the growth, migration, recurrence, and drug resistance of tumor cells, particularly in triple-negative breast cancer (TNBC). This study aims to investigate stemness-related lncRNAs (SRlncRNAs) as potential prognostic indicators for TNBC patients. Methods Utilizing RNA sequencing data and corresponding clinical information from the TCGA database, and employing Weighted Gene Co-expression Network Analysis (WGCNA) on TNBC mRNAsi sourced from an online database, stemness-related genes (SRGs) and SRlncRNAs were identified. A prognostic model was developed using univariate Cox and LASSO-Cox analysis based on SRlncRNAs. The performance of the model was evaluated using Kaplan–Meier analysis, ROC curves, and ROC-AUC. Additionally, the study delved into the underlying signaling pathways and immune status associated with the divergent prognoses of TNBC patients. Results The research identified a signature of six SRlncRNAs (AC245100.6, LINC02511, AC092431.1, FRGCA, EMSLR, and MIR193BHG) for TNBC. Risk scores derived from this signature were found to correlate with the abundance of plasma cells. Furthermore, the nominated chemotherapy drugs for TNBC exhibited considerable variability between different risk score groups. RT-qPCR validation confirmed abnormal expression patterns of these SRlncRNAs in TNBC stem cells, affirming the potential of the SRlncRNAs signature as a prognostic biomarker. Conclusion The identified signature not only demonstrates predictive power in terms of patient outcomes but also provides insights into the underlying biology, signaling pathways, and immune status associated with TNBC prognosis. The findings suggest the possibility of guiding personalized treatments, including immune checkpoint gene therapy and chemotherapy strategies, based on the risk scores derived from the SRlncRNA signature. Overall, this research contributes valuable knowledge towards advancing precision medicine in the context of TNBC.

Abstract Background As an essential part of Early Essential Newborn Care, 90 minutes of mother-infant skin-to-skin contact is significant in improving maternal and infant outcomes. However, due to human resource constraints and the consideration of maternal and infant safety, it is difficult to achieve continuous uninterrupted skin-to-skin contact for at least 90 minutes during and after cesarean delivery. The aim of this study was to investigate the efficacy and safety of the continuous uninterrupted skin-to-skin contact for at least 90 minutes during and after cesarean section for exclusive breastfeeding rate during hospitalization and maternal and infant health indicators during and after cesarean delivery. Methods This is a single-center, prospective randomized controlled trial conducted in one tertiary care hospital in China. We selected 280 cases of elective cesarean delivery in a tertiary maternal and child specialty hospital in Zhejiang Province from September 2018 to August 2022, which were randomly divided into two groups: in the conventional group, doulas performed at least 30 minutes for early continuous SSC within 10–30 minutes during and after cesarean delivery. In the EENC group, with immediate continuous SSC within 5–10 minutes of neonatal delivery until surgery is completed and continued SSC after returning to the ward. Exclusive breastfeeding rate during hospitalization and maternal and infant health indicators were compared between the groups. Results A total of 258 cases were analyzed. Compared with the control group, the EENC group had earlier first breastfeeding initiation (13.7 ± 3.6 vs 62.8 ± 6.5 minutes, P

Helicoverpa zea is a major target pest of pyramided transgenic crops expressing Cry1, Cry2 and/or Vip3Aa proteins from Bacillus thuringiensis (Bt) in the United States. Laboratory-selected Cry1Ac/Cry2Ab cross resistance and field-evolved practical dual resistance of H. zea to these two toxins have been widely reported. Whether the widespread Cry1Ac/Cy2Ab dual resistance of H. zea has resulted from the selection of one shared or two independent resistance mechanisms by pyramided Bt crops remains unclear. Cadherin is a well-confirmed receptor of Cry1Ac and a suggested receptor of Cry2Ab in at least three Lepidopteran species. To test whether cadherin may serve as one shared mechanism for the cross and dual resistance of H. zea to Cry1Ac and Cry2Ab, we cloned H. zea cadherin (HzCadherin) cDNA and studied its functional roles in the mode of action of Cry1Ac and Cry2Ab by gain- and loss-of-function analyses. Heterologous expression of HzCadherin in H. zea midgut, H. zea fat body and Sf9 cells made all three of these cell lines more susceptible to activated Cry1Ac but not activated Cry2Ab, whereas silencing HzCadherin of H. zea midgut and fat body cells significantly reduced the susceptibility to Cry1Ac but not Cry2Ab. Likewise, suppressing HzCadherin with siRNA made H. zea larvae resistant to Cry1Ac. These results clearly demonstrate that HzCadherin is not a receptor for Cry2Ab, and thus it is unlikely to serve as one shared mechanism for the cross and dual resistance of H. zea to Cry1Ac and Cry2Ab.

AIM: To observe the effect of ghrelin, a growth hormone-releasing peptide, on retinal angiogenesis in vitro under high glucose (HG) stress and to explore the possible mechanism of autophagy. METHODS: Human retinal microvascular endothelial cells (HRMECs) were treated with high concentration of glucose alone or in combination with ghrelin. The cell migration, tube formation and the expression of the autophagy-related proteins LC3-II/I, Beclin-1, p62, phosphorylated AKT (p-AKT)/AKT and phosphorylated mammalian target of rapamycin (p-mTOR)/mTOR were detected. Then, to clarify the correlation between ghrelin effect and autophagy, AKT inhibitor VIII was adopted to treat HRMECs, and cell migration, tube formation as well as the protein expressions of LC3-II/I, Beclin-1 and p62 were observed. RESULTS: Under HG stress, ghrelin inhibited migration and tube formation of HRMECs. Ghrelin inhibited the increases in the protein levels of LC3-II/I, Beclin-1 and the decreases in the protein levels of p62, p-AKT/AKT and p-mTOR/mTOR induced by HG stress. Moreover, under the action of AKT/mTOR pathway inhibitors, the effects of ghrelin on migration and tube formation were both reduced. In addition, the expression of LC3-II/I and Beclin-1 were significantly up-regulated and the expression of p62 was down-regulated. CONCLUSION: Retinal angiogenesis under in vitro HG stress can be inhibited by ghrelin through activating AKT/mTOR pathway to inhibit autophagy.

SUMMARY: Study design: Systematic review Background: Proximal phalangeal fractures of the hand are challenging to treat, and significantly impact hand function and quality of life if poorly managed. Purpose: A systematic review to determine the efficacy of conservatively managed extra-articular proximal phalanx fractures to optimise recovery and prevent the need for surgical intervention and its associated risks. Methods: A literature search that included variations of the phrases ‘proximal phalanx’, ‘fracture’ and ‘conservative management’ was performed on 17 December 2023 using seven electronic databases and trial registries. Article screening, data extraction and critical appraisal using the Structured Effectiveness Quality Evaluation scale was performed independently. Results: Seven studies that captured 389 fractures from 356 unique patients were included. Studies were of level II to IV evidence and included one comparative cohort study and six prospective case series. Interventions involved timely rehabilitation, a plaster or orthotic device, controlled metacarpophalangeal joint flexion and free mobilisation of the interphalangeal joints. A weighted mean total active motion score of 249° was achieved, with 99.5% (387/389) of fractures achieving union. Conclusions: This systematic review cautions against definitive recommendations on conservative techniques for managing proximal phalanx fractures due to limitations of the available literature. However, our findings tentatively supports non-operative approaches as an alternative to surgery.

Balancing the hardness and electrical conductivity of copper alloys within complex compositions and processes poses a formidable challenge. This study proposes a strategy combining machine learning with the Pareto front techniques to identify optimal combinations of composition and processing for Cu-xTi (1.5 ≤ x ≤ 5.4, in wt.%) alloys. Through thermodynamic calculations, precipitation simulations, and experimental characterizations, the microstructural evolution of β'-Cu4Ti precipitates in the designed alloys was explored. The interpretability and predictability of the machine learning model played a crucial role in understanding impact of complex alloy compositions and processing on the evolution of properties, thereby guiding the design of Cu-Ti alloys towards improved attributes.

Discontinuity is critical for strength, deformability, and permeability of rock mass. Set information is one of the essential discontinuity characteristics and is usually accessed by orientation grouping. Traditional methods of identifying optimal discontinuity set numbers are usually achieved by clustering validity indexes, which mainly relies on the aggregation and dispersion of clusters and leads to the inaccuracy and instability of evaluation. This paper proposes a new method of Fisher mixed evaluation (FME) to identify optimal group numbers of rock mass discontinuity orientation. In FME, orientation distribution is regarded as the superposition of Fisher mixed distributions. Optimal grouping results are identified by considering the fitting accuracy of Fisher mixed distributions, the probability monopoly and central location significance of independent Fisher centers. A Halley-Expectation-Maximization (EM) algorithm is derived to achieve an automatic fitting of Fisher mixed distribution. Three real rock discontinuity models combined with three orientation clustering algorithms are adopted for discontinuity grouping. Four clustering validity indexes are used to automatically identify optimal group numbers for comparison. The results show that FME is more accurate and robust than the other clustering validity indexes in optimal discontinuity group number identification for different rock models and orientation clustering algorithms.

Extensive research has been conducted to investigate the impact of capsaicin (CAP) on lipid metabolism, focusing specifically on its interaction with the vanilloid subtype 1 (TRPV1) ion channel. Additionally, studies have illuminated the role of Akkermansia muciniphila (A. muciniphila), a specific strain of intestinal microbiota, in lipid metabolism. In this study, a model utilizing resiniferatoxin (RTX) was employed to deactivate TRPV1 ion channels in germ-free mice, followed by the administration of A. muciniphila via gavage. Following the collection of intestinal tissues for a comprehensive analysis, employing histopathology, qPCR, and ELISA techniques, our findings revealed a significant upregulation of MUC2 and MUC3 expression induced by CAP. This upregulation resulted in the thickening of the colonic mucus layers. Notably, this effect was absent when TRPV1 was selectively inhibited. Moreover, there was no discernible impact on goblet cells. The findings strongly indicate that CAP influences the system by activating the TRPV1 ion channel, thereby enhancing the expression of mucin MUC2 and promoting an augmentation in the thickness of the mucous layer. This activation, in turn, supplies A. muciniphila with an ample source of carbon and nitrogen. This insight potentially clarify the underlying mechanism through which CAP facilitates the increase in A. muciniphila abundance.

Abstract Expansion of oceanic anoxia is a prevailing hypothesis for driving the marine end-Permian mass extinction and is mainly based on isotopic geochemical proxies. However, long-term oceanic redox conditions before the end-Permian mass extinction remain unresolved. Here we report a secular redox trend based on rock magnetic experiments and cerium anomalies through the Changhsingian and across the Permian-Triassic boundary at the Meishan section, China. Magnetic mineral assemblages changed dramatically at ca. 252.8 million years age (Ma), which indicates that oceanic deoxygenation started about 0.9 million years earlier than the end-Permian mass extinction. The magnetite-dominant post end-Permian mass extinction interval suggests a ferruginous dysoxic conditions with enhanced weathering in the earliest Triassic. Also, a gradual magnetite abundance decrease to pre-extinction levels is observed at ca. 251.5 Ma, coinciding temporally with the waning of Siberian Trap and arc volcanism. All of these observations demonstrate that environmental deterioration began much earlier than the end-Permian mass extinction and finally collapsed in the end-Permian.

Highlights MXene/TiO2 hybrids are prepared by a simple calcination treatment, and their electromagnetic response is customized by in situ atomic reconstruction engineering. Based on the excellent electromagnetic response of MXene/TiO2 hybrids, a series of electromagnetic devices are constructed. Multi-spectrum stealth is realized covering visible-light, infrared radiation and GHz.

Abstract Chemo-immunotherapy combinations have been regarded as one of the most practical ways to improve immunotherapy response in cancer patients. In this study, we integrate the transcriptomics data from anti-PD-1-treated tumors and compound-treated cancer cell lines to systematically screen for chemo-immunotherapy synergisms in silico. Through analyzing anti-PD-1 induced expression changes in patient tumors, we develop a shift ability score to measure if a chemotherapy or a small molecule inhibitor treatment can shift anti-PD-1 resistance in tumor cells. By applying shift ability analysis to 41,321 compounds and 16,853 shRNA treated cancer cell lines transcriptomic data, we characterize the landscape of chemo-immunotherapy synergism and experimentally validated a mitochondrial RNA-dependent mechanism for drug-induced immune activation in tumor. Our study represents an effort to mechanistically characterize chemo-immunotherapy synergism and will facilitate future pre-clinical and clinical studies.

Abstract Background ABCB4 gene-related cholestatic liver diseases have a wide spectrum of clinical and genetic variations. The correlation between genotype and clinical phenotype still unclear. This study retrospectively analyzed the clinical and pathological characteristics of 23 patients with ABCB4 gene-related cholestatic liver diseases. Next-generation sequencing was used to identify the genetic causes. Results The 23 included patients (15 children and 8 adults) were diagnosed as progressive familial intrahepatic cholestasis type 3 (PFIC3), drug-induced liver injury (DILI), cirrhosis cholestasis, cirrhosis, and mild liver fibrosis. Nineteen patients underwent liver pathological examination of the liver, exhibiting fibrosis, small bile duct hyperplasia, CK7(+), Cu(+), bile duct deletion, and cirrhosis. Thirty ABCB4 variants were identified, including 18 novel variants. Conclusion ABCB4 gene-related cholestatic liver diseases have a wide spectrum of clinical and genetic variations. Biallelic ABCB4 mutation carriers tended to severe PFIC3, which mostly occurs in children; while ABCB4 non-biallelic variants can lead to milder ICP, LACP, DILI or overlapping, mostly in adults. Thus, the ABCB4 genotype has a specific correlation with the phenotype, but there are exceptions. Non-biallelic null mutations can cause severe diseases. The mechanisms underlying this genetic phenotype require further investigation. Graphical Abstract

Abstract Background Atrial tachycardia (AT) originating from the left atrial appendage (LAA) is uncommon and the most difficult arrhythmia to eliminate. Therefore, we present the case of a 5-year-old girl with tachycardia-induced cardiomyopathy (TIC) caused by AT originating from the LAA and successfully treated with RFCA associated to left atrial appendectomy. With resolution of AT, we observed a progressive improvement of LV function. The effectiveness and safety of this combination therapy were evaluated over a one-month follow-up period. Case presentation A 5 -year-old female was evaluated for three days of incessant cough and a syncopal episode. Surface echocardiography and 24-hour monitoring showed that the infant had persistent atrial tachycardia. Echocardiography revealed an enlarged tele diastolic diameter (46.1 mm) and malfunctioning (EF 28.53%) left ventricle. The location of the lesion at the apex of the LAA was further confirmed by electrophysiological study and RFCA. After RFCA, the infant’s ECG monitor showed that sinus rhythm was maintained for up to 22 h. Subsequently, atrial tachycardia recurred and sinus rhythm disappeared. Finally, atrial appendectomy was performed and sinus rhythm returned to normal. Conclusions The heart function of the infant improved and sinus rhythm was maintained, further demonstrating the safety and effectiveness of combined treatment with RFCA and atrial appendectomy after electrophysiological localization of AT from LAA to TIC.

China is rich in karst resources and famous for its karst landscape. As a part of karst, the popularity of red karst is obviously low and has received little attention; moreover, the related scientific research and tourism development are relatively immature. Therefore, this paper takes the red karst in Tongren, Guizhou as the research object, analyzes the characteristics and causes of the red karst, comprehensively evaluates its landscape value, and puts forward development strategies and protection suggestions. Through the above research, the following three research results are obtained. (1) On the basis of a field investigation and a literature review, the geographical situation, background, and landscape characteristics of the red karst landform and its surrounding areas in Tongren City were investigated in detail. It forms isolated peaks, rock walls, protruding rocks, stone pillars, and other forms. The most prominent features of the red karst landscape in Tongren City are that the color is red and white, and the shape is concave and convex in order. (2) Geochemical test and structural data collection and analyses of the collected samples were performed. The obtain concave layer rock is dolomitic limestone, and that convex lay rock is argillaceous dolomitic limestone. Because the convex layer rock sample is high in silicon element content, the convex layer rock sample is not easy to be weathered, is rich in clay mineral, and is not easy to be corrode; the convex layer rock sample gradually protrudes with the passage of time to form an uneven shape. The red karst landform is developed in either the rock stratum or tectonic zone with moderate tectonic deformation intensity. First, the formation of a single-layer honeycomb morphology requires that the rock stratum is subjected to a sufficient horizontal compressive stress at a certain burial depth. Second, it is necessary to widely exist in areas with relatively gentle rock formation occurrence; too strong of a structural deformation will make the rock formation occurrence steep, which is not conducive to the occurrence of differential dissolution between adjacent strata. (3) Through the construction of an evaluation index system, the red karst in Tongren City is evaluated, and it is concluded that the geological heritage value is high, and the development and utilization conditions are weak. The conclusion of this article is a supplement to the geological and geomorphological system characteristics of southern karst. From the perspective of world natural heritage, the study enriches the academic evidence of red karst and enables its exemplary role to be well played. From the perspective of the tourism development value, more people should be made aware of the diverse types of karst landforms, which provide experience and suggestions for the value of landforms, tourism resources, and tourism development in similar areas.

Medical image generation has recently garnered significant interest among researchers. However, the primary generative models, such as Generative Adversarial Networks (GANs), often encounter challenges during training, including mode collapse. To address these issues, we proposed the AE-COT-GAN model (Autoencoder-based Conditional Optimal Transport Generative Adversarial Network) for the generation of medical images belonging to specific categories. The training process of our model comprises three fundamental components. The training process of our model encompasses three fundamental components. First, we employ an autoencoder model to obtain a low-dimensional manifold representation of real images. Second, we apply extended semi-discrete optimal transport to map Gaussian noise distribution to the latent space distribution and obtain corresponding labels effectively. This procedure leads to the generation of new latent codes with known labels. Finally, we integrate a GAN to train the decoder further to generate medical images. To evaluate the performance of the AE-COT-GAN model, we conducted experiments on two medical image datasets, namely DermaMNIST and BloodMNIST. The model’s performance was compared with state-of-the-art generative models. Results show that the AE-COT-GAN model had excellent performance in generating medical images. Moreover, it effectively addressed the common issues associated with traditional GANs.

Abstract Background Paraquat (PQ) is a widely used and highly toxic herbicide that poses a significant risk to human health. The main consequence of PQ poisoning is pulmonary fibrosis, which can result in respiratory failure and potentially death. Our research aims to uncover a crucial mechanism in which PQ poisoning induces senescence in epithelial cells, ultimately regulating the activation of pulmonary fibroblasts through the exosomal pathway. Methods Cellular senescence was determined by immunohistochemistry and SA-β-Gal staining. The expression of miRNAs was measured by qPCR. Pulmonary fibroblasts treated with specific siRNA of SIRT1 or LV-SIRT1 were used to analysis senescent exosomes-mediated fibroblasts activation. Luciferase reporter assay and western blot were performed to elucidated the underlying molecular mechanisms. The effects of miR-217-5p antagomir on pulmonary fibrosis were assessed in PQ-poisoned mice models. Results Impairing the secretion of exosomes effectively mitigates the harmful effects of senescent epithelial cells on pulmonary fibroblasts, offering protection against PQ-induced pulmonary fibrosis in mice. Additionally, we have identified a remarkable elevation of miR-217-5p expression in the exosomes of PQ-treated epithelial cells, which specifically contributes to fibroblasts activation via targeted inhibition of SIRT1, a protein involved in cellular stress response. Remarkably, suppression of miR-217-5p effectively impaired senescent epithelial cells-induced fibroblasts activation. Further investigation has revealed that miR-217-5p attenuated SIRT1 expression and subsequently resulted in enhanced acetylation of β-catenin and Wnt signaling activation. Conclusion These findings highlight a potential strategy for the treatment of pulmonary fibrosis induced by PQ poisoning. Disrupting the communication between senescent epithelial cells and pulmonary fibroblasts, particularly by targeting the miR-217-5p/SIRT1/β-catenin axis, may be able to alleviate the effects of PQ poisoning on the lungs.

Abstract Background Quinoa leaves demonstrate a diverse array of colors, offering a potential enhancement to landscape aesthetics and the development of leisure-oriented sightseeing agriculture in semi-arid regions. This study utilized integrated transcriptomic and metabolomic analyses to investigate the mechanisms underlying anthocyanin synthesis in both emerald green and pink quinoa leaves. Results Integrated transcriptomic and metabolomic analyses indicated that both flavonoid biosynthesis pathway (ko00941) and anthocyanin biosynthesis pathway (ko00942) were significantly associated with anthocyanin biosynthesis. Differentially expressed genes (DEGs) and differentially accumulated metabolites (DAMs) were analyzed between the two germplasms during different developmental periods. Ten DEGs were verified using qRT-PCR, and the results were consistent with those of the transcriptomic sequencing. The elevated expression of phenylalanine ammonia-lyase (PAL), chalcone synthase (CHS), 4-coumarate CoA ligase (4CL) and Hydroxycinnamoyltransferase (HCT), as well as the reduced expression of flavanone 3-hydroxylase (F3H) and Flavonol synthase (FLS), likely cause pink leaf formation. In addition, bHLH14, WRKY46, and TGA indirectly affected the activities of CHS and 4CL, collectively regulating the levels of cyanidin 3-O-(3’’, 6’’-O-dimalonyl) glucoside and naringenin. The diminished expression of PAL, 4CL, and HCT decreased the formation of cyanidin-3-O-(6”-O-malonyl-2”-O-glucuronyl) glucoside, leading to the emergence of emerald green leaves. Moreover, the lowered expression of TGA and WRKY46 indirectly regulated 4CL activity, serving as another important factor in maintaining the emerald green hue in leaves N1, N2, and N3. Conclusion These findings establish a foundation for elucidating the molecular regulatory mechanisms governing anthocyanin biosynthesis in quinoa leaves, and also provide some theoretical basis for the development of leisure and sightseeing agriculture.

Abstract Introduction Frailty has become a worldwide health burden that has a large influence on public health and clinical practice. The incidence of frailty is anticipated to increase as the ageing population increases. Myocardial injury after noncardiac surgery (MINS) is associated with short-term and long-term mortality. However, the incidence of MINS in frail geriatric patients is unknown. Methods and analysis This prospective, multicentre, real-world observational cohort study will be conducted at 18 designated centres in China from January 2023 to December 2024, with an anticipated sample size of 856 patients aged 65 years and older who are scheduled to undergo noncardiac surgery. The primary outcome will be the incidence of MINS. MINS is defined as a fourth-generation plasma cardiac troponin T (cTnT) concentration ≥ 0.03 ng/mL exhibited at least once within 30 days after surgery, with or without symptoms of myocardial ischaemia. All data will be collected via electronic data acquisition. Discussion This study will explore the incidence of MINS in frail patients. The characteristics, predictive factors and 30-day outcomes of MINS in frail patients will be further investigated to lay the foundation for identifying clinical interventions. Clinical trial registration https://beta.clinicaltrials.gov/study/NCT05635877 , NCT05635877.

Abstract For the processing of highly squinted synthetic aperture radar (SAR) echo signals, three key challenges need to be considered: rectifying the nonzero Doppler centroid, compensating for azimuthal side-lobe defocusing (ASLD), and correcting the range cell migration (RCM). To address these three problems, we developed a reliable improved fourth-order spectral analysis (SPECAN) algorithm for highly squinted SAR imaging in this study. First, we present a fourth-order phase model (FoPM) that is more suitable for the highly squinted SAR system through a theoretical analysis. Second, based on the FoPM, we derive an improved fourth-order SPECAN algorithm in detail. In this derivation, the nonzero Doppler centroid, the ASLD, and the RCM caused by the high squint angle are corrected. Moreover, the whole simulation procedure of the improved algorithm only contains fast Fourier transform and complex multiplication, so the proposed algorithm can efficiently process highly squinted SAR echoes. Furthermore, the results of a comparison with the traditional SPECAN algorithm show the better performance of the proposed algorithm.

Abstract The reorientation of Earth through rotation of its solid shell relative to its spin axis is known as True polar wander (TPW). It is well-documented at present, but the occurrence of TPW in the geologic past remains controversial. This is especially so for Late Jurassic TPW, where the veracity and dynamics of a particularly large shift remain debated. Here, we report three palaeomagnetic poles at 153, 147, and 141 million years (Myr) ago from the North China craton that document an ~ 12° southward shift in palaeolatitude from 155–147 Myr ago (~1.5° Myr−1), immediately followed by an ~ 10° northward displacement between 147–141 Myr ago (~1.6° Myr−1). Our data support a large round-trip TPW oscillation in the past 200 Myr and we suggest that the shifting back-and-forth of the continents may contribute to the biota evolution in East Asia and the global Jurassic–Cretaceous extinction and endemism.

Abstract Background Occupational stress is becoming a common phenomenon around the world. Being in a high occupational stress state for a long time may destroy the metabolic balance of the body, thereby increasing the risk of metabolic diseases. There is limited evidence regarding the correlation between occupational stress and metabolic syndrome (MetS), particularly in the petrochemical workers. Methods A total of 1683 workers of a petrochemical enterprise in China were included in the survey by cluster sampling method. The occupational stress assessment was carried out by the Job Content Questionnaire and the Effort-Reward Imbalance Questionnaire, and the general demographic characteristics, work characteristics, occupational hazards, lifestyle and health examination data of the participants were collected. Logistic regression and multiple linear regression were used to analyze the correlations and influencing factors between occupational stress and its dimensions with MetS and its components. Results A total of 1683 questionnaires were sent out, and 1608 were effectively collected, with an effective recovery rate of 95.54%. The detection rates of occupational stress in Job Demand-Control (JDC) and Effort-Reward Imbalance (ERI) models were 28.4% and 27.2%, respectively. In this study, 257 participants (16.0%) were diagnosed with MetS. Compared with the non-MetS group, body mass index (BMI), waist circumference (WC), systolic blood pressure (SBP), diastolic blood pressure (DBP), triglycerides (TG) and fasting blood-glucose (FBG) levels were significantly higher in the MetS group, and high density lipoprotein-cholesterol (HDL-C) levels were significantly lower (P

Dredged marine soils (DMS) have poor engineering properties, which limit their usage in construction projects. This research examines the application of reactive magnesia (rMgO) containing supplementary cementitious materials (SCMs) to stabilize DMS under ambient and carbon dioxide (CO2) curing conditions. Several proprietary experimental tests were conducted to investigate the stabilized DMS. Furthermore, the carbonation-induced mineralogical, thermal, and microstructural properties change of the samples were explored. The findings show that the compressive strength of the stabilized DMS fulfilled the 7-d requirement (0.7–2.1 MPa) for pavement and building foundations. Replacing rMgO with SCMs such as biochar or ground granulated blast-furnace slag (GGBS) altered the engineering properties and particle packing of the stabilized soils, thus influencing their performances. Biochar increased the porosity of the samples, facilitating higher CO2 uptake and improved ductility, while GGBS decreased porosity and increased the dry density of the samples, resulting in higher strength. The addition of SCMs also enhanced the water retention capacity and modified the pH of the samples. Microstructural analysis revealed that the hydrated magnesium carbonates precipitated in the carbonated samples provided better cementation effects than brucite formed during rMgO hydration. Moreover, incorporating SCMs reduced the overall global warming potential and energy demand of the rMgO-based systems. The biochar mixes demonstrated lower toxicity and energy consumption. Ultimately, the rMgO and biochar blend can serve as an environmentally friendly additive for soft soil stabilization and permanent fixation of significant amounts of CO2 in soils through mineral carbonation, potentially reducing environmental pollution while meeting urbanization needs.

PURPOSEThe current meta-analysis aimed to compare the diagnostic performance of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) with 18F-FDG PET/magnetic resonance imaging (MRI) in non-small cell lung cancer (NSCLC) lymph node metastasis staging.METHODSWe searched the PubMed, Web of Science, and Embase databases for relevant articles between November 1992 and September 2022. Studies evaluating the head-to-head comparison of 18F-FDG PET/CT and 18F-FDG PET/MRI for lymph node metastasis in patients with NSCLC were included. The quality of each study was assessed using the Quality Assessment of Diagnostic Performance Studies-2 tool.RESULTSThe analysis includes six studies with a total of 434 patients. The pooled sensitivity of 18F-FDG PET/CT and 18F-FDG PET/MRI was 0.78 [95% confidence interval (CI): 0.59-0.90] and 0.84 (95% CI: 0.68-0.93), and the pooled specificity was 0.87 (95% CI: 0.72-0.94) and 0.87 (95% CI: 0.80-0.92), respectively. The accuracy of 18F-FDG PET/CT and 18F-FDG PET/MRI was 0.81 (95% CI: 0.71-0.90) and 0.84 (95% CI: 0.75-0.92), respectively. When the pre-test probability was set at 50%, the post-test probability for 18F-FDG PET/CT could increase to 85%, and the post-test probability for 18F-FDG PET/MRI could increase to 87%.CONCLUSION18F-FDG PET/CT and 18F-FDG PET/MRI have similar diagnostic performance in detecting lymph node metastasis in NSCLC. However, the results of this study were from a small sample study, and further studies with larger sample sizes are needed.

Abstract Background There have been studies on the relationship between hepatitis B virus (HBV) infection and diet. We hypothesized HBV infection is related to dietary calcium intake, but the evidence is limited. This study aimed to examine whether dietary calcium intake is independently related to HBV infection in the United States population. Methods A total of 20,488 participants aged over 20 years from the National Health and Nutrition Examination Survey (NHANES), conducted from 2007 to 2020, were included in this study. Pearson correlation was used to test the association between dietary calcium and serum calcium. The relationships of HBV infection with dietary calcium and serum calcium were assessed by logistic regression models. Results There was a weak correlation between dietary calcium and serum calcium (r = 0.048). Logistic regression models indicated that HBV infection had a linear negative correlation with dietary calcium (OR 0.37; 95%CI 0.19, 0.76). For each additional 10 mg dietary calcium, the possibility of HBV infection was reduced by 63%. Hepatitis B positive participants had lower serum calcium content than negative participants. Stratified analysis shown the linear relationship between calcium and HBV infection varied among sex, race/ethnicity, and body mass index. Conclusion Our findings demonstrated HBV infection was linearly and inversely correlated with dietary calcium. The current study is expected to offer a fresh perspective on reducing HBV infection.

Abstract As testicular mesenchymal stromal cells, stem Leydig cells (SLCs) show great promise in the treatment of male hypogonadism. The therapeutic functions of mesenchymal stromal cells are largely determined by their reciprocal regulation by immune responses. However, the immunoregulatory properties of SLCs remain unclear. Here, we observe that SLCs transplantation restore male fertility and testosterone production in an ischemia‒reperfusion injury mouse model. SLCs prevent inflammatory cascades through mitochondrial transfer to macrophages. Reactive oxygen species (ROS) released from activated macrophages inducing mitochondrial transfer from SLCs to macrophages in a transient receptor potential cation channel subfamily member 7 (TRPM7)-mediated manner. Notably, knockdown of TRPM7 in transplanted SLCs compromised therapeutic outcomes in both testicular ischemia‒reperfusion and testicular aging mouse models. These findings reveal a new mechanism of SLCs transplantation that may contribute to preserve testis function in male patients with hypogonadism related to immune disorders.

Abstract Study objectives To assess whether preoperative dexmedetomidine (DEX) nasal drips combined with conventional treatment could mitigate the occurrence of postoperative delirium (POD). Design A prospective randomised controlled study. Setting The cardiac surgery intensive care unit (CSICU) and patient hospitalisation ward at a university hospital. Participants A total of 100 patients (aged ≥60 years) undergoing cardiac surgery at a university hospital between 7 January 2022, and 30 November 2022 met the eligibility criteria and were included in the study. Interventions Patients with sleep disorders (Pittsburgh Sleep Quality Index ≥8) were divided into two groups: Group A (the placebo group, n=50), receiving a short-term preoperative placebo combined with conventional treatment and Group B (the DEX group, n=50), receiving short-term preoperative DEX combined with conventional treatment. Measurements and results The Confusion Assessment Method for the ICU (CAM-ICU) was used for POD assessment in the CSICU, while the CAM was employed to assess delirium in the patient ward. Group B demonstrated a reduced incidence of POD compared to Group A (12% vs. 30%, odds ratio: 0.318, 95% confidence interval: 0.112–0.905, p=0.027). Conclusion The combined treatment involving DEX demonstrated a decreased incidence of POD in elderly individuals with sleep disorders undergoing cardiac surgery compared to the placebo combination treatment. Trial registration URL: www.chictr.org.cn with registration number ChiCTR 2100043968, registered on 06/03/2021.

Sulfation is a crucial and prevalent conjugation reaction involved in cellular processes and mammalian physiology. 3′-Phosphoadenosine 5′-phosphosulfate (PAPS) synthase 2 (PAPSS2) is the primary enzyme to generate the universal sulfonate donor PAPS. The involvement of PAPSS2-mediated sulfation in adenomatous polyposis coli (APC) mutation-promoted colonic carcinogenesis has not been reported. Here, we showed that the expression of PAPSS2 was decreased in human colon tumors along with cancer stages, and the lower expression of PAPSS2 was correlated with poor prognosis in advanced colon cancer. Gut epithelial-specific heterozygous Apc deficient and Papss2-knockout (ApcΔgut-HetPapss2Δgut) mice were created, and the phenotypes were compared to the spontaneous intestinal tumorigenesis of ApcΔgut-Het mice. ApcΔgut-HetPapss2Δgut mice were more sensitive to gut tumorigenesis, which was mechanistically accounted for by the activation of Wnt/β-catenin signaling pathway due to the suppression of chondroitin sulfation and inhibition of the farnesoid X receptor (FXR)-transducin-like enhancer of split 3 (TLE3) gene regulatory axis. Chondroitin sulfate supplementation in ApcΔgut-HetPapss2Δgut mice alleviated intestinal tumorigenesis. In summary, we have uncovered the protective role of PAPSS2-mediated chondroitin sulfation and bile acids–FXR–TLE3 activation in the prevention of gut carcinogenesis via the antagonization of Wnt/β-catenin signaling. Chondroitin sulfate may be explored as a therapeutic agent for Papss2 deficiency-associated colonic carcinogenesis.

Abstract The presence of light absorption and scattering in underwater conditions results in underwater images with missing details, low contrast, and color bias. The current deep learning-based methods bring unlimited potential for underwater image restoration (UIR) tasks. These methods, however, do not adequately take into account the inconsistency of the attenuation of different color channels and spatial regions when performing image restoration. To solve these gaps, we propose a dual information modulation network (DIMN) for accurate UIR tasks. To be specific, we design a multi-information enhancement module (MIEM), empowered by spatial-aware attention block (SAAB) and multi-scale structural Transformer block (MSTB), to guide the inductive bias of image degradation processes under nonhomogeneous media distributions. SAAB focuses on different spatial locations, capturing more spatial-aware cues to correct color deviations and recover details. MSTB utilizes the difference and complementarity between features at different scales to effectively complement the network’s structural and global perceptual capabilities, enhancing image sharpness and contrast further. Experimental results reveal that the proposed DIMN exceeds most state-of-the-art UIR methods. Our code and results are available at: https://github.com/wwaannggllii/DIMN .

The clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) system is an acquired immune system of many bacteria and archaea, comprising CRISPR loci, Cas genes, and its associated proteins. This system can recognize exogenous DNA and utilize the Cas9 protein's nuclease activity to break DNA double-strand and to achieve base insertion or deletion by subsequent DNA repair. In recent years, multiple laboratory and clinical studies have revealed the therapeutic role of the CRISPR/Cas9 system in neurological diseases. This article reviews the CRISPR/Cas9-mediated gene editing technology and its potential for clinical application against neurological diseases.

Abstract B-cell maturation antigen (BCMA), expressed in plasmablasts and plasma cells, could serve as a promising therapeutic target for autoimmune diseases. We reported here chimeric antigen receptor (CAR) T cells targeting BCMA in two patients with highly relapsed and refractory myasthenia gravis (one with AChR-IgG, and one with MuSk-IgG). Both patients exhibited favorable safety profiles and persistent clinical improvements over 18 months. Reconstitution of B-cell lineages with sustained reduced pathogenic autoantibodies might underlie the therapeutic efficacy. To identify the possible mechanisms underlying the therapeutic efficacy of CAR-T cells in these patients, longitudinal single-cell RNA and TCR sequencing was conducted on serial blood samples post infusion as well as their matching infusion products. By tracking the temporal evolution of CAR-T phenotypes, we demonstrated that proliferating cytotoxic-like CD8 clones were the main effectors in autoimmunity, whereas compromised cytotoxic and proliferation signature and profound mitochondrial dysfunction in CD8+ Te cells before infusion and subsequently defect CAR-T cells after manufacture might explain their characteristics in these patients. Our findings may guide future studies to improve CAR T-cell immunotherapy in autoimmune diseases.