Single-cell RNA sequencing reveals the altered innate immunity in immune checkpoint inhibitor-related myocarditis.

Myocarditis has emerged as a rare but lethal immune checkpoint inhibitor (ICI)-associated toxicity. However, the exact mechanism and the specific therapeutic targets remain underexplored. In this study, we aim to characterise the transcriptomic profiles based on single-cell RNA sequencing from ICI-related myocarditis. Peripheral blood mononuclear cell (PBMC) samples were collected from four groups for single-cell RNA sequencing: (1) patients with newly diagnosed lung squamous cell carcinoma before treatment (Control Group); (2) patients with lung squamous cell carcinoma with PD-1 inhibitor therapy who did not develop myocarditis (PD-1 Group); (3) patients during fulminant ICI-related myocarditis onset (Myocarditis Group); and (4) Patients with fulminant ICI-related myocarditis during disease remission (Recovery Group). Subcluster determination, functional analysis, single-cell trajectory and cell-cell interaction analysis were performed after scRNA-seq. Bulk-RNA sequencing was performed for further validation. Our results revealed the diversity of cellular populations in ICI-related myocarditis, marked by their distinct transcriptional profiles and biological functions. Monocytes, NKs as well as B cells contribute to the regulation of innate immunity and inflammation in ICI-related myocarditis. With integrated analysis of scRNA-seq and bulk sequencing, we identified S100A protein family as a potential serum marker for ICI-related myocarditis. Our study has created a cell atlas of PBMC during ICI-related myocarditis, which would shed light on the pathophysiological mechanism and potential therapeutic targets of ICI-related myocarditis in continuous exploration.

Endothelial POFUT1 controls injury-induced liver fibrosis by repressing fibrinogen synthesis.

BACKGROUND & AIMS: NOTCH signaling in liver sinusoidal endothelial cells (LSECs) regulates liver fibrosis, a pathological feature of chronic liver diseases. POFUT1 is an essential regulator of NOTCH signaling. Here, we investigated the role of LSEC-expressed POFUT1 in liver fibrosis. METHODS: Endothelial-specific Pofut1 knockout mice were generated and experimental liver fibrosis was induced by chronic carbon tetrachloride exposure or common bile duct ligation. Liver samples were assessed by ELISA, histology, electron microscopy, immunostaining and RNA in situ hybridization. LSECs and hepatic stellate cells (HSCs) were isolated for gene expression analysis by RNA sequencing, qPCR, and western blotting. Signaling crosstalk between LSECs and HSCs was investigated by treating HSCs with supernatant from LSEC cultures. Liver single-cell RNA sequencing datasets from patients with cirrhosis and healthy individuals were analyzed to evaluate the clinical relevance of gene expression changes observed in mouse studies. RESULTS: POFUT1 loss promoted injury-induced LSEC capillarization and HSC activation, leading to aggravated liver fibrosis. RNA sequencing analysis revealed that POFUT1 deficiency upregulated fibrinogen expression in LSECs. Consistently, fibrinogen was elevated in LSECs of patients with cirrhosis. HSCs treated with supernatant from LSECs of Pofut1 null mice showed exacerbated activation compared to those treated with supernatant from control LSECs, and this effect was attenuated by knockdown of fibrinogen or by pharmacological inhibition of fibrinogen receptor signaling, altogether suggesting that LSEC-derived fibrinogen induced the activation of HSCs. Mechanistically, POFUT1 loss augmented fibrinogen expression by enhancing NOTCH/HES1/STAT3 signaling. CONCLUSIONS: Endothelial POFUT1 prevents injury-induced liver fibrosis by repressing the expression of fibrinogen, which functions as a profibrotic paracrine signal to activate HSCs. Therapies targeting the POFUT1/fibrinogen axis offer a promising strategy for the prevention and treatment of fibrotic liver diseases. IMPACT AND IMPLICATIONS: Paracrine signals produced by liver vasculature play a major role in the development of liver fibrosis, which is a pathological hallmark of most liver diseases. Identifying those paracrine signals is clinically relevant in that they may serve as therapeutic targets. In this study, we discovered that genetic deletion of Pofut1 aggravated experimental liver fibrosis in mouse models. Moreover, fibrinogen was identified as a downstream target repressed by Pofut1 in liver endothelial cells and functioned as a novel paracrine signal that drove liver fibrosis. In addition, fibrinogen was found to be relevant to cirrhosis and may serve as a potential therapeutic target for this devastating human disease.

Willingness to Use Long-Acting Injectable Cabotegravir and Associated Factors Among Men Who Have Sex with Men in Guangxi, China.

Cabotegravir (CAB-LA), the first long-acting injectable pre-exposure prophylaxis (PrEP), has been approved for use in the USA and is not currently on the market in China. However, willingness to use CAB-LA and associated factors among men who have sex with men (MSM) have not yet been evaluated in China. A cross-sectional study was conducted in Guangxi, China, in 2022 recruiting 1,006 MSM. Their mean age was 30.2 years, 74.2% had college or above education, and 48.6% had a monthly income between 3,000 and 5,999 Chinese yuan (CNY). Most (73.4%) had previously heard of PrEP while few (8.3%) had ever used this type of preventative medication. Willingness to use CAB-LA was 79.8% and was positively associated with eight variables: younger age, being married to a woman, having a low monthly income, having six or more male partners in the past six months, having only regular male partners in the past month, having a high perceived risk of HIV infection, and history of using PrEP. Ten other variables were not significantly associated with willingness to use CAB-LA. Among 894 participants who were willing to use or did not definitely reject using CAB-LA, the main concerns about CAB-LA were its side effects (90.2%), efficacy (63.6%), and high cost (58.2%). Only 14.7% were willing to pay more than 1,200 CNY (~US$180) every two months to use CAB-LA. The preferred injection places were centers for disease control facilities, hospitals, and social organizations. Many (89.0%) said that they would recommend CAB-LA to their male sexual partners. We conclude that willingness to use CAB-LA was high among MSM in Guangxi. However, implementation of CAB-LA faces tough challenges due to its high cost and the low use of PrEP. Peer education may play a large role in the implementation of CAB-LA in China.

Highly sensitive and selective fluorescent "turn-on" sensor for Ag+ detection using MAPbBr3@PCN-221(Fe): An efficient Ag+-bridged energy transfer from perovskite to MOF.

Metal ion-induced water pollution is attracting increasing public attention. Perovskite quantum dots and metal-organic frameworks (MOFs), owing to their outstanding properties, hold promise as ideal probes for detecting metal ions. In this study, a composite material, MAPbBr3@PCN-221(Fe), was prepared by encapsulating MAPbBr3 quantum dots with PCN-221(Fe), demonstrating high chemical stability and good reusability. The composite material shows a sensitive fluorescence turn-on signal in the presence of silver ions. The fluorescence intensity of the composite material exhibits a linear relationship with the concentration of Ag+ in the solution, with a low detection limit of 8.68 µM. Moreover, the fluorescence signal exhibits a strong selectivity for Ag+, enabling the detection of Ag+ concentration. This fluorescence turn-on signal originates from the Ag+-bridged energy transfer from the conductive band of MAPbBr3 to the excited state of the MOF, which is directly proportional to the concentration of silver ions. Simultaneously, this finding may open up a new possibility in artificial controlled energy transfer from perovskite to MOF for future development.

In vivo therapy of osteosarcoma using anion transporters-based supramolecular drugs.

BACKGROUND: Osteosarcoma represents a serious clinical challenge due to its widespread genomic alterations, tendency for drug resistance and distant metastasis. New treatment methods are urgently needed to address those treatment difficulties in osteosarcoma to improve patient prognoses. In recent years, small-molecule based anion transporter have emerged as innovative and promising therapeutic compound with various biomedical applications. However, due to a lack of efficient delivery methods, using ion transporters as therapeutic drugs in vivo remains a major challenge. RESULT: Herein, we developed self-assembled supramolecular drugs based on small-molecule anion transporters, which exhibited potent therapeutic effect towards osteosarcoma both in vitro and in vivo. The anion transporters can disrupt intracellular ion homeostasis, inhibit proliferation, migration, epithelial-mesenchymal transition process, and lead to osteosarcoma cell death. RNA sequencing, western blot and flow cytometry indicated reprogramming of HOS cells and induced cell death through multiple pathways. These pathways included activation of endoplasmic reticulum stress, autophagy, apoptosis and cell cycle arrest, which avoided the development of drug resistance in osteosarcoma cells. Functionalized with osteosarcoma targeting peptide, the assembled supramolecular drug showed excellent targeted anticancer therapy against subcutaneous xenograft tumor and lung metastasis models. Besides good tumor targeting capability and anti-drug resistance, the efficacy of the assembly was also attributed to its ability to regulate the tumor immune microenvironment in vivo. CONCLUSIONS: In summary, we have demonstrated for the first time that small-molecule anion transporters are capable of killing osteosarcoma cells through multiple pathways. The assemblies, OTP-BP-L, show excellent targeting and therapeutic effect towards osteosarcoma tumors. Furthermore, the supramolecular drug shows a strong ability to regulate the tumor immune microenvironment in vivo. This work not only demonstrated the biomedical value of small-molecule anion transporters in vivo, but also provided an innovative approach for the treatment of osteosarcoma.

Effect of macrophage polarization on parasitic protection against type 1 diabetes mellitus.

Type 1 diabetes mellitus is a chronic disease caused by the destruction of pancreatic beta cells. Based on the hygiene hypothesis, a growing body of evidence suggests a negative association between parasitic infections and diabetes in humans and animal models. The mechanism of parasite-mediated prevention of type 1 diabetes mellitus may be related to the adaptive and innate immune systems. Macrophage polarization is a new paradigm for the treatment of type 1 diabetes mellitus, and different host macrophage subsets play various roles during parasite infection. Proinflammatory cytokines are released by M1 macrophages, which are important in the development of type 1 diabetes mellitus. Parasite-activated M2 macrophages prevent the development of type 1 diabetes mellitus and can influence the development of adaptive immune responses through several mechanisms, including Th2 cells and regulatory T cells. Here, we review the role and mechanism of macrophage polarization in parasitic protection against type 1 diabetes mellitus.

Quantitative Risk Assessment of Salmonella in Breaded Pork Products in China.

Pork products were the most common media of Salmonella in China, breaded pork products as a very popular meat presently, whose Salmonella risk should be drawn to attention. Given that quantitative risk assessment is a more scientific method for risk evaluation, a quantitative risk assessment model of Salmonella in breaded pork products was first constructed from processing to consumption, and was used for assessing the risk and the effective interventions in this study. The data of Salmonella contamination in breaded pork products during processing were obtained from the actual detection data of samples from a representative meat processing plant. With combining the predictive microbial modeling and dose-response relationship, the risk of Salmonella in breaded pork products was charactered, and the probability of Salmonella infection per meal was found to be 5.585 × 10-9. Based on the results of sensitivity analysis, the curing and seasoning process was found to be the key control point for Salmonella contamination during the processing, and consumer behavior was the key control point affecting the probability of Salmonella infection from processing to consumption. The model was also applied for assessing the effectiveness of risk interventions, and among the nine interventions given, control of thawing temperature before cooking such as microwave thawing could reduce the risk of infection by 30.969-fold, while cooking the products thoroughly, Salmonella would not pose a pathogenic hazard to consumers. The model and the assessed results in this study may provide guidance on microbial control in producing process and safety consumption of breaded pork products.

Tryptophan metabolites and gut microbiota play an important role in pediatric migraine diagnosis.

BACKGROUND: The pathogenesis of pediatric migraine remains unclear and presents challenges in diagnosis. Recently, growing evidence has indicated that the gut microbiota can exert modulatory functions at the gut-brain axis by directly or indirectly regulating tryptophan metabolism. Consequently, we aimed to elucidate the potential association among gut microbiota, tryptophan metabolism, and pediatric migraine while also identifying diagnostic biomarkers for pediatric migraine. METHODS: The gut microbiota composition of 33 migraine children and 42 healthy children, aged less than ten years, from the GMrepo database, was analyzed using the Shannon index, Simpson index, principal coordinates analysis, and Wilcoxon rank-sum test. Microbial diagnostic biomarkers were identified using linear discriminant analysis effect size, ridge regression, and random forest. Plasma concentrations of tryptophan metabolites investigated by enzyme-linked immunosorbent assay were compared between 51 migraine children and 120 healthy children, aged less than eighteen years, using t tests and analysis of variance. The receiver operating characteristic curve was performed to evaluate the diagnostic value of microbial and metabolite biomarkers in pediatric migraine. RESULTS: Differences in the composition of gut microbiota, notably the genera that regulate tryptophan metabolism, were observed in pediatric migraine children. Further investigations revealed a significant decrease in plasma kynurenic acid levels (p < 0.001) among migraine children, along with a significant increase in serotonin (p < 0.05) and quinolinic acid (p < 0.001). Subsequently, we established the normal reference intervals for plasma concentrations of tryptophan metabolites in children. More importantly, the ratio of kynurenic acid to quinolinic acid (AUC: 0.871, sensitivity: 86.3%, specificity: 83.3%) exhibited excellent diagnostic efficacy for pediatric migraine. CONCLUSION: Our study suggests that the gut microbiota may play an important role in the development of pediatric migraine by regulating tryptophan metabolism. We believe that microbial and metabolite biomarkers are sensitive diagnostic tests for pediatric migraine. TRIAL REGISTRATION: The study was registered at ClinicalTrials.gov (NCT05969990).

Identification of the novel markers of PPAR signalling affecting immune microenvironment and immunotherapy response of lung adenocarcinoma patients.

Peroxisome proliferator-activated receptors (PPARs) are essential for cellular physiological processes. However, there is less research on the PPAR-related genes in lung adenocarcinoma (LUAD). Open-access data were get from the cancer genome atlas (TCGA) and gene expression omnibus (GEO) databases. All the analysis were conducted in the R software based on different R packages. In this study, we gauged the PPAR score employing a set of 72 PPAR-associated genes and probed the biological impact of this score on lung adenocarcinoma (LUAD). Subsequently, we established a unique signature composed of eight PPAR-related genes (ANGPTL4, ACSL3, ADIPOQ, FABP1, SLC27A1, ACOX2, PPARD and OLR1) to forecast the prognosis of LUAD. The signature's effectiveness in predicting survival was validated through the receiver operating characteristic curve in the TCGA-LUAD cohort. As per the pathway enrichment analysis, several crucial oncogenic pathways and metabolic processes were enriched in high-risk individuals. Further, we observed that these high-risk patients exhibited heightened genomic instability. Additionally, compared to the low-risk cohort, high-risk patients demonstrated diminished immune components and function. Intriguingly, high-risk patients exhibited a potential heightened sensitivity to immunotherapy and certain drugs, including Gefitinib, Afatinib, Erlotinib, IAP_5620, Sapitinib, LCL161, Lapatinib and AZD3759. The prognosis model based on eight PPAR-related genes has satisfactory prognosis prediction efficiency. Meanwhile, our results can provide direction for future studies in the relevant aspects.

Mediator subunit MED1 deficiency prevents carbon tetrachloride-induced hepatic fibrosis in mice.

Mediator subunit mediator 1 (MED1) mediates ligand-dependent binding of the mediator coactivator complex to various nuclear receptors and plays a critical role in embryonic development, lipid and glucose metabolism, liver regeneration, and tumorigenesis. However, the precise role of MED1 in the development of liver fibrosis has been unclear. Here, we showed that MED1 expression was increased in livers from nonalcoholic steatohepatitis (NASH) patients and mice and positively correlated with transforming growth factor ß (TGF-ß) signaling and profibrotic factors. Upon treatment with carbon tetrachloride (CCl4), hepatic fibrosis was much less in liver-specific MED1 deletion (MED1ΔLiv) mice than in MED1fl/fl littermates. TGF-ß/Smad2/3 signaling pathway was inhibited, and gene expression of fibrotic markers, including α-smooth muscle actin (α-SMA), collagen type 1 α 1 (Col1a1), matrix metalloproteinase-2 (Mmp2), and metallopeptidase inhibitor 1 (Timp1) were decreased in livers of MED1ΔLiv mice with CCl4 injection. Transcriptomic analysis revealed that the differentially expressed genes in livers of CCl4-administered MED1ΔLiv mice were enriched in the pathway of oxidoreductase activity, followed by robustly reduced oxidoreductase activity-related genes, such as Gm4756, Txnrd3, and Etfbkmt. More importantly, we found that the reduction of reactive oxygen species (ROS) in MED1 knockdown hepatocytes blocked the activation of TGF-ß/Smad2/3 pathway and the expression of fibrotic genes in LX2 cells. These results indicate that MED1 is a positive regulator for hepatic fibrogenesis, and MED1 may be considered as a potential therapeutic target for the regression of liver fibrosis.NEW & NOTEWORTHY In this study, we present the first evidence that liver mediator 1 (MED1) deficiency attenuated carbon tetrachloride-induced hepatic fibrosis in mouse. The underlying mechanism is that MED1 deficiency reduces reactive oxygen species (ROS) production in hepatocytes, thus restricts the activation of TGF-ß/Smad2/3 signaling pathway and fibrogenic genes expression in hepatic stellate cells (HSCs). These data suggest that MED1 is an essential regulator for hepatic fibrogenesis, and MED1 may be considered as a potential therapeutic target for liver fibrosis.

Establishment of a risk classifier to predict the in-hospital death risk of nosocomial fungal infections in cancer patients.

BACKGROUND: Patients with malignancy are at a higher risk of developing nosocomial infections. However, limited studies investigated the clinical features and prognostic factors of nosocomial infections due to fungi in cancer patients. Herein, this study aims to investigate the clinical characteristics of in-hospital fungal infections and develop a nomogram to predict the risk of in-hospital death during fungal infection of hospitalized cancer patients. METHODS: This retrospective observational study enrolled cancer patients who experienced in-hospital fungal infections between September 2013 and September 2021. Univariate and multivariate logistic regression analyses were performed to identify independent predictors of in-hospital mortality. Variables demonstrating significant statistical differences in the multivariate analysis were utilized to construct a nomogram for personalized prediction of in-hospital death risk associated with nosocomial fungal infections. The predictive performance of the nomogram was evaluated using receiver operating characteristic (ROC) curves, calibration curves, and decision curve analysis. RESULTS: A total of 216 participants were included in the study, of which 57 experienced in-hospital death. C.albicans was identified as the most prevalent fungal species (68.0%). Respiratory infection accounted for the highest proportion of fungal infections (59.0%), followed by intra-abdominal infection (8.8%). The multivariate regression analysis revealed that Eastern Cooperative Oncology Group Performance Status (ECOG-PS) 3-4 (odds ratio [OR] = 6.08, 95% confidence interval [CI]: 2.04-18.12), pulmonary metastases (OR = 2.76, 95%CI: 1.11-6.85), thrombocytopenia (OR = 2.58, 95%CI: 1.21-5.47), hypoalbuminemia (OR = 2.44, 95%CI: 1.22-4.90), and mechanical ventilation (OR = 2.64, 95%CI: 1.03-6.73) were independent risk factors of in-hospital death. A nomogram based on the identified risk factors was developed to predict the individual probability of in-hospital mortality. The nomogram demonstrated satisfactory performance in terms of classification ability (area under the curve [AUC]: 0.759), calibration ability, and net clinical benefit. CONCLUSIONS: Fungi-related nosocomial infections are prevalent among cancer patients and are associated with poor prognosis. The constructed nomogram provides an invaluable tool for oncologists, enabling them to make timely and informed clinical decisions that offer substantial net clinical benefit to patients.

In situ fabrication of Z-scheme C3N4/Ti3C2/CdS for efficient photocatalytic hydrogen peroxide production.

Photocatalysis is a potential technology to produce hydrogen peroxide with low energy consumption and no pollution. However, when using traditional photocatalysts it is hard to meet the requirements of wide visible light absorption, high carrier separation rate and sufficient active sites. Graphitic carbon nitride (g-C3N4) has great potential in the photocatalytic production of hydrogen peroxide, but its photocatalytic performance is limited by a high carrier recombination ratio. Here, we fabricated the Z-Scheme heterojunction of C3N4/Ti3C2/CdS in situ. The large specific surface area of C3N4 can provide plenty of reactive sites, and the absorption efficiency under visible light is improved with the addition of Ti3C2 and CdS. The better conductivity of Ti3C2 reduces the charge transfer resistance. With the increase of surface charge carriers, the width of the space charge region decreases and the photocurrent density increases significantly. Under visible light irradiation, the H2O2 yield of the ternary photocatalyst reaches 256 µM L-1 h-1, which is about 6 times that of pristine C3N4. After three cycles, the high photocatalytic efficiency can still be maintained. In this paper, the reaction mechanism of photocatalytic hydrogen peroxide production by the C3N4/Ti3C2/CdS composite material is proposed through an in-depth study of energy band theory, which provides a new reference for the design and preparation of high-performance materials for photocatalytic hydrogen peroxide production.

Synergetic enhancement effect of two-dimensional MoS2 nanosheets and metal organic framework-derived porous ZnO nanorods for photodegradation performance.

Two-dimensional transition metal dichalcogenides and semiconductor metal oxides have shown great potential in photocatalysis. However, their stability and efficiency need to be further improved. In this paper, porous ZnO nanorods with high specific surface area were prepared from metal-organic framework ZIF-8 by a simple hydrothermal method. A MoS2/ZnO composite was constructed by loading MoS2 onto the surface of porous ZnO nanorods. Compared with ZnO materials prepared by other methods, MoS2/ZnO prepared in this paper exhibits superior photocatalytic performance. The enhanced photocatalytic activity of the MoS2/ZnO composite can be attributed to the formation of heterojunctions and strong interaction between them, which greatly facilitate the separation of electrons and holes at the contact interface. In addition, due to the wide absorption region of the visible spectrum, MoS2 can greatly broaden the light absorption range of the material after the formation of the composite material, increase the utilization rate of visible light, and reduce the combination of electrons and holes. This study provides a new way to prepare cheap and efficient photocatalysts.

Hepatoprotective effect of Artemisia Argyi essential oil on bisphenol A-induced hepatotoxicity via inhibition of ferroptosis in mice.

The environmental pollutant bisphenol A (BPA), used in the manufacture of plastic packaging materials for various diets, is widely distributed in the environment and causes severe hepatotoxicity by inducing oxidative stress. Artemisia argyi essential oil (AAEO), a volatile oil component isolated from Artemisia argyi H.Lév. & Vaniot, has pharmacological effects, especially for hepatoprotective actions. However, the potential effect of AAEO in BPA induced hepatotoxicity has not been characterized. First, we analyzed the chemical composition in AAEO by gas chromatography-mass spectrometry. Herein, we investigated the effect of AAEO on hepatic metabolic changes in mice exposed to BPA. Results showed that compared with the BPA group, AAEO could reduce the level of liver function enzymes in BPA mice serum, and ameliorate hepatic lesions and fibrosis. Additionally, 20 differential metabolites screened by metabolomics were mainly involved in the reprogramming of glutathione metabolism, purine metabolism, and polyunsaturated fatty acid synthesis. Moreover, AAEO could reduce hepatic ferroptosis induced by BPA, as demonstrated by reducing xanthine oxidase activity, up-regulating the activities of glutathione peroxidase 4 (GPX4), superoxide dismutase, and catalase and the expression of SLC7A11 to promote the glutathione synthetic, while inhibiting transferrin receptor 1 (TFR1) expression to reduce the accumulation of Fe2+ in cells. Therefore, our study identified AAEO as a hepatic protectant against BPA-induced hepatotoxicity by reversing the occurrence of ferroptosis.

Preparation and Application of Magnetic Composites Using Controllable Assembly for Use in Water Treatment: A Review.

The use of magnetic composites in wastewater treatment has become widespread due to their high flocculating characteristics and ferromagnetism. This review provides an analysis and summary of the preparation and application of magnetic composites through controllable assembly for use in wastewater treatment. The applications of magnetic composites include the treatment of dye wastewater, heavy metal wastewater, microalgae suspensions, and oily wastewater. Additionally, the recycling and regeneration of magnetic composites have been investigated. In the future, further research could be focused on improving the assembly and regeneration stability of magnetic composites, such as utilizing polymers with a multibranched structure. Additionally, it would be beneficial to explore the recycling and regeneration properties of these composites.

Osteal Tissue Macrophages Are Involved in Endplate Osteosclerosis through the OSM-STAT3/YAP1 Signaling Axis in Modic Changes.

Modic changes (MCs) are radiographic manifestations of lumbar degenerative diseases. Various types of MCs are often associated with endplate osteosclerosis. Osteal tissue macrophages (Osteomacs) were reported to be crucial for bone homeostasis and bone repair, but whether osteomacs participate in the endplate osteosclerosis in MCs remained unclear. In this study, we tried to explore the critical role of osteomacs in regulating osteogenesis in MCs. We collected MCs from patient samples and developed a Propionibacterium acnes-induced rat MCs model, using microcomputed tomography and immunohistochemistry to detect the endplate bone mass and distribution of osteomacs. In patients' MCs, osteomacs increased in endplate subchondral bone, especially in Modic type II. Endplate in Modic type III presented a stable osteosclerosis. In rat MCs model, osteomacs increased in the bone hyperplasia area but not in the inflammation area of the endplate region, whereas the distribution of osteomacs was consistent with the area of osteosclerosis. To further explore the functions of osteomacs in vitro, we isolated osteomacs using MACS technology and found osteomacs secreted oncostatin M (OSM) and strongly promoted osteoblast differentiation rather than osteoclast through the mechanism of OSM-mediated tyrosine phosphorylation and interaction of STAT3 and Yes-associated protein 1 (YAP1). STAT3 phosphorylation inhibition or YAP1 knockdown attenuated OSM-mediated osteoblast differentiation. Finally, we confirmed that blockade of OSM in vivo using anti-OSM-neutralizing Ab prevented endplate osteosclerosis in rat MCs model. Taken together, these findings confirmed that endplate osteosclerosis in MCs was accompanied by an increased number of osteomacs, which regulated osteogenesis via the OSM-STAT3/YAP1 signaling axis.

Stimulant use and bone health in US children and adolescents: analysis of the NHANES data.

Stimulants have become the most popular psychopharmacologic drugs used in therapy for attention-deficit/hyperactivity disorder (ADHD). Childhood and adolescence are crucial periods for optimizing bone health to prevent osteoporosis-related fractures in old age. However, controversy remains regarding the relationship between stimulant use and bone health. The present study was designed to examine the bone mineral content (BMC) and bone mineral density (BMD) of 5472 individuals aged 8-16 years with or without stimulant use based on National Health and Nutrition Examination Survey (NHANES) 2011-2018 data and to further assess the association between stimulant use and bone health. Among these, 284 (5.2%) participants were using stimulants. In analyses stratified by sex, the BMC and BMD at the level of the lumbar spine, pelvis, and total body were generally lower among stimulant users than among nonusers in males (all P < 0.001), while the differences were not statistically significant in females. In multivariable linear regression models, the increasing range of BMCs and BMDs with age was lower in participants using stimulants than in those not using stimulants after fully adjusting for potential confounding factors. Compared to participants not using stimulants, stimulant use ≥ 3 months was associated with significantly lower BMCs [lumbar spine: ß = - 1.35, (95% CI: - 2.56, - 0.14); pelvis: ß = - 9.06, (95% CI: - 15.21, - 2.91); and total: ß = - 52.96, (95% CI: - 85.87, - 20.04)] and BMDs [pelvis: ß = - 0.03, (95% CI: - 0.04, - 0.01), total: ß = - 0.01, (95% CI: - 0.02, - 0.00)]. CONCLUSIONS: Children and adolescents using stimulants exhibited reductions in BMC and BMD at the lumbar spine, pelvis, and total body compared to those who were not using stimulants, especially among males. WHAT IS KNOWN: • Childhood and adolescence are crucial periods for optimizing bone health to prevent osteoporosis-related fractures in old age. • Controversy remains regarding the relationship between stimulant use and bone health. WHAT IS NEW: • The bone mineral content and bone mineral density at the level of the lumbar spine, pelvis, and total body were generally lower among stimulant users than among nonusers in males, while the differences were not statistically significant in females. • Body mass index and serum alkaline phosphatase may be predictors for loss of bone mineral content and bone mineral density in stimulant users.

In-hospital initiation of PCSK9 inhibitor and short-term lipid control in patients with acute myocardial infarction.

BACKGROUND: Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have been shown to improve cardiovascular outcomes when added to conventional statin therapy. This study aims to investigate the efficacy and safety of in-hospital initiation of PCSK9 inhibitors among patients with acute myocardial infarction (AMI) based on real-world experience. METHODS AND RESULTS: Data were collected from the Biobank of the First Affiliated Hospital of Xi'an Jiaotong University between January 2016 and December 2020. A total of 7556 AMI patients were screened for eligibility. Propensity Score Match (PSM) was employed, and covariates were age, sex, admission blood pressure and lipid profiles. Eligible participants were (1) propensity-matched 1:2:2 of statin plus evolocumab (dual therapy) vs. statin vs. statin plus ezetimibe. Ninety-five statin plus evolocumab users achieved significantly decreased low density lipoprotein (LDL) levels (0.92 ± 0.62 mmol/L in the 1st month and 1.17 ± 0.73 in the 3rd month) and a promising attainment rate of LDL (79.5% in the 1st month and 80.0% in the 3rd month) compared to the other two groups. (2) Propensity-matched 1:2:2 of statin plus ezetimibe evolocumab (triple therapy) vs. statin vs. statin plus ezetimibe. Similarly, 75 triple medication users achieved significantly decreased LDL levels and a promising attainment rate of LDL compared to the other two groups. In-hospital mortality and readmission rates within 3 months were then analyzed, and a decreased readmission rate was observed with PCSK9i therapy. CONCLUSIONS: Based on the present single-center real-world PSM-adjusted study, PCSK9i has been effective in short-term lipid control among AMI patients. The long-term effectiveness for reducing major cardiovascular events among AMI patients based on real-world experience remains to be explored. TRIAL REGISTRATION: The study was registered at ClinicalTrials.gov, ClinicalTrials.gov ID: NCT05184530.

Lactate/albumin ratio as a predictor of in-hospital mortality in critically ill children.

OBJECTIVE: Managing critically ill patients with high mortality can be difficult for clinicians in pediatric intensive care units (PICU), which need to identify appropriate predictive biomarkers. The lactate/albumin (L/A) ratio can precisely stratify critically ill adults. However, the role of the L/A ratio in predicting the outcomes of critically ill children remains unclear. Therefore, this study aimed to evaluate the prognostic performance of the L/A ratio in predicting in-hospital mortality in unselected critically ill patients in the PICU. METHODS: This was a single-center retrospective study. Clinical data of 8,832 critical patients aged between 28 days and 18 years were collected from the pediatric intensive care (PIC) database from 2010 to 2018. The primary outcome was the in-hospital mortality rate. RESULTS: There was a higher level of L/A ratio in non-survivors than survivors (P < 0.001). Logistic regression indicated that the association between the L/A ratio and in-hospital mortality was statistically significant (OR 1.44, 95% CI 1.31-1.59, P < 0.001). The AUROC of the L/A ratio for predicting in-hospital mortality was higher than lactate level alone (0.74 vs 0.70, P < 0.001). Stratification analysis showed a significant association between the L/A ratio and in-hospital mortality in the age and primary disease groups (P < 0.05). CONCLUSIONS: Our study suggested that the L/A ratio was a clinical tool to predict in-hospital mortality in critically ill children better than lactate level alone. However, given that the study was retrospective, more prospective studies should be conducted to test the predictive value of the L/A ratio in critical illness.

Shear stress regulation of miR-93 and miR-484 maturation through nucleolin.

Pulsatile shear (PS) and oscillatory shear (OS) elicit distinct mechanotransduction signals that maintain endothelial homeostasis or induce endothelial dysfunction, respectively. A subset of microRNAs (miRs) in vascular endothelial cells (ECs) are differentially regulated by PS and OS, but the regulation of the miR processing and its implications in EC biology by shear stress are poorly understood. From a systematic in silico analysis for RNA binding proteins that regulate miR processing, we found that nucleolin (NCL) is a major regulator of miR processing in response to OS and essential for the maturation of miR-93 and miR-484 that target mRNAs encoding Krüppel-like factor 2 (KLF2) and endothelial nitric oxide synthase (eNOS). Additionally, anti-miR-93 and anti-miR-484 restore KLF2 and eNOS expression and NO bioavailability in ECs under OS. Analysis of posttranslational modifications of NCL identified that serine 328 (S328) phosphorylation by AMP-activated protein kinase (AMPK) was a major PS-activated event. AMPK phosphorylation of NCL sequesters it in the nucleus, thereby inhibiting miR-93 and miR-484 processing and their subsequent targeting of KLF2 and eNOS mRNA. Elevated levels of miR-93 and miR-484 were found in sera collected from individuals afflicted with coronary artery disease in two cohorts. These findings provide translational relevance of the AMPK-NCL-miR-93/miR-484 axis in miRNA processing in EC health and coronary artery disease.