Aberrant Expression of SLC7A11 Impairs the Antimicrobial Activities of Macrophages in Staphylococcus Aureus Osteomyelitis in Mice.

Staphylococcus aureus (S. aureus) persistence in macrophages, potentially a reservoir for recurrence of chronic osteomyelitis, contributes to resistance and failure in treatment. As the mechanisms underlying survival of S. aureus in macrophages remain largely unknown, there has been no treatment approved. Here, in a mouse model of S. aureus osteomyelitis, we identified significantly up-regulated expression of SLC7A11 in both transcriptomes and translatomes of CD11b+F4/80+ macrophages, and validated a predominant distribution of SLC7A11 in F4/80+ cells around the S. aureus abscess. Importantly, pharmacological inhibition or genetic knockout of SLC7A11 promoted the bactericidal function of macrophages, reduced bacterial burden in the bone and improved bone structure in mice with S. aureus osteomyelitis. Mechanistically, aberrantly expressed SLC7A11 down-regulated the level of intracellular ROS and reduced lipid peroxidation, contributing to the impaired bactericidal function of macrophages. Interestingly, blocking SLC7A11 further activated expression of PD-L1 via the ROS-NF-κB axis, and a combination therapy of targeting both SLC7A11 and PD-L1 significantly enhanced the efficacy of clearing S. aureus in vitro and in vivo. Our findings suggest that targeting both SLC7A11 and PD-L1 is a promising therapeutic approach to reprogram the bactericidal function of macrophages and promote bacterial clearance in S. aureus osteomyelitis.

Identification and validation of a prognostic anoikis-related gene signature in papillary thyroid carcinoma by integrated analysis of single-cell and bulk RNA-sequencing.

Papillary thyroid carcinoma (PTC) prognosis may be deteriorated due to the metastases, and anoikis palys an essential role in the tumor metastasis. However, the potential effect of anoikis-related genes on the prognosis of PTC was unclear. The mRNA and clinical information were obtained from the cancer genome atlas database. Hub genes were identified and risk model was constructed using Cox regression analysis. Kaplan-Meier (K-M) curve was applied for the survival analysis. Immune infiltration and immune therapy response were calculated using CIBERSORT and TIDE. The identification of cell types and cell interaction was performed by Seurat, SingleR and CellChat packages. GO, KEGG, and GSVA were applied for the enrichment analysis. Protein-protein interaction network was constructed in STRING and Cytoscape. Drug sensitivity was assessed in GSCA. Based on bulk RNA data, we identified 4 anoikis-related risk signatures, which were oncogenes, and constructed a risk model. The enrichment analysis found high risk group was enriched in some immune-related pathways. High risk group had higher infiltration of Tregs, higher TIDE score and lower levels of monocytes and CD8 T cells. Based on scRNA data, we found that 4 hub genes were mainly expressed in monocytes and macrophages, and they interacted with T cells. Hub genes were significantly related to immune escape-related genes. Drug sensitivity analysis suggested that cyclin dependent kinase inhibitor 2A may be a better chemotherapy target. We constructed a risk model which could effectively and steadily predict the prognosis of PTC. We inferred that the immune escape may be involved in the development of PTC.

In situ cell condensation-based cartilage tissue engineering via immediately implantable high-density stem cell core and rapidly degradable shell microgels.

Formation of chondromimetic human mesenchymal stem cells (hMSCs) condensations typically required in vitro culture in defined environments. In addition, extended in vitro culture in differentiation media over several weeks is usually necessary prior to implantation, which is costly, time consuming and delays clinical treatment. Here, this study reports on immediately implantable core/shell microgels with a high-density hMSC-laden core and rapidly degradable hydrogel shell. The hMSCs in the core formed cell condensates within 12 hours and the oxidized and methacrylated alginate (OMA) hydrogel shells were completely degraded within 3 days, enabling spontaneous and precipitous fusion of adjacent condensed aggregates. By delivering transforming growth factor-ß1 (TGF-ß1) within the core, the fused condensates were chondrogenically differentiated and formed cartilage microtissues. Importantly, these hMSC-laden core/shell microgels, fabricated without any in vitro culture, were subcutaneously implanted into mice and shown to form cartilage tissue via cellular condensations in the core after 3 weeks. This innovative approach to form cell condensations in situ without in vitro culture that can fuse together with each other and with host tissue and be matured into new tissue with incorporated bioactive signals, allows for immediate implantation and may be a platform strategy for cartilage regeneration and other tissue engineering applications.

S100A16 is a potential target for reshaping the tumor microenvironment in the hypoxic context of liver cancer.

BACKGROUND: The research on the S100 family has garnered significant attention; however, there remains a dearth of understanding regarding the precise role of S100A16 in the tumor microenvironment of liver cancer. METHOD: Comprehensive analysis was conducted on the expression of S100A16 in tumor tissues and its correlation with hypoxia genes. Furthermore, an investigation was carried out to examine the association between S100A16 and infiltration of immune cells in tumors as well as immunotherapy. Relevant findings were derived from the analysis of single cell sequencing data, focusing on the involvement of S100A16 in both cellular differentiation and intercellular communication. Finally, we validated the expression of S100A16 in liver cancer by Wuhan cohort and multiplexed immunofluorescence to investigate the correlation between S100A16 and hypoxia. RESULT: Tumor tissues displayed a notable increase in the expression of S100A16. A significant correlation was observed between S100A16 and genes associated with hypoxic genes. Examination of immune cell infiltration revealed an inverse association between T cell infiltration and the level of S100A16 expression. The high expression group of S100A16 exhibited a decrease in the expression of genes related to immune cell function. Single-cell sequencing data analysis revealed that non-immune cells predominantly expressed S100A16, and its expression levels increased along with the trajectory of cell differentiation. Additionally, there were significant variations observed in hypoxia genes as cells underwent differentiation. Cellular communication identified non-immune cells interacting with immune cells through multiple signaling pathways. The Wuhan cohort verified that S100A16 expression was increased in liver cancer. The expression of S100A16 and HIF was simultaneously elevated in endothelial cells. CONCLUSION: The strong association between S100A16 and immune cell infiltration is observed in the context of hypoxia, indicating its regulatory role in shaping the hypoxic tumor microenvironment in liver cancer.

Cornuside alleviates psoriasis-like skin lesions in mice by relieving inflammatory effects.

Psoriasis is a chronic inflammatory skin disease substantially affecting the quality of life, with no complete cure owing to its complex pathogenesis. Cornuside, a major bioactive compound present in Cornus officinalis Sieb. et Zucc., which is a well-known traditional Chinese medicine with a variety of biological and pharmacological activities, such as anti-apoptotic, antioxidant, and anti-inflammatory properties. However, its effects on psoriasis remain unclear. Our preliminary analysis of network pharmacology showed that cornuside may be involved in psoriasis by regulating the inflammatory response and IL-17 signaling pathway. Thus, we investigated the protective role and mechanism of cornuside in the pathogenesis of psoriasis in an imiquimod (IMQ)-induced psoriasis mouse model. In-vivo experiments demonstrated that cornuside-treated mice had reduced skin erythema, scales, thickness, and inflammatory infiltration. The Psoriasis Area Severity Index score was significantly lower than that of the IMQ group. Flow cytometry analysis indicated that cornuside effectively inhibited Th1- and Th17-cell infiltration and promoted aggregation of Th2 cells in skin tissues. Cornuside also inhibited the infiltration of macrophages to the skin. Furthermore, in-vitro experiments indicated that cornuside also decreased the polarization of M1 macrophages and reduced the levels of associated cytokines. Western blotting demonstrated that cornuside suppressed the phosphorylation of c-Jun N-terminal kinase (JNK) and extracellular receptor kinase (ERK) in bone marrow-derived macrophages. Our findings indicate that cornuside has a protective effect against IMQ-induced psoriasis by inhibiting M1 macrophage polarization through the ERK and JNK signaling pathways and modulating the infiltration of immune cells as well as the expression of inflammatory factors.

Palmitic acid impairs human and mouse placental function by inhibiting trophoblast autophagy through induction of acyl-coenzyme A-binding protein (ACBP) upregulation.

STUDY QUESTION: Can exposure to palmitic acid (PA), a common saturated fatty acid, modulate autophagy in both human and mouse trophoblast cells through the regulation of acyl-coenzyme A-binding protein (ACBP)? SUMMARY ANSWER: PA exposure before and during pregnancy impairs placental development through mechanisms involving placental autophagy and ACBP expression. WHAT IS KNOWN ALREADY: High-fat diets, including PA, have been implicated in adverse effects on human placental and fetal development. Despite this recognition, the precise molecular mechanisms underlying these effects are not fully understood. STUDY DESIGN, SIZE, DURATION: Extravillous trophoblast (EVT) cell line HTR-8/SVneo and human trophoblast stem cell (hTSC)-derived EVT (hTSCs-EVT) were exposed to PA or vehicle control for 24 h. Female wild-type C57BL/6 mice were divided into PA and control groups (n = 10 per group) and subjected to a 12-week dietary intervention. Afterward, they were mated with male wild-type C57BL/6 mice and euthanized on Day 14 of gestation. Female ACBPflox/flox mice were also randomly assigned to control and PA-exposed groups (each with 10 mice), undergoing the same dietary intervention and mating with ACBPflox/floxELF5-Cre male mice, followed by euthanasia on Day 14 of gestation. The study assessed the effects of PA on mouse embryonic development and placental autophagy. Additionally, the role of ACBP in the pathogenesis of PA-induced placental toxicity was investigated. PARTICIPANTS/MATERIALS, SETTING, METHODS: The findings were validated using real-time PCR, Western blot, immunofluorescence, transmission electron microscopy, and shRNA knockdown approaches. MAIN RESULTS AND THE ROLE OF CHANCE: Exposure to PA-upregulated ACBP expression in both human HTR-8/SVneo cells and hTSCs-EVT, as well as in mouse placenta. PA exposure also induced autophagic dysfunction in HTR-8/SVneo cells, hTSCs-EVT, and mouse placenta. Through studies on ACBP placental conditional knockout mice and ACBP knockdown human trophoblast cells, it was revealed that reduced ACBP expression led to trophoblast malfunction and affected the expression of autophagy-related proteins LC3B-II and P62, thereby impacting embryonic development. Conversely, ACBP knockdown partially mitigated PA-induced impairment of placental trophoblast autophagy, observed both in vitro in human trophoblast cells and in vivo in mice. LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: Primary EVT cells from early pregnancy are fragile, limiting research use. Maintaining their viability is tough, affecting data reliability. The study lacks depth to explore PA diet cessation effects after 12 weeks. Without follow-up, understanding postdiet impacts on pregnancy stages is incomplete. Placental abnormalities linked to elevated PA diet in embryos lack confirmation due to absence of control groups. Clarifying if issues stem solely from PA exposure is difficult without proper controls. WIDER IMPLICATIONS OF THE FINDINGS: Consuming a high-fat diet before and during pregnancy may result in complications or challenges in successfully carrying the pregnancy to term. It suggests that such dietary habits can have detrimental effects on the health of both the mother and the developing fetus. STUDY FUNDING/COMPETING INTEREST(S): This work was supported in part by the National Natural Science Foundation of China (82171664, 82301909) and the Natural Science Foundation of Chongqing Municipality of China (CSTB2022NS·CQ-LZX0062, cstc2019jcyj-msxmX0749, and cstc2021jcyj-msxmX0236). The authors declare that they have no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.

Relationship of long-term exposure to air pollutant mixture with metabolic-associated fatty liver disease and subtypes: A retrospective cohort study of the employed population of Southwest China.

BACKGROUND: While evidence suggests that PM2.5 is associated with overall prevalence of Metabolic (dysfunction)-Associated Fatty Liver Disease (MAFLD), effects of comprehensive air pollutant mixture on MAFLD and its subtypes remain unclear. OBJECTIVE: To investigate individual and joint effects of long-term exposure to comprehensive air pollutant mixture on MAFLD and its subtypes. METHODS: Data of 27,699 participants of the Chinese Cohort of Working Adults were analyzed. MAFLD and subtypes, including overweight/obesity, lean, and diabetes MAFLD, were diagnosed according to clinical guidelines. Concentrations of NO3-, SO42-, NH4+, organic matter (OM), black carbon (BC), PM2.5, SO2, NO2, O3 and CO were estimated as a weighted average over participants' residential and work addresses for the three years preceding outcome assessment. Logistic regression and weighted quantile sum regression were used to estimate individual and joint effects of air pollutant mixture on presence of MAFLD. RESULTS: Overall prevalence of MAFLD was 26.6 % with overweight/obesity, lean, and diabetes MAFLD accounting for 92.0 %, 6.4 %, and 1.6 %, respectively. Exposure to SO42-, NO3-, NH4+, BC, PM2.5, NO2, O3and CO was significantly associated with overall MAFLD, overweight/obesity MAFLD, or lean MAFLD in single pollutant models. Joint effects of air pollutant mixture were observed for overall MAFLD (OR = 1.10 [95 % CI: 1.03, 1.17]), overweight/obesity (1.09 [1.02, 1.15]), and lean MAFLD (1.63 [1.28, 2.07]). Contributions of individual air pollutants to joint effects were dominated by CO in overall and overweight/obesity MAFLD (Weights were 42.31 % and 45.87 %, respectively), while SO42- (36.34 %), SO2 (21.00 %) and BC (12.38 %) were more important in lean MAFLD. Being male, aged above 45 years and smoking increased joint effects of air pollutant mixture on overall MAFLD. CONCLUSIONS: Air pollutant mixture was associated with MAFLD, particularly the lean MAFLD subtype. CO played a pivotal role in both overall and overweight/obesity MAFLD, whereas SO42- were associated with lean MAFLD.

Self-assembled lignin-based flame retardant hybrids carrying Cu2+ for poly(lactic acid) composites with improved fire safety and mechanical properties.

To enhance the flame retardancy and mechanical performance of PLA, a polyelectrolyte complex predicated on lignin was obtained by electrostatic mutual adsorption of ammonium polyphosphate (APP), polyethyleneimine (PEI), and copper ions as raw materials. The FT-IR spectra and EDX analysis confirmed the successful synthesis of a lignin-based flame retardant hybrid (APL-Cu2+) containing copper, phosphorus, and nitrogen elements. The combustion test results showed that the peak heat release rate and total heat release of the PLA composite containing 12 wt% APL-Cu2+ were decreased by 15.1 % and 18.2 %, respectively, as compared to those of pure PLA. The char residue morphology observation revealed that the addition of APL-Cu2+ could promote the formation of a highly dense and stable graphitized char layer, while TG-MS detected the emission of refractory gases such as ammonia gas, carbon dioxide, and water during combustion. The strong hydrogen bonding between APL-Cu2+ and the PLA matrix kept the composite maintaining good strength and toughness. The tensile strength and impact strength of PLA/6APL-Cu2+ increased by 4.73 % and 65.71 %, respectively, due to its high crystallinity and good interfacial compatibility. This work provides a feasible method to develop biobased flame retardant hybrids for PLA composites with better fire safety and improved mechanical properties.

Effects of tumor marker regression load score on long-term prognosis of gastric cancer patients undergoing radical surgery after neoadjuvant chemotherapy.

BACKGROUND: The effects of the dynamics of serum tumor markers (CA72-4, CEA, CA19-9, CA125 and AFP) before and after neoadjuvant chemotherapy (NACT) on the prognosis of gastric cancer(GC) patients remain unclear. METHODS: The training set contained 334 GC patients from Fujian Medical University Union Hospital (FJMUUH) and 113 GC patients in Qinghai University Affiliated Hospital (QhUAH) were used as an external validation set. Tumor marker regression load (ΔTMRL) indicator, including ΔCA72-4, ΔCEA, ΔCA19-9, ΔCA125, and ΔAFP, is defined as [(postNACT marker- preNACT marker)/preNACT marker]. Tumor marker regression load score (TMRLS) consists of ΔCA72-4, ΔCEA and ΔCA125. The predictive performance of the nomogram-TMRLS was evaluated using the area under the receiver operating characteristic(ROC) curve(AUC), decision curve analysis(DCA), and C-index. RESULTS: Patients from FJMUUH were divided into two groups, TMRLS-low and TMRLS-high, determined by R package maxstat. Survival analysis revealed a higher 3-year overall survival(OS) in the TMRLS-low than in the TMRLS-high group. The TMRLS-high group who received postoperative adjuvant chemotherapy(AC) showed a significantly higher 3-year OS rate than those who did not. Multivariate COX regression analysis indicated that TMRLS was an independent prognostic factor for OS. A nomogram for predicting OS based on TMRLS showed a significantly higher C-index and AUC than the ypTNM stage. The above results were also found in the QhUAH external validation cohort. CONCLUSION: TMRLS is a novel independent prognostic factor for GC who underwent NACT and a radical gastrectomy. Furthermore, the TMRLS-high group, who received postoperative AC, may achieve better survival outcomes. Notably, the predictive performance of the nomogram-TMRLS significantly outperformed that of the ypTNM stage.

Rapid detection of hypobromous acid by a tetraphenylethylene-based turn-on fluorescent AIE probe and its applications.

BACKGROUND: Similar to hypochlorous acid (HClO), hypobromous acid (HBrO) is one of the most notable reactive oxygen species (ROS). Overexpression of HBrO is linked to various diseases causing organ and tissue loss. Due to HBrO's role in the oxidation of micropollutants, real-time monitoring of HBrO in water-based systems is essential. Tetraphenylethylene (TPE)-based organic aggregation-induced emission luminophores (AIEgens) are an emerging category of fluorescent probe materials that have attracted considerable attentions. However, AIE probes are rarely applied to detect HBrO. Developing faster, more precise, and more sensitive AIE probes is thus crucial for detecting biological and environmental HBrO. RESULTS: A small molecule fluorescent probe 4-(1,2,2-triphenylvinyl)benzamidoxime (SWJT-21) was synthesized for the sensitive and selective detection of hypobromous acid (HBrO) based on aggregation-induced emission (AIE). The amidoxime unit of SWJT-21 would undergo an oxidation reaction with HBrO, leading to a structure differentiation between the probe and the product, and therefore the turn-on fluorescence by the AIE effect. The probe could recognize hypobromous acid rapidly (less than 3 s) in high aqueous phase (99 % water) with a turn-on fluorescence response. It was determined that the limit of detection for HBrO was 5.47 nM. Moreover, SWJT-21 demonstrates potential as a test strip for the detection of HBrO. SWJT-21 was also successfully used for the monitoring of HBrO in water samples and for the detection of endogenous/exogenous HBrO in living cells and zebrafish. SIGNIFICANCE: A special AIE fluorescence turn-on probe SWJT-21 based on tetraphenylethylene was designed for detecting HBrO in the environmental and biological systems. This probe has an extremely low detection limit of 5.47 nM and is able to detect HBrO in 99 % aqueous phase in less than 3 s.

Targeting endothelial PDGFR-ß facilitates angiogenesis-associated bone formation through the PAK1/NICD axis.

The intricate orchestration of osteoporosis (OP) pathogenesis remains elusive. Mounting evidence suggests that angiogenesis-driven osteogenesis serves as a crucial foundation for maintaining bone homeostasis. This study aimed to explore the potential of the endothelial platelet-derived growth factor receptor-ß (PDGFR-ß) in mitigating bone loss through its facilitation of H-type vessel formation. Our findings demonstrate that the expression level of endothelial PDGFR-ß is reduced in samples obtained from individuals suffering from OP, as well as in ovariectomy mice. Depletion of PDGFR-ß in endothelial cells ameliorates angiogenesis-mediated bone formation in mice. The regulatory influence of endothelial PDGFR-ß on H-type vessels is mediated through the PDGFRß-P21-activated kinase 1-Notch1 intracellular domain signaling cascade. In particular, the endothelium-specific enhancement of PDGFR-ß facilitates H-type vessels and their associated bone formation in OP. Hence, the strategic targeting of endothelial PDGFR-ß emerges as a promising therapeutic approach for the management of OP in the near future.

RPI-GGCN: Prediction of RNA-Protein Interaction Based on Interpretability Gated Graph Convolution Neural Network and Co-Regularized Variational Autoencoders.

RNA-protein interactions (RPIs) play an important role in several fundamental cellular physiological processes, including cell motility, chromosome replication, transcription and translation, and signaling. Predicting RPI can guide the exploration of cellular biological functions, intervening in diseases, and designing drugs. Given this, this study proposes the RPI-gated graph convolutional network (RPI-GGCN) method for predicting RPI based on the gated graph convolutional neural network (GGCN) and co-regularized variational autoencoder (Co-VAE). First, different types of feature information were extracted from RNA and protein sequences by nine feature extraction methods. Second, Co-VAEs are used to eliminate the redundancy of fused features and generate optimal features. Finally, this study introduces gated cyclic units into graph convolutional networks (GCNs) to construct a model for RPI prediction, which efficiently extracts topological information and improves the model's interpretable feature learning and expression capabilities. In the fivefold cross-validation test, the RPI-GGCN method achieved prediction accuracies of 97.27%, 97.32%, 96.54%, 95.76%, and 94.98% on the RPI369, RPI488, RPI1446, RPI1807, and RPI2241 datasets. To test the generalization performance of the model, we used the model trained on RPI369 to predict the independent NPInter v3.0 dataset and achieved excellent performance in all six independent validation sets. By visualizing the RPI network graph based on the prediction results, we aim to provide a new perspective and reference for studying RPI mechanisms and exploring new RPIs. Extensive experimental results demonstrate that RPI-GGCN can provide an efficient, accurate, and stable RPI prediction method.

Association between visceral obesity index and diabetes: a systematic review and meta-analysis.

CONTENT: The correlation between visceral obesity index (VAI) and diabetes and accuracy of early prediction of diabetes are still controversial. OBJECTIVE: This study aims to review the relationship between high level of VAI and diabetes, and early predictive value of diabetes. DATA SOURCES: The databases of PubMed, Cochrane, Embase, and Web of Science were searched until October 17, 2023. STUDY SELECTION: After adjusting for confounding factors, the original study on the association between VAI and diabetes was analyzed. DATA EXTRACTION: We extracted odds ratio (OR) between VAI and diabetes management after controlling for mixed factors, and the sensitivity, specificity and diagnostic four grid table for early prediction of diabetes. DATA SYNTHESIS: 53 studies, comprising 595,946 participants were included. The findings of the meta-analysis elucidated that in cohort studies, a high VAI significantly increased the risk of diabetes mellitus in males (OR = 2.83 (95% CI: 2.30-3.49)) and females (OR = 3.32 (95% CI: 2.48-4.45)). The ROC, sensitivity, and specificity of VAI for early prediction of diabetes in males were 0.64 (95% CI: 0.62-0.66), 0.57 (95% CI: 0.53-0.61), and 0.65 (95% CI: 0.61-0.69), respectively, and 0.67 (95% CI: 0.65-0.69), 0.66 (95% CI: 0.60-0.71), and 0.61 (95% CI: 0.57-0.66) in females, respectively. CONCLUSIONS: VAI is an independent predictor of the risk of diabetes, yet its predictive accuracy remains limited. In future studies, determine whether VAI can be utilized in conjunction with other related indicators to early predict the risk of diabetes, to enhance the accuracy of prediction of the risk of diabetes.

The antitumor action of endocannabinoids in the tumor microenvironment of glioblastoma.

Approximately 80% of all malignant brain tumors are gliomas, which are primary brain tumors. The most prevalent subtype of glioma, glioblastoma multiforme (GBM), is also the most deadly. Chemotherapy, immunotherapy, surgery, and conventional pharmacotherapy are currently available therapeutic options for GBM; unfortunately, these approaches only prolong the patient's life by 5 years at most. Despite numerous intensive therapeutic options, GBM is considered incurable. Accumulating preclinical data indicate that overt antitumoral effects can be induced by pharmacologically activating endocannabinoid receptors on glioma cells by modifying important intracellular signaling cascades. The complex mechanism underlying the endocannabinoid receptor-evoked antitumoral activity in experimental models of glioma may inhibit the ability of cancer cells to invade, proliferate, and exhibit stem cell-like characteristics, along with altering other aspects of the complex tumor microenvironment. The exact biological function of the endocannabinoid system in the development and spread of gliomas, however, is remains unclear and appears to rely heavily on context. Previous studies have revealed that endocannabinoid receptors are present in the tumor microenvironment, suggesting that these receptors could be novel targets for the treatment of GBM. Additionally, endocannabinoids have demonstrated anticancer effects through signaling pathways linked to the classic features of cancer. Thus, the pharmacology of endocannabinoids in the glioblastoma microenvironment is the main topic of this review, which may promote the development of future GBM therapies.

Integrating Network Pharmacology, Quantitative Metabolic Network Analysis, In Vitro Experiments, and Molecular Dynamics to Explore the Mechanism of Angelica Sinensis for Regulating Bone Metabolism.

BACKGROUND: Bone metabolic diseases are serious health issues worldwide. Angelica sinensis (AS) is traditionally used in Chinese medicine for treating bone metabolism diseases clinically. However, the mechanism of AS in regulating bone metabolism remains uncertain. OBJECTIVE: The current investigation was structured to elucidate the potential mechanisms of AS for modulating bone metabolism. METHODS: Firstly, targets of AS regulating bone metabolism were collected by network pharmacology. Then, the transcriptional regulation of RUNX2 was enriched as one of the key pathways for AS to regulate bone metabolism, constructing its metabolic network. Secondly, combining molecular docking, network efficiency, and network flux analyses, we conducted a quantitative evaluation of the metabolic network to reveal the potential mechanisms and components of AS regulating bone metabolism. Finally, we explored the effect of AS on the differentiation of osteoclasts from M-CSF and RANKL-induced RAW264.7 cells, as well as its impact on the osteogenic induction of MC3T3-E1 cells. We verified the mechanism and key targets of AS on bone metabolism using qRT-PCR. Furthermore, the key component was preliminarily validated through molecular dynamics simulation. RESULTS: Quantitative metabolic network of the transcriptional regulation of RUNX2 was constructed to illustrate the potential mechanism of AS for regulating bone metabolism, indicating that ferulic acid may be a pharmacological component of AS that interferes with bone metabolism. AS suppressed osteoclast differentiation in M-CSF and RANKL-induced RAW264.7 cells and reversed the expressions of osteoclastic differentiation markers, including RUNX2 and SRC. Additionally, AS induced osteogenic generation in MC3T3-E1 cells and reversed the expressions of markers associated with osteoblastic generation, such as RUNX2 and HDAC4. Molecular dynamics simulation displayed a strong binding affinity among ferulic acid, HDAC4 and SRC. CONCLUSION: This study reveals a systematic perspective on the intervention bone mechanism of AS by transcriptive regulation by RUNX2, guiding the clinical use of AS in treating diseases of the skeletal system.

Identification of sorbitol esterification of glutamic acid by LC-MS/MS in a monoclonal antibody stability assessment.

The stability of monoclonal antibodies (mAbs) is vital for their therapeutic success. Sorbitol, a common mAb stabilizer used to prevent aggregation, was evaluated for any potential adverse effects on the chemical stability of mAb X. An LC-MS/MS based analysis focusing on the post-translational modifications (PTMs) of mAb X was conducted on samples that had undergone accelerated aging at 40°C. Along with PTMs that are known to affect mAbs' structure function and stability (such as deamidation and oxidation), a novel mAb PTM was discovered, the esterification of glutamic acid by sorbitol. Incubation of mAb X with a 1:1 ratio of unlabeled sorbitol and isotopically labeled sorbitol (13C6) further corroborated that the modification was the consequence of the esterification of glutamic acid by sorbitol. Levels of esterification varied across glutamic acid residues and correlated with incubation time and sorbitol concentration. After 4 weeks of accelerated stability with isotopically labeled sorbitol, it was found that 16% of the total mAb possesses an esterified glutamic acid. No esterification was observed at aspartic acid sites despite the free carboxylic acid side chain. This study unveils a unique modification of mAbs, emphasizing its potential significance for formulation and drug development.

Earthworm-Inspired Ultra-Durable Sliding Triboelectric Nanogenerator with Bionic Self-Replenishing Lubricating Property for Wind Energy Harvesting and Self-Powered Intelligent Sports Monitoring.

Triboelectric nanogenerators (TENGs), a promising strategy for harvesting distributed low-quality power sources, face inevitable bottlenecks regarding long-term abrasion and poor durability. Herein, both issues are addressed by selecting an earthworm-inspired self-replenishing bionic film (ERB) as the tribo-material of sliding-freestanding TENGs (SF-TENGs), it consists of an interconnected 3D porous network structure capable of storing and releasing lubricant under cyclic mechanical stimuli. Thanks to the superiority of self-replenishing property, there is no need for periodic replenishment and accurate content control of lubricant over the interfacial-lubricating SF-TENGs based on dense tribo-layers. Additionally, an SF-TENG based on ERB film (ERB-TENG) demonstrates remarkable output stability with only a slight attenuation of 1% after continuous operation for 100 000 cycles. Moreover, the ERB-TENG displays a distinguished anti-wear property, exhibiting no distinct abrasion with an ultra-low coefficient of friction (0.077) and maintaining output stability over a prolonged period of 35 days. Furthermore, integration with an energy management circuit enables the ERB-TENG to achieve a 39-fold boost in charging speed. This work proposes a creative approach to enhance the durability and extend the lifespan of TENG devices, which is also successfully applied to wind energy harvesting and intelligent sports monitoring.

Prospective association between social isolation, loneliness and lung function among Chinese middle-aged and older adults.

OBJECTIVE: Previous research has highlighted a heightened occurrence of social isolation and loneliness in older adults diagnosed with chronic lung diseases. Nevertheless, there exists a dearth of studies that have explored the influence of impoverished social relationships on lung function. This study aimed to examine the longitudinal association between social isolation, loneliness and lung function over 4 years among middle-aged and older Chinese adults. METHODS: This study employed two waves (2011 and 2015) of data from the China Health and Retirement Longitudinal Study (CHARLS). The analysis was limited to participants aged 45 years and above and stratified based on gender (3325 men and 3794 women). The measurement of peak expiratory flow (PEF) served as an indicator for assessing lung function. Lagged dependent variable regression models, accounting for covariates, were employed to explore the relationship between baseline social isolation and loneliness and the subsequent PEF. RESULTS: For women, social isolation was significantly associated with the decline in PEF at follow-up (ß = -.06, p < .001) even after adjusting for all covariates; no significant correlation was observed between loneliness and PEF. Among men, there was no significant association found between either social isolation or loneliness and PEF. CONCLUSIONS: Social isolation is prospectively associated with worse lung function in middle-aged and older Chinese women but not men. The results highlight the importance of promoting social relationships in public health initiatives, especially in groups that are more vulnerable.

Impact of Infection Prevention Programs on Catheter-Associated Urinary Tract Infections Analyzed in Multicenter Study.

BACKGROUND: Catheter-associated urinary tract infections (CAUTIs) account for a large proportion of healthcare-associated infections and have a significant impact on morbidity, length of hospital stay, and mortality. Adherence to the recommended infection prevention practices can effectively reduce the incidence of CAUTIs. This study aimed to assess the characteristics of CAUTIs and the efficacy of prevention programs across hospitals of various sizes. METHODS: Intervention programs, including training, surveillance, and monitoring, were implemented. Data on the microorganisms responsible for CAUTIs, urinary catheter utilization ratio, rate of CAUTIs per 1,000 device days, and factors associated with the use of indwelling catheters were collected from 2017 to 2019. The incidence of CAUTIs and associated data were compared between university hospitals and small- and medium-sized hospitals. RESULTS: Thirty-two hospitals participated in the study, including 21 university hospitals and 11 small- and medium-sized hospitals. The microorganisms responsible for CAUTIs and their resistance rates did not differ between the two groups. In the first quarter of 2018, the incidence rate was 2.05 infections/1,000 device-days in university hospitals and 1.44 infections/1,000 device-days in small- and medium-sized hospitals. After implementing interventions, the rate gradually decreased in the first quarter of 2019, with 1.18 infections/1,000 device-days in university hospitals and 0.79 infections/1,000 device-days in small- and medium-sized hospitals. However, by the end of the study, the infection rate increased to 1.74 infections/1,000 device-days in university hospitals and 1.80 infections/1,000 device-days in small- and medium-sized hospitals. CONCLUSION: We implemented interventions to prevent CAUTIs and evaluated their outcomes. The incidence of these infections decreased in the initial phases of the intervention when adequate support and personnel were present. The rate of these infections may be reduced by implementing active interventions such as consistent monitoring and adherence to guidelines for preventing infections.