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Objectives: Wnt16 is implicated in bone fracture and bone mass accrual both in animals and humans. However, its functional roles and molecular mechanism in chondrocyte differentiation and osteoarthritis (OA) pathophysiology remain largely undefined. In this study, we analysed its mechanistic association and functional relationship in OA progression in chondrocyte lineage.Methods: The role of Wnt16 during skeletal development was examined by Col2a1-Wnt16 transgenic mice and Wnt16fl/fl;Col2a1-Cre (Wnt16-cKO) mice. OA progression was assessed by micro-CT analysis and Osteoarthritis Research Society International score after anterior cruciate ligament transection (ACLT) surgery with Wnt16 manipulation by adenovirus intra-articular injection. The molecular mechanism was investigated in vitro using 3D chondrocyte pellet culture and biochemical analyses. Histological analysis was performed in mouse joints and human cartilage specimens.Results: Wnt16 overexpression in chondrocytes in mice significantly inhibited chondrocyte hypertrophy during skeletal development. Wnt16 deficiency exaggerated OA progression, whereas intra-articular injection of Ad-Wnt16 markedly attenuated ACLT-induced OA. Cellular and molecular analyses showed that, instead of β-catenin and calcium pathways, Wnt16 activated the planar cell polarity (PCP) and JNK pathway by interacting mainly with AP2b1, and to a lesser extend Ror2 and CD146, and subsequently induced PTHrP expression through phosphor-Raptor mTORC1 pathway.Conclusions: Our findings indicate that Wnt16 activates PCP/JNK and crosstalks with mTORC1-PTHrP pathway to inhibit chondrocyte hypertrophy. Our preclinical study suggests that Wnt16 may be a potential therapeutic target for OA treatment. [ABSTRACT FROM AUTHOR]

Direct nitridation method was used to prepare dense Si-based ceramics for solar thermal storage, and the effect of cordierite as sintering additive on the sintering behaviors of the ceramics was studied. The influence priority between densification and nitride content on the properties of thermal storage ceramics was discussed. Cordierite exhibited a good capability of promoting densification, and the densification temperature could reach 1500 °C. The liquid formed by cordierite helped to construct an interlocking structure of well-grown Si 2 N 2 O flakes. Results of hot stage microscopy and DTA indicated that the endothermic silicothermic reaction between Si and cordierite proceeded at 1440–1460 °C, and released SiO gas. The SiO gas inhibited the densification, but resulted in the low-temperature synthesis of nano-sized Si 3 N 4 whiskers. Samples added with more cordierite showed the cost-effective merits as the smaller costs of raw materials, lower densification temperature, higher thermal conductivity (1.72 W m−1 K−1 deviation), and higher bending strength (34.3–68.1 MPa deviations), compared with the samples having the larger nitride content. Densification by adding cordierite as sintering additive showed the priority on the properties of thermal storage ceramics than increasing the nitride content. [Display omitted] • Sintering behaviors and shrinkage contours were studied by using hot-stage microscope. • The release temperature of SiO gas in the Si-cordierite system was determined. • Nano-sized Si 3 N 4 whiskers were incorporated with the ceramics via an in-situ way. • Si 3 N 4 finally converted to the interlocking Si 2 N 2 O flakes to enhance the strength. • For thermal properties, densification showed the superiority over nitride content. [ABSTRACT FROM AUTHOR]

To explore the association between serum calcium levels within normal ranges and Diabetic Kidney Disease (DKD) in type 2 diabetes patients. In this cross-sectional study, we analyzed clinical data from type 2 diabetes patients admitted to the Endocrinology Department of the Affiliated Hospital of Qingdao University from January 1, 2021, to December 1, 2022. We measured serum calcium levels, corrected for albumin, and screened for diabetes-related complications, including DKD. The association between corrected serum calcium levels and DKD was evaluated using logistic regression, with adjustments made for potential confounders and a generalized additive model (GAM) to explore non-linear relationships, supplemented by subgroup analyses. Among the 3016 patients (52.55% male, 47.45% female), the mean corrected serum calcium was 2.29 ± 0.08 mmol/L. DKD was present in 38.73% of patients. A 0.1 mmol/L increase in corrected serum calcium was associated with a 44% increased risk of DKD (OR = 1.44, 95% CI 1.28–1.61, p < 0.0001). The GAM indicated a linear relationship between corrected serum calcium and DKD risk, consistent across subgroups. Corrected serum calcium levels were linearly associated with DKD risk in type 2 diabetes patients, underlining its potential role in risk assessment. These findings emphasize the clinical importance of monitoring serum calcium levels. However, the need for further prospective studies to confirm these findings is underscored by the study's cross-sectional design. [ABSTRACT FROM AUTHOR]

Introduction: Atopic dermatitis (AD) is a chronic immuno-inflammatory skin disease. Crisaborole ointment, 2%, is a nonsteroidal phosphodiesterase 4 inhibitor approved for the treatment of mild to moderate AD. This post hoc analysis assesses the efficacy and safety of crisaborole in Chinese patients aged ≥ 2 years with mild to moderate AD. Methods: We evaluated the efficacy and safety of crisaborole in Chinese patients from the vehicle-controlled, phase 3 CrisADe CLEAR study. Patients were randomly assigned 2:1 to receive crisaborole or vehicle twice daily, respectively, for 28 days. The primary endpoint was percent change from baseline in Eczema Area and Severity Index (EASI) total score at day 29. Key secondary endpoints were improvement in Investigator's Static Global Assessment (ISGA), ISGA success, and change from baseline in weekly average Peak Pruritus Numerical Rating Scale (PP-NRS) score. Adverse events were documented. Results: Of 391 patients in the overall study, 237 were from China, 157 assigned to crisaborole and 80 assigned to vehicle. A greater reduction in percent change from baseline in EASI total score at day 29 was shown in the crisaborole vs. vehicle group (least squares mean [LSM]: −66.34 [95% (confidence interval) CI −71.55 to −61.12] vs. −50.18 [95% CI −58.02 to −42.34]). Response rates for achievement of ISGA improvement (43.2% [95% CI 35.4–51.1] vs. 33.4% [95% CI 22.5–44.2]) and ISGA success (31.7% [95% CI 24.3–39.0] vs. 21.5% [95% CI 12.1–30.9]) at day 29 were higher in the crisaborole vs. vehicle group. A greater reduction in change from baseline in weekly average PP-NRS score at week 4 was observed in the crisaborole vs. vehicle group (LSM: −1.98 [95% CI −2.34 to −1.62] vs. −1.08 [95% CI −1.63 to −0.53]). No new safety signals were observed. Conclusion: Crisaborole was effective and well tolerated in Chinese patients aged ≥ 2 years with mild to moderate AD. Trial Registration: ClinicalTrials.gov, NCT04360187. [ABSTRACT FROM AUTHOR]

As climate conditions deteriorate, human health faces a broader range of threats. This study aimed to determine the risk of death from metabolic syndrome (MetS) due to meteorological factors. We collected daily data from 2014 to 2020 in Wuhu City, including meteorological factors, environmental pollutants and death data of common MetS (hypertension, hyperlipidemia and diabetes), as well as a total number of 15,272 MetS deaths. To examine the relationship between meteorological factors, air pollutants, and MetS mortality, we used a generalized additive model (GAM) combined with a distributed delay nonlinear model (DLNM) for time series analysis. The relationship between the above factors and death outcomes was preliminarily evaluated using Spearman analysis and structural equation modeling (SEM). As per out discovery, diurnal temperature range (DTR) and daily mean temperature (T mean) increased the MetS mortality risk notably. The ultra low DTR raised the MetS mortality risk upon the general people, with the highest RR value of 1.033 (95% CI: 1.002, 1.065) at lag day 14. In addition, T mean was also significantly associated with MetS death. The highest risk of ultra low and ultra high T mean occured on the same day (lag 14), RR values were 1.043 (95% CI: 1.010, 1.077) and 1.032 (95% CI: 1.003, 1.061) respectively. Stratified analysis's result showed lower DTR had a more pronounced effect on women and the elderly, and ultra low and high T mean was a risk factor for MetS mortality in women and men. The elderly need to take extra note of temperature changes, and different levels of T mean will increase the risk of death. In warm seasons, ultra high RH and T mean can increase the mortality rate of MetS patients. [ABSTRACT FROM AUTHOR]

Background: Observational studies have reported the association between tea consumption and the risk of lower respiratory tract infections (LRTIs). However, a consensus has yet to be reached, and whether the observed association is driven by confounding factors or reverse causality remains unclear. Method: A two-sample Mendelian randomization (MR) analysis was conducted to determine whether genetically predicted tea intake is causally associated with the risk of common LRTI subtypes. Genome-wide association study (GWAS) from UK Biobank was used to identify single-nucleotide polymorphisms (SNPs) associated with an extra cup of tea intake each day. The summary statistics for acute bronchitis, acute bronchiolitis, bronchiectasis, pneumonia, and influenza and pneumonia were derived from the FinnGen project. Results: We found that genetically predicted an extra daily cup of tea intake was causally associated with the decreased risk of bronchiectasis [odds ratio (OR) = 0.61, 95% confidence interval (CI) = 0.47–0.78, P < 0.001], pneumonia (OR = 0.90, 95% CI = 0.85–0.96, P = 0.002), influenza and pneumonia (OR = 0.91, 95% CI = 0.85–0.97, P = 0.002), but not with acute bronchitis (OR = 0.91, 95% CI = 0.82–1.01, P = 0.067) and acute bronchiolitis (OR = 0.79, 95% CI = 0.60–1.05, P = 0.100). Sensitivity analyses showed that no heterogeneity and pleiotropy could bias the results. Conclusions: Our findings provided new evidence that genetically predicted an extra daily cup of tea intake may causally associated with a decreased risk of bronchiectasis, pneumonia, and influenza and pneumonia. [ABSTRACT FROM AUTHOR]

Background: Hepatocellular carcinoma (HCC) is an extensive heterogeneous disease where epigenetic factors contribute to its pathogenesis. Polycomb group (PcG) proteins are a group of subunits constituting various macro-molecular machines to regulate the epigenetic landscape, which contributes to cancer phenotype and has the potential to develop a molecular classification of HCC. Results: Here, based on multi-omics data analysis of DNA methylation, mRNA expression, and copy number of PcG-related genes, we established an epigenetic classification system of HCC, which divides the HCC patients into two subgroups with significantly different outcomes. Comparing these two epigenetic subgroups, we identified different metabolic features, which were related to epigenetic regulation of polycomb-repressive complex 1/2 (PRC1/2). Furthermore, we experimentally proved that inhibition of PcG complexes enhanced the lipid metabolism and reduced the capacity of HCC cells against glucose shortage. In addition, we validated the low chemotherapy sensitivity of HCC in Group A and found inhibition of PRC1/2 promoted HCC cells' sensitivity to oxaliplatin in vitro and in vivo. Finally, we found that aberrant upregulation of CBX2 in Group A and upregulation of CBX2 were associated with poor prognosis in HCC patients. Furthermore, we found that manipulation of CBX2 affected the levels of H3K27me3 and H2AK119ub. Contributions: Our study provided a novel molecular classification system based on PcG-related genes data and experimentally validated the biological features of HCC in two subgroups. Our founding supported the polycomb complex targeting strategy to inhibit HCC progression where CBX2 could be a feasible therapeutic target. [ABSTRACT FROM AUTHOR]

Melatonin (MLT) has been shown to induce polarization of macrophages towards M2-like phenotype and inhibit polarization of macrophages towards M1-like phenotype through exogenous administration, which affects the development of many macrophage polarization-related diseases, such as infectious diseases, cardiovascular diseases, bone diseases, and tumors. However, whether endogenous melatonin has similar influences on macrophage polarization as exogenous melatonin is still under investigation. This study revealed that the process of lipopolysaccharide (LPS) inducing macrophages to polarize towards M1-like phenotype was accompanied by an increase in endogenous MLT secretion. To explore the role of increased endogenous MLT in the polarization process of macrophages, whether similar to the function of exogenous MLT in inhibiting polarization of macrophages towards M1-like phenotype, we established LPS-induced MLT deficiency models in vitro to investigate the effects of endogenous MLT on the secretion of cytokines, co-stimulatory molecules, ROS, and phagocytic function in LPS-induced M1-like macrophages. Additionally, we aimed to elucidate the mechanism by which LPS affects the secretion of endogenous MLT by macrophages. Our results confirm that LPS induces transcription of Aanat through the TLR4/TRIF pathway, consequently facilitating the secretion of MLT by macrophages. In this way, IRF3 is the main transcription factor that regulates Aanat transcription. Endogenous MLT plays a role in inhibiting the polarization of macrophages towards M1 phenotype and delaying cell apoptosis during LPS-induced polarization towards M1 phenotype. This phenomenon may be a form of self-protection that occurs when macrophages engulf pathogens while avoiding oxidative stress and apoptosis caused by LPS. This conclusion clarifies the role of endogenous MLT in the clearance of pathogens by macrophages, providing a theoretical basis for understanding its role in innate immunity. • LPS activates Aanat transcription via the TLR4/TRIF pathway. • IRF3 is one of the main transcription factors that regulates Aanat transcription. • Endogenous MLT inhibits the polarization of macrophages towards M1-like phenotype. [ABSTRACT FROM AUTHOR]

• We advocate the molecular etiology of AS in which the inflammatory microenvironment induces vascularization at the site of bone lesions. • We believe that Tfhs are the prelude to the characteristic angiogenic bony outgrowth in AS known as syndesmophytes. • We speculate that devising therapeutics against angiogenesis or even working higher upstream to control Tfh blockage may be one of the selective options toward a halt in AS progression. Ankylosing spondylitis (AS) is a chronic autoimmune arthritis that mainly affects spine joints. To date, the pathogenesis of AS remains unclear, although immune cells and innate immune response cytokines have been suggested to be crucial players. Methods : By adopting a single-cell RNA sequencing approach in the AS cynomolgus model, we profiled and characterized PBMC proportions along disease progression. Results : Here, our primary focus was on the activation of an immune cascade-initiating lymphocyte subtype known as CD4+CXCR5+ T follicular helper (Tfh) cells. These Tfhs demonstrated a localized residence in AS bone lesion as an ectopic lymphoid structure. Moreover, Tfhs would serve as an upstream initiator for a pro-angiogenic cascade. Then, an expansion in CD14+ monocytes and DC cells subsets resulted in enhanced expression of angiogenesis genes in these AS cynomolgus monkeys. With a confirmed higher abundance of TNF-α accompanying H-type vascular invasion in the osteophytic region, pronounced expansion of Tfhs at such lesion site signaling for monocytes and DCs intrusion is considered as the prelude to the characteristic angiogenic bony outgrowth in AS known as syndesmophytes. Conclusions : We explored the intimate relationship between local inflammation and bone formation in AS from the perspective of nascent vascularisation. Hence, our study lays the foundation for elucidating a unified AS pathogenesis through the immune-angiogenesis-osteogenesis axis. [ABSTRACT FROM AUTHOR]

Melatonin (MLT) was reported to have therapeutic effects on inflammatory bowel disease (IBD) such as ulcerative colitis (UC) and Crohn's disease (CD) due to its anti-inflammatory and immunomodulatory properties. However, whether the beneficial effects of melatonin on colitis are through altering the immune response of bone marrow-derived dendritic cells (BMDCs) has not been well characterized. Here, we propose that MLT alleviates dextran sulfate sodium (DSS)-induced colitis in mice through its regulation of the immune response of BMDCs, in which some lncRNA, circRNA, miRNA, and mRNA may be involved. We at first established a DSS-induced colitis mouse model and found that the concentration of MLT in the serum of DSS-induced colitis mice was significantly lower than that in the control mice. Supplementation with MLT alleviated DSS-induced colitis in mice, which was reflected by preventing mouse body weight loss, colon length shortening, inflammation, and epithelial tissue destruction and abscission in the colon. We then isolated and cultured BMDCs and found that MLT could inhibit the activation of BMDCs from the colitis mice, which was reflected by reducing the phagocytotic ability of the cells, inhibiting their migration, and decreasing their secretion of pro-inflammatory cytokines. RNA sequencing results showed that MLT promoted the transformation of BMDCs into immune tolerant phenotypes in DSS-induced colitis mice through affecting non-coding RNAs (ncRNAs). Among them, lncRNA ENSMUST00000226323, circRNA-0520, and circRNA-2243 were predicted to interact with miRNA-709, and mRNAs of Ywhaz and Ccl9 were the targets of miRNA-709, all of which were involved in MLT-induced alteration of BMDCs functions in DSS-induced colitis mice via PI3K-Akt pathway. Our findings may provide some clues for understanding MLT inhibiting inflammatory response in DSS-induced colitis, which may be through alteration of BMDCs function. [Display omitted] • MLT alleviated DSS-induced colitis in mice through its regulation of the immune response in BMDCs. • MLT inhibited phagocytosis, migration, and proinflammatory cytokine production of BMDCs from the colitis mice. • MLT promoted the transformation of BMDCs into immune tolerant phenotypes in colitis through affecting ncRNAs. • lncRNA_ENSMUST00000226323, circRNA-0520, and circRNA-2243 were predicted to interact with miR-709. • Ywhaz and CCL19 were the targets of miR-709 and involved in altered PI3K-Akt pathway in colitis. [ABSTRACT FROM AUTHOR]

• The IRF5 gene was first studied in AS and was hypomethylated. • IRF5 methylation profiles might be a potential biomarker for the diagnosis of AS and HC. • IRF5 regulated T helper subsets to possibly participate in the development of AS. Interferon regulatory factor 5 (IRF5) plays an important role in the inflammation and immune responses, but its association with ankylosing spondylitis (AS) is under investigated. We aimed to examine the association of IRF5 promoter methylation patterns and transcript levels with the susceptibility to AS. A total of 60 AS patients and 60 healthy controls were included in this study. We used the bisulfite conversion to detect the DNA methylation pattern of IRF5 promoter in whole blood, and the quantitative real-time PCR (qRT-PCR) to detect the relative mRNA expression level in peripheral blood mononuclear cells (PBMCs). The overall methylation level of IRF5 promoter was lower in AS patients compared to healthy controls (P < 0.001). The methylation level of IRF5 promoter was negatively correlated with mRNA level (P = 0.005). The results of receiver operating characteristic curve (ROC) showed that the area under the curve (AUC) was 0.810 (P < 0.001), and the sensitivity and specificity were 71.67% and 85.00%, respectively. There were significant differences between the severe dysfunction group and healthy control group, and between the mild dysfunction group and healthy control group (P = 0.006 and P < 0.001, respectively). Only CRP was significantly correlated with mRNA relative level, while the others were not significant. These findings indicate that IRF5 methylation profile may be involved in the pathological process of AS, and that it may help identify AS patients. [ABSTRACT FROM AUTHOR]

Objectives: T helper 9 (Th9) cells are recognised for their characteristic expression of the transcription factor PU.1 and production of interleukin-9 (IL-9), which has been implicated in various autoimmune diseases. However, its precise relationship with rheumatoid arthritis (RA) pathogenesis needs to be further clarified., Methods: The expression levels of PU.1 and IL-9 in patients with RA were determined by ELISA, western blotting (WB) and immunohistochemical staining. PU.1-T cell-conditional knockout (KO) mice, IL-9 KO and IL-9R KO mice were used to establish collagen antibody-induced arthritis (CAIA), respectively. The inhibitor of PU.1 and IL-9 blocking antibody was used in collagen-induced arthritis (CIA). In an in vitro study, the effects of IL-9 were investigated using siRNAs and IL-9 recombinant proteins. Finally, the underlying mechanisms were further investigated by luciferase reporter analysis, WB and Chip-qPCR., Results: The upregulation of IL-9 expression in patients with RA exhibited a positive correlation with clinical markers. Using CAIA and CIA model, we demonstrated that interventions targeting PU.1 and IL-9 substantially mitigated the inflammatory phenotype. Furthermore, in vitro assays provided the proinflammatory role of IL-9, particularly in the hyperactivation of macrophages and fibroblast-like synoviocytes. Mechanistically, we uncovered that PU.1 and IL-9 form a positive feedback loop in RA: (1) PU.1 directly binds to the IL-9 promoter, activating its transcription and (2) Th9-derived IL-9 induces PU.1 via the IL-9R-JAK1/STAT3 pathway., Conclusions: These results support that the PU.1-IL-9 axis forms a positive loop in Th9 dysregulation of RA. Targeting this signalling axis presents a potential target approach for treating RA., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ on behalf of EULAR.)

Background: Post-translational modification pathway of protein ubiquitination is intricately associated with tumorigenesis. We previously reported elevated ubiquitin-conjugating enzyme 2T (UBE2T) as an independent risk factor in stage I lung adenocarcinoma and promoting cellular proliferation. However, its underlying mechanisms needed further investigation., Methods: Immunohistochemistry was used to assess the expression of UBE2T and retinoic acid receptor-related orphan receptor α (RORA) in stage I LUAD. Cell proliferation, migration, and invasion of LUAD cell lines were measured by Cell Counting Kit-8 assay (CCK-8), Colony-forming assay and Transwell assay, respectively. Western blot analysis was performed to determine the expression of epithelial-mesenchymal transition (EMT) markers. A xenograft model was established to evaluate the proliferative capacity of UBE2T and its interaction with RORA in promoting LUAD. Mechanistic insights into the promotion of early-stage LUAD by UBE2T were obtained through luciferase reporter assay, chromatin immunoprecipitation and co-immunoprecipitation., Results: UBE2T and RORA expression was significantly up- and down-regulated in early-stage LUAD patients which's proved to be associated with unfavorable outcomes, strengthened cell proliferation, migration, EMT and invasion through its interaction with RORA both in vivo and in vitro. The growth NSCLC xenografts was reduced by down-expression of UBE2T but was suppressed by RORA knockout. Mechanistically, UBE2T mediated the ubiquitination of the intermediate transcription factor PBX1, which played a transcriptional role in downstream regulation of RORA., Conclusion: The oncogenic role of UBE2T and the UBE2T-PBX1-RORA axis in driving malignant progression in Stage I LUAD had been established. UBE2T might be a novel and promising therapeutic target for LUAD treatment., (© 2024. The Author(s).)

Herein, we have developed a complementary entry to enable hydroheteroarylation of alkenes involving basically photoredox dearomatizative heterocyclic carbon radical formation through acid-coupled electron transfer followed by Giese addition. While protonic solvent and thiophenol additive enabled two molecular hydroheteroarylations of alkenes, the nonproton environment with BF 3 altered the chemoselectivity over cascade hydroheteroarylation of alkenes by radical addition of heteroaromatics with two molecular alkenes. This chemoselectivity can be mechanistically attributed to the dynamically favored hydrogen atom transfer via the cyclic transition state.

Background and Aims: The Triglyceride-Glucose Index (TyG) has been proposed as a predictor to mortality, yet its association remains incompletely understood for individuals with or without chronic kidney disease (CKD)., Methods and Results: We analyzed data from the National Health and Nutrition Examination Survey spanning the years 1999-2018. CKD was defined as eGFR level <60 ml/min/1.73 m 2 or urinary albumin creatinine ratio ≥30 mg/g. We employed the Cox proportional-hazards model to evaluate the incident risk of mortality associated with TyG among both non-CKD and CKD individuals. In the current analysis, 19,426 individuals were without CKD, while 2975 individuals had CKD. The overall mean TyG was 8.65, with significant difference between non-CKD and CKD individuals (8.60 vs 8.95, P < 0.001). The TyG index exhibited linear associations with incident cardiovascular disease (CVD) mortality and all-cause mortality among non-CKD and CKD individuals, respectively. A per-unit increase in the TyG index was significantly associated with CVD mortality for both non-CKD (HR = 1.24, 95%CI = 1.09-1.41) and CKD participants (HR = 1.19, 95%CI = 1.04-1.36), with no significant difference in the associations between the two groups (P = 0.091). For both non-CKD and CKD participants, TyG index was significantly associated with CVD mortality and all-cause mortality among those with age <65, but not for those with age ≥65., Conclusions: Our findings underscore the TyG index's as a valuable predictive tool for assessing the risk of all-cause and CVD mortality in both individuals with and without CKD., Competing Interests: Declaration of competing interest Authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)