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Background: Abnormal osteoclast and osteoblast differentiation is an essential pathological process in osteoporosis. As an important deubiquitinase enzyme, ubiquitin-specific peptidase 7 (USP7) participates in various disease processes through posttranslational modification. However, the mechanism by which USP7 regulates osteoporosis remains unknown. Herein, we aimed to investigate whether USP7 regulates abnormal osteoclast differentiation in osteoporosis. Methods: The gene expression profiles of blood monocytes were preprocessed to analyze the differential expression of USP genes. CD14+ peripheral blood mononuclear cells (PBMCs) were isolated from whole blood collected from osteoporosis patients (OPs) and healthy donors (HDs), and the expression pattern of USP7 during the differentiation of CD14+ PBMCs into osteoclasts was detected by western blotting. The role of USP7 in the osteoclast differentiation of PBMCs treated with USP7 siRNA or exogenous rUSP7 was further investigated by the F-actin assay, TRAP staining and western blotting. Moreover, the interaction between high-mobility group protein 1 (HMGB1) and USP7 was investigated by coimmunoprecipitation, and the regulation of the USP7-HMGB1 axis in osteoclast differentiation was further verified. Osteoporosis in ovariectomized (OVX) mice was then studied using the USP7-specific inhibitor P5091 to identify the role of USP7 in osteoporosis. Results: The bioinformatic analyses and CD14+ PBMCs from osteoporosis patients confirmed that the upregulation of USP7 was associated with osteoporosis. USP7 positively regulates the osteoclast differentiation of CD14+ PBMCs in vitro. Mechanistically, USP7 promoted osteoclast formation by binding to and deubiquitination of HMGB1. In vivo, P5091 effectively attenuates bone loss in OVX mice. Conclusion: We demonstrate that USP7 promotes the differentiation of CD14+ PBMCs into osteoclasts via HMGB1 deubiquitination and that inhibition of USP7 effectively attenuates bone loss in osteoporosis in vivo.The translational potential of this article:The study reveals novel insights into the role of USP7 in the progression of osteoporosis and provides a new therapeutic target for the treatment of osteoporosis.

Abstract Background Kidney stone disease (KSD) is a common condition that affects 10% population in the United States (US). The relationship between thiamine and riboflavin intake and KSD has not been well-studied. We aimed to investigate the prevalence of KSD and the association between dietary thiamine and riboflavin intake with KSD in the US population. Methods This large-scale, cross-sectional study included subjects from the National Health and Nutrition Examination Survey (NHANES) 2007–2018. KSD and dietary intake were collected from questionnaires and 24-hour recall interviews. Logistic regression and sensitivity analyses were performed to investigate the association. Results This study included 26,786 adult participants with a mean age of 50.12 ± 17.61 years old. The prevalence of KSD was 9.62%. After adjusting for all potential covariates, we found that higher riboflavin intake was negatively related to KSD compared with dietary intake of riboflavin

Abstract Background Cross‐lineage expression of the myeloid‐associated antigens CD13/CD33 is common in adult B‐lymphoblastic leukemia (B‐ALL) patients, yet its prognostic value is still controversial. Methods We conducted a retrospective study of 1005 de novo adult B‐ALL patients from January 2009 to December 2019 in our hospital. Logistic and Cox regression were used to analyze the prognostic value of CD13/CD33 expression in B‐ALL. A Cox regression model was established to predict overall survival (OS) for B‐ALL patients. Results Of the 1005 B‐ALL patients, 53.7% (n = 540) aberrantly expressed CD13/CD33 (CD13/CD33+). Patients in the CD13/CD33+ group showed a higher incidence of BCR::ABL1 rearrangement and minimal/measurable residual disease (MRD) positivity but similar complete remission rate, relapse‐free survival, mortality, and OS with CD13/CD33‐. CD13/CD33+ patients had a higher risk of MRD positivity than CD13/CD33‐ patients. Notably, CD13/CD33+ patients who underwent tyrosine kinase inhibitor (TKI) therapy had a better long‐term prognosis than those without TKI experience. Sex, group based on CD13/CD33 expression and TKI experience and white blood cell count were variables independently associated with OS. The Cox regression model integrating these three variables showed a moderate performance for OS prediction (C‐index: 0.724). Conclusions In real‐world practice, CD13/CD33 expression can predict the risk of MRD in patients without TKI experience, but has no adverse effect on the prognosis of adult B‐ALL patients. Incorporating CD13/CD33 into the standard antibody panels of B‐ALL diagnosis and MRD measurements can help predict relapse risk and decisions on therapy options.

As train speeds continuously increase, the crosswind stability of high-speed trains (HSTs) has been a prominent research topic. Benefiting from advances in railway technology, the coupled operation of different HSTs has been proven to be permissible, but the crosswind performance of double-connected train groups composed of different kinds of HSTs has rarely been studied. This paper therefore studied the differences in the aerodynamic performance of double-connected train groups composed of same and different train units under crosswinds. We employed an improved delayed detached-eddy simulation (IDDES) method to investigate the flow features around different groups of double-connected train. Two one-eighth-scale standard HSTs—Train 1 (T 1) and Train 2 (T 2)—currently operating in China were selected to form different group configurations for double-connected trains: T 1-T 1 (Case 1–1), T 1-T 2 (Case 1–2), T 2-T 1 (Case 2–1), and T 2-T 2 (Case 2–2). First, the reliability of the numerical algorithm and mesh independence were verified to ensure the accuracy of the numerical results. Second, the aerodynamic force coefficients, time-averaged, and instantaneous flow structures of different double-connected train group types were compared and analyzed.

Literature regarding the impacts of heavy metal exposure on erectile dysfunction (ED) is scarce. We aimed to evaluate the correlation between 10 urinary metals and ED in a large, nationally representative adult male sample. The dataset was extracted from the National Health and Nutrition Examination Survey (NHANES) during the period of 2001–2002 and 2003–2004. Weighted proportions and multivariable logistic regression analysis adjusted for confounding variables were utilized to determine the relationship between metal exposure and ED. Weighted quantile sum (WQS) regression was utilized to evaluate the impact of a mixture of urinary metals on ED. A total of 1328 participants were included in our study. In multivariable logistic regression analysis, cobalt (Co) and antimony (Sb) were positively associated with ED (odds ratio [OR]: 1.36, 95% confidence interval [CI]: 1.10–1.73, P = 0.020; and OR: 1.41, 95% CI: 1.12–1.77, P = 0.018, respectively) after full adjustment. Men in tertile 4 for Co (OR: 1.49, 95% CI: 1.02–2.41, P for trend = 0.012) and Sb (OR: 1.53, 95% CI: 1.08–2.40, P for trend = 0.041) had significantly higher odds of ED than those in tertile 1. Furthermore, the WQS index was significantly linked with increased odds of ED after full adjustment (OR: 1.31, 95% CI: 1.04–1.72, P < 0.05). Our study expanded on previous literature indicating the possible role of heavy metal exposure in the etiology of ED. The evaluation of heavy metal exposure should be included in the risk assessment of ED.

Abstract Autophagy is a conserved lysosomal degradation pathway where cellular components are dynamically degraded and re-processed to maintain physical homeostasis. However, the physiological effect of autophagy appears to be multifaced. On the one hand, autophagy functions as a cytoprotective mechanism, protecting against multiple diseases, especially tumor, cardiovascular disorders, and neurodegenerative and infectious disease. Conversely, autophagy may also play a detrimental role via pro-survival effects on cancer cells or cell-killing effects on normal body cells. During disorder onset and progression, the expression levels of autophagy-related regulators and proteins encoded by autophagy-related genes (ATGs) are abnormally regulated, giving rise to imbalanced autophagy flux. However, the detailed mechanisms and molecular events of this process are quite complex. Epigenetic, including DNA methylation, histone modifications and miRNAs, and post-translational modifications, including ubiquitination, phosphorylation and acetylation, precisely manipulate gene expression and protein function, and are strongly correlated with the occurrence and development of multiple diseases. There is substantial evidence that autophagy-relevant regulators and machineries are subjected to epigenetic and post-translational modulation, resulting in alterations in autophagy levels, which subsequently induces disease or affects the therapeutic effectiveness to agents. In this review, we focus on the regulatory mechanisms mediated by epigenetic and post-translational modifications in disease-related autophagy to unveil potential therapeutic targets. In addition, the effect of autophagy on the therapeutic effectiveness of epigenetic drugs or drugs targeting post-translational modification have also been discussed, providing insights into the combination with autophagy activators or inhibitors in the treatment of clinical diseases.

Abstract Background To identify potential targets related to nicotinamide adenine dinucleotide (NAD+) metabolism in gliomas, we used RNA immunoprecipitation to identify a novel long noncoding RNA renamed malate dehydrogenase degradation helper (MDHDH) (NONCODE annotation ID: NONHSAT138800.2, NCBI Reference Sequence: NR_028345), which bound to MDH2 (malate dehydrogenase 2), that is downregulated in glioblastoma multiforme (GBM) and associated with metabolic regulation. However, its underlying mechanisms in the progression of GBM have not been well studied. Methods To investigate the clinical significance of MDHDH, we analyzed its expression levels in publicly available datasets and collected clinical samples from Shandong Provincial Hospital, affiliated with Shandong University. Functional assays, including FISH/CISH, CCK8, EdU, wound healing, and transwell assays, were used to determine the cellular/subcellular localization, tissue expression profile and anti-oncogenic role of MDHDH. Furthermore, RNA pulldown, mass spectrometry RNA immunoprecipitation, coimmunoprecipitation, JC-1 probe, and cell energy-production assays were used to determine the mechanisms of MDHDH in the development of GBM. Animal experiments were conducted to determine the antitumorigenic role of MDHDH in GBM in vivo. Results In public datasets, MDHDH expression was significantly downregulated in GBM and LGG compared with GTEx normal brain tissues. The results of the tissue microarray showed that the MDHDH expression level negatively correlated with the tumor grade. Altered MDHDH expression led to significant changes in the proliferation, migration and invasion of GBM cells both in vitro and in vivo. Mechanistically, we found that MDHDH directly bound to MDH2 and PSMA1 (20S proteasomal core subunit alpha-type 1) as a molecular scaffold and accelerated the degradation of MDH2 by promoting the binding of ubiquitinated MDH2 to the proteasome. The degradation of MDH2 subsequently led to changes in the mitochondrial membrane potential and NAD+/NADH ratio, which impeded glycolysis in glioma cells. Conclusions In conclusion, this study broadened our understanding of the functions of lncRNAs in GBM. We demonstrated that the tumor suppressor MDHDH might act as a clinical biomarker and that the overexpression of MDHDH might be a novel synergistic strategy for enhancing metabolism-based, epigenetic-based, and autophagy regulation-based therapies with clinical benefits for glioblastoma multiforme patients.

Metal organic frameworks (MOF) coated with mammalian cell membranes have good biocompatibility. Here, the authors develop a cobalt based hydrogen sulphide producing MOF cloaked with a macrophage membrane and show that the subsequent system can reduce tumour growth in mice.

For studying the effects of different addition ways of graphene on the properties of polyaniline/epoxy coatings, the in - situ polymerization method was applied to synthesize polyaniline (PANI)/graphene(G) composite powders on graphene surface, and the as - prepared powders were characterized by X - ray diffractometer, Fourier transform infrared spectrometer and scanning electron microscope. The as - synthesized composite powders, the mixed powders of PANI and G, and the PANI powders were uniformly dispersed in epoxy resin respectively to prepare coatings on the surface of AZ91D magnesium alloy. Subsequently, the effects of different graphene addition methods on the properties of polyaniline/epoxy coatings were studied through electrochemical impedance measurement, water absorption, etc. Results showed that after an immersion within 2 160 h in 3.5% (mass fraction) NaCl solution, the coating added with PANI/G composite powders not only had a higher impedance value in comparision with those added with PANI powders or with PANI/G powders, but also had better flexibility and impact resistance. Compared with the mixed powders of PANI and G, the PANI/G composite powders obtained through in - situ polymerization could better exhibit the shielding effect of G and the corrosion inhibition effect of PANI, and therefore provid better protection to magnesium alloy.

Abstract Purpose The purpose of this research was to assess the value of homocysteine (HCY) levels in predicting cognitive dysfunction in patients after acute carbon monoxide (CO) poisoning. Methods A total of 115 patients who were admitted to the emergency department of Yinzhou NO. 2 Hospital after CO poisoning between January 2017 and December 2021 were enrolled in this retrospective study. All patients were followed up for 1 month. According to the Mini–Mental State Examination (MMSE) scores, patients were divided into two groups. The demographic and clinical characteristics and magnetic resonance imaging (MRI) results were gathered and statistically analysed. Results Twenty-six and 89 patients were ultimately enrolled in the cognitive dysfunction and control groups, respectively. There were significant differences between the groups in terms of age, coma duration, and carboxyhaemoglobin (COHB), lactate and HCY levels (p 0.05). Univariate and multivariate analyses identified that a higher HCY level (OR 2.979, 95% CI 1.851-5.596, p