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The separation of nuclear waste is one of the urgent problems to be solved in the nuclear industry; therefore, designing a new and promising extractant to deal with nuclear waste is a desirable but difficult task. Here, using quantum-mechanical calculations at the scalar-relativistic and spin-orbit coupling levels, we assessed the complexation of a series of actinyl moieties by phenanthroline-derived organophosphorus ligands. Specifically, we considered the [UO 2 (L)] 2+ and [AnO 2 (BPP)] 2+ , An = U, Np, Pu, and L = DAP, BPP, and PIP species. First, we find that ligand BPP binds more strongly to the uranyl dication than DAP or PIP, and similarly, BPP binds more strongly to uranyl and neptunyl than plutonyl, as a result of the significant ionic bonding and covalent bonding in the equatorial plane. The results of this work generate a fundamental and qualitative understanding of bonding properties in actinyl complexes, suggest phosphine oxide-derived phenanthroline ligands as a potential extractant for uranyl, and provide some knowledge when designing efficient ligands for the extraction behaviors toward actinide elements.

Background/objectives: Attention-deficit/hyperactivity disorder (ADHD) currently lacks a universally accepted biomarker or diagnostic test, underscoring the need for objective and effective assessment methods. Transcranial magnetic stimulation (TMS) has emerged as a promising tool for both assessing cortical excitability and providing therapeutic interventions. This study conducted two independent meta-analyses to evaluate: 1) the potential of TMS in assessing cortical excitability, and 2) its therapeutic efficacy in managing ADHD symptoms., Methods: A systematic search was conducted in EMBASE, MEDLINE, PsycINFO, ClinicalTrials, and PubMed following PRISMA guidelines. The "cortical excitability" meta-analysis included studies comparing TMS-EMG or TMS-EEG neurophysiological measures between ADHD patients and healthy controls. The "therapeutic" meta-analysis focused on randomized controlled trials (RCTs) evaluating repetitive TMS (rTMS) effects on ADHD symptoms. Standardized mean differences (SMDs) were calculated for pooled effect sizes., Results: In the "cortical excitability" meta-analysis, 17 studies were included, demonstrating significantly reduced short-interval intracortical inhibition (SICI) in ADHD compared to healthy controls (pooled SMD = 0.65, 95% CI: 0.41-0.88, P < 0.00001). No significant differences were observed for motor evoked potentials (MEP), motor thresholds (aMT/rMT), cortical silent period (cSP), ipsilateral silent period (iSP), or intracortical facilitation (ICF). The "therapeutic" meta-analysis, encompassing 8 samples from 7 studies, demonstrated that rTMS significantly improved ADHD symptoms compared to control conditions (pooled SMD = 0.45, 95% CI: 0.19-0.70, P = 0.0006)., Conclusions: This study highlights the potential of TMS as both a diagnostic and therapeutic tool in ADHD. Reduced SICI appears to be a key neurophysiological marker of ADHD, reflecting cortical GABAergic dysfunction. Additionally, rTMS shows promise in alleviating ADHD symptoms, though further studies are needed to confirm long-term therapeutic benefits and optimize stimulation protocols., Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42024507867., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling editor LY declared a past co-authorship with the author Y-FZ., (Copyright © 2025 Han, Wei, Zhao, Zhuang, Zhang, Fang, Zang and Feng.)

In this study, the hierarchical porous materials for adsorbing mycotoxins were prepared by one-step carbonization-activation method using potassium permanganate (KMnO 4 ) and chitin as activators and carbon source, respectively. The hierarchical porous materials had different specific surface area and pore distribution owing to different carbonization temperatures. In this paper, the effects of pH, time and temperature of adsorption as well as the concentration of patulin on the adsorption characteristics were systematically investigated. And we analyzed the adsorption properties and mechanism between hierarchical porous materials and patulin. The results showed that the adsorption process conformed to the pseudo-second-order kinetics and Langmuir model. HPC-600 (hierarchical porous chitin prepared in 600 °C) had the largest specific surface area (1047.8 m 2 ·g -1 ) and the best adsorption performance with adsorption capacity above 9.2 μg/mg. The prepared hierarchical porous materials are expected to be applied to the patulin adsorption., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Atherosclerosis is one of the leading causes of ischemic cardiovascular disease worldwide. Recent studies indicated that vascular smooth muscle cells (VSMCs) play an indispensable role in the progression of atherosclerosis. Exosomes derived from mesenchymal stem cells (MSCs) have demonstrated promising clinical applications in the treatment of atherosclerosis. However, there are still challenges and limitations persist in targeted therapy. This study aims to develop a bionic nano-delivery system by fusing platelet membranes with exosomes (MSC-Exo P ) and explore the anti-atherosclerosis effect of MSC-Exo P by improving the targeting efficiency and participating in regulating the pathophysiological processes associated with VSMCs. The morphology, particle size, stability, and fusion efficiency of MSC-Exo P were assessed using transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), immunofluorescence staining, and Western blotting, respectively. MSC-Exo P was administered intravenously into ApoE -/- mice via the tail vein. In vivo, immunofluorescence staining was used to assess the targeting efficacy of MSC-Exo P . The ORO staining, H&E staining, Masson staining, aortic root immunofluorescence staining, and Western blot were utilized to evaluate the VSMC autophagy and anti-atherosclerosis effects of MSC-Exo P . In vitro, the autophagy activation of MSC-Exo P on VSMCs was further assessed by immunofluorescence staining and Western blotting. The effects of MSC-Exo P on VSMCs proliferation, migration, and foam cell formation were detected by EdU experiment, Transwell experiment, wound healing experiment, ORO staining, and BODIPY staining. The TEM revealed that MSC-Exo P retained a ring nanostructure, which was similar to MSC-Exo in morphology. NTA analysis indicated the MSC-Exo P exhibited a slight increase after cell membrane fusion. Besides, the stability analysis of exosomes and MSC-Exo P resulted in no significant changes in particle size. Western blot analysis confirmed that MSC-Exo P simultaneously expressed platelet-specific markers (GPVI, GPIbα, CD62P) and exosome-specific markers (CD81, TSG101, and Alix). In ApoE -/- mice, the immunofluorescence of aorta and its roots was significantly enhanced after injection of DiI-labeled MSC-Exo P , indicating enhanced targeting of MSC-Exo to atherosclerotic plaques by platelets. In vivo experiments demonstrated that MSC-Exo P could significantly suppress the progression of atherosclerosis and reduce the area of atherosclerotic plaques by reducing lipid deposition and necrotic nucleus area and increasing collagen content. In vitro experiments further revealed that the uptake of MSC-Exo P by foam cells significantly increased, and their proliferation, migration, and foam formation were inhibited by autophagy activation. This study demonstrated successful fusion of platelet membranes with exosomes derived from MSCs. MSC-Exo P could significantly improve the targeting efficiency of atherosclerosis and play an anti-atherosclerosis effect by activating VSMC autophagy., Competing Interests: Declarations. Ethics approval and consent to participate: Animal studies were approved by the Animal Department of Fuwai Hospital and conducted under the approval and supervision of the Experimental Animals Ethics Committee of Fuwai Hospital (FW-2022-0027). Consent for publication: All authors read and agreed to submit the manuscript. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Background: Despite the recent advancements in the treatment of cancer, the 5-year survival of patients with non-small cell lung cancer (NSCLC) remains unsatisfactory. Lung adenocarcinoma (LUAD) is NSCLC's most common subtype, and metastasis is the major cause of death in patients with cancer. Therefore, identifying novel targets associated with metastasis in NSCLC is crucial to improving treatment. This study aimed to characterize the expression of GNGT1 in LUAD and to clarify the mechanism underlying the association between the higher expression level of GNGT1 and worse prognosis in patients., Methods: The transcriptome datasets and clinical information of patients with LUAD were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database. Bioinformatics analyses were performed in 515 patients who were stratified into two groups (high- and low-GNGT1 expression group) according to the GNGT1 level. Overall survival, DNA promotor methylation, immune cell infiltration, gene set enrichment analysis (GSEA), and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed to elucidate the functions of GNGT1 and to identify the related hub genes in LUAD. Their expression and functions in LUAD were verified using tissues from patients and transgenic mice overexpressing GNGT1 under the control of a lung-specific promoter (Scgb1a1-Cre)., Results: GNGT1 was overexpressed in patients with LUAD and was associated with poor prognosis. GNGT1 expression was significantly correlated with gene alteration and hypomethylated promoter status. High GNGT1 expression in patients with LUAD was associated with advanced lymph node metastasis and the degree of immune cell infiltration. Functional enrichment analyses indicated that differentially expressed genes (DEGs) in the high-GNGT1 group participated in DNA replication, DNA replication preinitiation, and M phase, while cell adhesion molecules, apoptosis, and natural killer cell-mediated cytotoxicity were all downregulated. Messenger RNA and protein levels were correspondingly regulated in human LUAD tissues and the Scgb1a1-Cre; LSL-GNGT1 mouse model (GNGT1 fl/+ mice)., Conclusions: GNGT1 was associated with tumor cell proliferation via the enhancement of tumor cell stemness and interaction with driver genes. Elevated GNGT1 expression promoted epithelial-mesenchymal transformation, remodeled the tumor microenvironment, and led to tumor metastasis, ultimately worsening the survival-related prognosis of patients with LUAD., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2024-1200/coif). R.A.d.M. serves as an unpaid editorial board member of Translational Lung Cancer Research from January 2024 to December 2025. The other authors have no conflicts of interest to declare., (Copyright © 2025 AME Publishing Company. All rights reserved.)

Repairing osteochondral defects necessitates the intricate reestablishment of the microenvironment. The cartilage layer consists of a porous gelatin methacryloyl hydrogel (PGelMA) covalently crosslinked with the chondroinductive peptide CK2.1 via a "linker" acrylate-PEG-N-hydroxysuccinimide (AC-PEG-NHS). This layer is optimized for remodeling the senescent microenvironment in the cartilage region, thereby establishing a regenerative microenvironment that supports chondrogenesis. For the bone layer, silk fibroin methacryloyl (SilMA) is coated onto a three dimensional (3D)-printed 45S5 bioactive glass scaffold (BG scaffold). The "exercise hormone" N-lactoyl-phenylalanine (Lac-Phe) is loaded onto the SilMA, endowing it with diversified functions to regulate the osteogenic microenvironment. Systematic analysis in vitro reveals that PGelMA-CK2.1 shifts the microenvironment from a pro-inflammatory into an anti-inflammatory condition, and alleviates cellular senescence, thus modifying the cartilage microenvironment to improve the recruitment, proliferation and chondral differentiation of bone marrow mesenchymal stem cells (BMSCs). The scaffold bone layer enhances microvascular endothelial cell proliferation, migration, and angiogenic activities, which, couple with increased BMSC recruitment and regulatory mechanisms directing BMSC differentiation, favor a shift in the "osteogenesis-adipogenesis" balance toward enhanced osteogenesis. In vivo, it is found that this biphasic biomimetic scaffold favors simultaneous dual tissue regeneration. This approach facilitates the development of bioactive regenerative scaffolds and holds great potential for clinical application., (© 2024 Wiley‐VCH GmbH.)

Bone defect healing is a multi-factorial process involving the inflammatory microenvironment, bone regeneration and the formation of blood vessels, and remains a great challenge in clinical practice. Combined use of three-dimensional (3D)-printed scaffolds and bioactive factors is an emerging strategy for the treatment of bone defects. Scaffolds can be printed using 3D cryogenic printing technology to create a microarchitecture similar to trabecular bone. Melatonin (MT) has attracted attention in recent years as an excellent factor for promoting cell viability and tissue repair. In this study, porous scaffolds were prepared by cryogenic printing with poly(lactic-co-glycolic acid) and ultralong hydroxyapatite nanowires. The hierarchical pore size distribution of the scaffolds was evaluated by scanning electron microscopy (SEM) and micro-computed tomography (micro-CT). Sleep-inspired small extracellular vesicles (MT-sEVs) were then obtained from MT-stimulated cells and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-poly(ethylene glycol)-inorganic pyrophosphate (DSPE-PEG-PPi) was used to modify the membrane of MT-sEVs to obtain PPi-MT-sEVs. RNA sequencing was performed to explore the potential mechanisms. The results demonstrated that PPi-MT-sEVs not only enhanced cell proliferation, migration and angiogenesis, but also regulated the osteogenic/adipogenic fate determination and M1/M2 macrophage polarization switch in vitro. PPi-MT-sEVs were used to coat scaffolds, enabled by the capacity of PPi to bind to hydroxyapatite, and computational simulations were used to analyze the interfacial bonding of PPi and hydroxyapatite. The macrophage phenotype-modulating and osteogenesis-angiogenesis coupling effects were evaluated in vivo. In summary, this study suggests that the combination of hierarchical porous scaffolds and PPi-MT-sEVs could be a promising candidate for the clinical treatment of bone defects., Competing Interests: Declarations. Ethics approval and consent to participate: Ethics approval was granted by the Ethics Committee of Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine. All animal experiments were approved by the Animal Care Committee of Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, and followed the Animal Research: Reporting of In Vivo Experiments (ARRIVE) guidelines. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Originally native to South America, tobacco and is now distributed worldwide as a major cash crop. Nicotine is the main harmful component of tobacco leaves, cigarette smoke and tobacco waste, which severely affects not only the flavor of the tobacco leaf, but also causes great damage to human health. As the anti-smoking movement continued to grow since the 1950s, and consumers become more aware of their health and environmental protection, the world tobacco industry has been committed to research, develop and produce low nicotine cigarette products with relatively low risk to human health. Among various approaches, the use of microorganisms to reduce nicotine content and improve tobacco quality has become one of the most promising methods. Due to increasing interest in nicotine-degrading microorganisms (NDMs), this article reviews recent reports on NDMs, nicotine-degrading enzymes, regulation of nicotine-degrading bacterial consortia and optimization of fermentation conditions, aiming to provide updated references for the in-depth research and application of microorganisms for the degradation of nicotine., Competing Interests: Declarations. Ethics approval and consent to participate: No applicable. Consent for publication: All authors approved the final manuscript and the submission to this journal. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

The understanding of activated sludge microbial status and roles is imperative for improving and enhancing the performance of wastewater treatment plants (WWTPs). In this study, we conducted a deep analysis of activated sludge microbial communities across five compartments (inflow, effluent, and aerobic, anoxic, anaerobic tanks) over temporal scales, employing high-throughput sequencing of 16S rRNA amplicons and metagenome data. Clearly discernible seasonal patterns, exhibiting cyclic variations, were observed in microbial diversity, assembly, co-occurrence network, and metabolic functions. Notably, summer samples exhibited higher α-diversity and were distinctly separated from winter samples. Our analysis revealed that microbial community assembly is influenced by both stochastic processes (66%) and deterministic processes (34%), with winter samples demonstrating more random assembly compared to summer. Co-occurrence patterns were predominantly mutualistic, with over 96% positive correlations, and summer networks were more organized than those in winter. These variations were significantly correlated with temperature, total phosphorus and sludge volume index. However, no significant differences were found among microbial community across five compartments in terms of β diversity. A core community of keystone taxa was identified, playing key roles in eight nitrogen and eleven phosphorus cycling pathways. Understanding the assembly mechanisms, co-occurrence patterns, and functional roles of microbial communities is essential for the design and optimization of biotechnological treatment processes in WWTPs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Diabetic ulcers (DUs) present significant physical and psychological challenges to patients, while placing a significant economic burden on healthcare systems. Promoting the blood vessel regeneration is critical for ensuring the delivery of essential nutrients and oxygen to the injured area, thereby supporting the healing process. To gain insight into the complex molecular mechanisms that drive DUs healing, we performed a comprehensive analysis of single-cell transcriptomic data from healing and non-healing DU states. This analysis revealed a key role of Schlafen5 (SLFN5) signal in modulating key healing processes. SLFN5, a protein known to regulate cellular processes like migration, invasion, inflammation, and cell death, emerged as an important player. Yet, although it is prominent, the specific function of SLFN5 in diabetic skin wounds remained unclear. Our study discovered a marked elevation of SLFN5 levels in endothelial cells within DUs and its suppression notably mitigates the oxidative stress and endoplasmic reticulum stress (ERS)-mediated cell death pathways, including pyroptosis and apoptosis. This finding implies that excessive SLFN5 activity might obstruct wound closure by intensifying cellular stress reactions. Upon further investigation, we found that the antioxidant and cytoprotective effects were mediated through enhanced NRF2 activity, facilitated by the PI3K/Akt signaling pathway. Moreover, our investigation identified that c-Fos as a pivotal transcription factor governing SLFN5 transcription during the development of DUs, offering valuable insights into the regulation of SLFN5 expression. In diabetic mice model, SLFN5 knockdown accelerating wound healing, which was intervened by PI3K/Akt inhibitor. These results hold significant therapeutic potential, indicating that targeting SLFN5 may represent a novel and effective strategy for improving wound healing outcomes in patients with DUs., Competing Interests: Declaration of competing interest The authors have reported no potential conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Previous studies have demonstrated the roles of both microglia homeostasis and RNA editing in sepsis-associated encephalopathy (SAE), yet their relationship remains to be elucidated. In this study, we analyzed bulk and single-cell RNA-seq (scRNA) datasets containing 107 brain tissue and microglia samples from mice with microglial depletion and repopulation to explore canonical RNA editing associated with microglia homeostasis and evaluate its role in SAE. Analysis of mouse brain RNA-Seq revealed hallmarks of microglial repopulation, including peak expressions of Apobec1 and Apobec3 at Day 5 of repopulation and dramatically altered B2m RNA editing. Significant time-dependent changes in brain RNA editing during microglial depletion and repopulation were primarily observed in synapse-related genes, such as Tbc1d24 and Slc1a2. ScRNA-Seq revealed heterogeneous RNA editing among microglia subpopulations and their distinct changes associated with microglia homeostasis. Moreover, repopulated microglia from lipopolysaccharide (LPS)-induced sepsis mice exhibited intensified up-regulation of Apobec1 and Apobec3, with distinct RNA editing responses to LPS, mainly involved in immune-related pathways. The hippocampus from sepsis mice induced by peritoneal contamination and infection showed upregulated Apobec1 and Apobec3 expression, and altered RNA editing in immune-related genes, such as B2m and Mier1, and nervous-related lncRNA Meg3 and Snhg11, both of which were repressed by microglial depletion. Furthermore, the expression of complement-related genes, such as C4b and Cd47, was substantially correlated with RNA editing activity in microglia homeostasis and SAE. Our study demonstrates canonical RNA editing associated with microglia homeostasis and provides new insights into its potential role in SAE., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 International Brain Research Organization (IBRO). Published by Elsevier Inc. All rights reserved.)

Objective: To explore the characteristics and eye disease distribution of human immunodeficiency virus (HIV)-infected or acquired immune deficiency syndrome (AIDS) patients reported by Beijing Tongren Hospital, Capital Medical University. Methods: A retrospective case series study was conducted. Data of HIV-infected or AIDS patients who were reported for the first time in the Chinese Center for Disease Control and Prevention Information System by Beijing Tongren Hospital, Capital Medical University from January 1, 2012 to December 31, 2021 were collected. Epidemiological data such as the patient's gender and age were recorded, and information such as the patient's clinical diagnosis, department classification, and laboratory test results were retrieved from the hospital's outpatient and emergency system and laboratory information system. Results: A total of 191 HIV-infected or AIDS patients were included, with an average age of (36.71±13.52) years, including 177 males and 14 females. The proportion of male and female patients showed no statistically significant change over the years ( P >0.05). Most cases were initially diagnosed in the department of ophthalmology (75 cases, 38.22%), followed by the department of dermatology (49 cases, 25.65%). There were 42 cases (56.00%) reported in the fundus group, 10 cases (13.33%) in the cataract group, 8 cases (10.67%) in the refractive center, and other cases in the glaucoma, cornea, and ocular tumor groups. The ophthalmological diagnoses included uveitis (21 cases, 28.00%), retinopathy (13 cases, 17.33%), cataract (11 cases, 14.67%), refractive error (7 cases, 9.33%), glaucoma (4 cases, 5.33%), retinal detachment (3 cases, 4.00%), vitreous hemorrhage (3 cases, 4.00%), cytomegalovirus retinitis (2 cases, 2.67%), ocular tumor (2 cases, 2.67%), optic neuropathy (2 cases, 2.67%), conjunctivitis (2 cases, 2.67%), keratoconus (1 case, 1.33%), chronic dacryocystitis (1 case, 1.33%), lacrimal duct obstruction (1 case, 1.33%), corneal endothelial decompensation (1 case, 1.33%), and ectropion (1 case, 1.33%). Some patients had co-infections with syphilis, hepatitis B, and hepatitis C. Conclusions: There are undiagnosed HIV-infected or AIDS patients in some departments of non-infectious general hospitals, and the ophthalmological manifestations are mostly uveitis and retinopathy. Ophthalmologists should pay attention to the HIV infection or AIDS infection status of patients with eye diseases such as uveitis and retinopathy to reduce the risk of occupational exposure.

Achieving effective treatment and resource reuse of municipal sludge is a worthwhile research issue. Currently, anaerobic digestion treatment is an effective way to achieve the resource utilization of municipal sludge. However, due to the slow start-up, poor stability and low gas production efficiency of anaerobic digestion systems, sludge anaerobic digestion faces many challenges in practical engineering applications. Iron-based material has been proven to be a good conductive material for promoting anaerobic digestion of municipal sludge. On the basis of previous studies, this article summarized the effects of different iron-based materials on anaerobic digestion of municipal sludge. Simultaneously, from the perspectives of alleviating toxic substance inhibition, enhancing microbial metabolism, and promoting electron transfer between symbiotic microorganisms, the mechanism of iron-based materials enhancing anaerobic digestion of municipal sludge was summarized. The mechanism of direct interspecific electron transfer mediated by iron-based materials in enhancing anaerobic digestion of municipal sludge was described, and the research direction of iron-based materials enhancing anaerobic digestion of municipal sludge was prospected.

Background: Chronic total occlusions (CTO) occur in about 20% of patients referred for coronary angiography, and right coronary artery (RCA) CTO has been reported in 38-50% of the entire CTO population. Limited data on angiographic and procedural characteristics of RCA-CTO and the risk of adverse cardiac events asks for a detailed study., Methods: From 2010 to 2013, patients with attempted revascularization of at least one CTO lesion were included and followed up to 5 years after PCI. Eligible patients are assigned to RCA-CTO and non-RCA-CTO groups based on their target vessels. The primary endpoint was major adverse cardiovascular events (MACEs; a composite of all-cause death, myocardial infarction (MI) or rehospitalization for heart failure), and secondary endpoints were cardiac death, target lesion revascularization (TLR) and target vessel revascularization (TVR)., Results: The present study included 2659 eligible patients, among which 1285 patients were assigned to the RCA-CTO group, whereas 1374 patients were assigned to the non-RCA-CTO group. Lesions in RCA had longer lesion length, higher J-CTO score, higher rates of severe vessel tortuosity, a higher percentage of Rentrop grade 2-3, and more likely to be re-try lesion than those in LAD or LCX (all P < 0.01). CTO lesions in RCA reached less successful recanalization and post-procedural TIMI 3 flow (all <0.01). Multivariate Cox analysis revealed that RCA-CTO was not associated with primary outcome MACEs. Besides MACEs, RCA-CTO was also not associated with cardiac death, but was significantly associated with TLR and TVR (adjusted HR: 1.37 [95% CI:1.07-1.76], P = 0.01; adjusted HR: 1.43 [95% CI:1.13-1.82], P = 0.003)., Conclusion: RCA-CTO lesions, which had more complex angiographic features, independently contributed to TLR and TVR but not to MACEs or cardiac death in the 5 years of follow-up., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Antiphospholipid syndrome (APS) is a systemic autoimmune disorder that can manifest as thrombosis in the pediatric population, characterized by persistently positive antiphospholipid antibodies. APS is infrequently observed in children and could represent non-criteria manifestations., Case Presentation: A six-year-old Chinese female presented with jaundice and dark urine, leading to a diagnosis of hemolytic anemia. Prednisone therapy initially improved her complexion, but she later developed neurological symptoms. Further laboratory tests showed intravascular hemolysis, coagulation abnormalities, and a positive lupus anticoagulant (LA) test result. Magnetic resonance imaging (MRI) scan revealed abnormal signals in the pons and cerebellar hemispheres, and an occluded part of the basilar artery. She was subsequently diagnosed with autoimmune encephalitis and received IG(immunoglobulin) and high-dose glucocorticoid (GC) treatment, leading to improvement in her clinical symptoms. However, the symptoms of hemolytic anemia worsened after two years. Subsequent laboratory assessments demonstrated the presence of intravascular hemolysis, coagulation abnormalities, and positive tests of anticardiolipin, LA, and anti-beta2 glycoprotein I antibodies. Elevated troponin I and N-terminal pro-brain natriuretic peptide levels, along with electrocardiogram and echocardiogram findings, indicated a myocardial infarction and a thrombus-like mass in the left auricle. Brain MRI showed multifocal infarction and cerebrovascular obstruction. She was diagnosed with APS accompanied by hemolytic anemia, cerebrovascular obstruction, and myocardial infarction. After several weeks of treatment with GC, IG, rituximab, hydroxychloroquine alone with low-molecular-weight heparin sodium, and warfarin, there was a marked improvement in the patient's condition., Conclusion: Pediatricians should be familiar with various presentations of pediatric APS to promptly detect possible aPL-related complications and initiate appropriate management strategies early on., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Zheng, Wei, Lin, Wang and Fang.)

Background: Hydrogen sulfide (H 2 S), the third gasotransmitter discovered, regulates a variety of physiological functions. Whether H 2 S alleviates skeletal muscle ageing by regulating autophagy has not been reported., Methods: Mice were administered 150 mg/kg/day of D-galactose (D-gal), and C2C12 myotubes were cultured in 20 g/L D-gal to induce ageing. Sodium hydrosulfide (NaHS) was employed as an exogenous donor in the treatment group. The intracellular concentration of H 2 S was quantified by the 7-azido-4-methylcoumarin fluorescence probe. The proteins involved in the ubiquitin-mediated degradation of AMPKα1 were detected by liquid chromatography tandem mass spectrometry (LC-MS/MS) and co-immunoprecipitation (Co-IP). S-sulfhydration of USP5 was tested by a biotin-switch assay. Associated proteins were analysed by western blot., Results: NaHS was found to effectively restore the H 2 S content in both ageing gastrocnemius (+91.89%, P < 0.001) and C2C12 myotubes (+27.55%, P < 0.001). In comparison to the D-gal group, NaHS was observed to increase the mean cross-sectional area of muscle fibres (+44.91%, P < 0.001), to decrease the collagen volume fraction of gastrocnemius (-81.32%, P = 0.001) and to reduce the β-galactosidase-positive area of C2C12 myotubes (-28.74%, P < 0.001). NaHS was also found to reverse the expression of muscle atrophy F box protein (MAFbx), muscle-specific RING finger protein 1 (MuRF1), Cyclin D1 and p21 in the ageing gastrocnemius tissue (MAFbx: -31.73%, P = 0.008; MuRF1: -32.37%, P = 0.003; Cyclin D1: +45.34%, P = 0.010; p21: -25.53%, P = 0.022) and C2C12 myotubes (MAFbx: -16.38%, P < 0.001; MuRF1: -16.45%, P = 0.003; Cyclin D1: +40.23%, P < 0.001; p21: -35.85%, P = 0.026). The AMPKα1-ULK1 pathway was activated and autophagy was up-regulated in NaHS-treated gastrocnemius tissue (p-AMPKα1: +61.61%, P = 0.018; AMPKα1: +30.64%, P = 0.010; p-ULK1/ULK1: +85.87%, P = 0.005; p62: -29.07%, P < 0.001; Beclin1: +24.75%, P = 0.007; light chain 3 II/I [LC3 II/I]: +55.78%, P = 0.004) and C2C12 myotubes (p-AMPKα1: +77.49%, P = 0.018; AMPKα1: +26.18%, P = 0.022; p-ULK1/ULK1: +38.34%, P = 0.012; p62: -9.02%, P = 0.014; Beclin1: +13.36%, P < 0.001; LC3 II/I: +79.38%, P = 0.017; autophagy flux: +24.88%, P = 0.034) compared with the D-gal group. The effects of NaHS on autophagy were comparable to those of acadesine and LYN-1604, and chloroquine could reverse its effects on ageing. LC-MS/MS and Co-IP experiments demonstrated that USP5 is a deubiquitinating enzyme of AMPKα1. Following the knockdown of USP5, the activation of AMPKα1 was decreased (p-AMPKα1: -42.10%, P < 0.001; AMPKα1: -43.93%, P < 0.001), autophagy was inhibited (p-ULK1/ULK1: -27.51, P = 0.001; p62: +36.00, P < 0.001; Beclin1: -22.15%, P < 0.001) and NaHS lost its ability to up-regulate autophagy. NaHS was observed to restore the expression (gastrocnemius: +62.17%, P < 0.001; C2C12 myotubes: +37.51%, P = 0.003) and S-sulfhydration (+53.07%, P = 0.009) of USP5 and reduce the ubiquitination of AMPKα1., Conclusions: H 2 S promotes the deubiquitination of AMPKα1 by increasing the expression and S-sulfhydration of USP5, thereby up-regulating autophagy and alleviating skeletal muscle ageing., (© 2024 The Author(s). Journal of Cachexia, Sarcopenia and Muscle published by Wiley Periodicals LLC.)

The F11 receptor (F11R) gene encoding junctional adhesion molecule A has been associated with gastric cancer (GC) and colorectal cancer (CRC), in which its role and regulation remain to be further elucidated. Recently F11R was also identified as a potential target of adenosine-to-inosine (A-to-I) mediated by the adenosine deaminases acting on RNA (ADARs). Herein, using RNA-Seq and experimental validation, our current study revealed an F11R RNA trinucleotide over-edited by ADAR, with its regulation of gene expression and clinical significance in four GC and three CRC cohorts. Our results found an over-edited AAA trinucleotide in an AluSg located in the F11R 3'-untranslated region (3'-UTR), which showed editing levels correlated with elevated ADAR expression across all GC and CRC cohorts in our study. Overexpression and knockdown of ADAR in GC and CRC cells, followed by RNA-Seq and Sanger sequencing, confirmed the ADAR-mediated F11R 3'-UTR trinucleotide editing, which potentially disrupted an RBM45 binding site identified by crosslinking immunoprecipitation sequencing (CLIP-seq) and regulated F11R expression in luciferase reporter assays. Moreover, the F11R trinucleotide editing showed promising predictive performance for diagnosing GC and CRC across GC and CRC cohorts. Our findings thus highlight both the potential biological and clinical significance of an ADAR-edited F11R trinucleotide in GC and CRC, providing new insights into its application as a novel diagnostic biomarker for both cancers., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Preoperative risk stratification is significant for the management of endometrial cancer (EC) patients. Radiomics based on magnetic resonance imaging (MRI) in combination with clinical features may be useful to predict the risk grade of EC., Aim: To construct machine learning models to predict preoperative risk stratification of patients with EC based on radiomics features extracted from MRI., Methods: The study comprised 112 EC patients. The participants were randomly separated into training and validation groups with a 7:3 ratio. Logistic regression analysis was applied to uncover independent clinical predictors. These predictors were then used to create a clinical nomogram. Extracted radiomics features from the T2-weighted imaging and diffusion weighted imaging sequences of MRI images, the Mann-Whitney U test, Pearson test, and least absolute shrinkage and selection operator analysis were employed to evaluate the relevant radiomic features, which were subsequently utilized to generate a radiomic signature. Seven machine learning strategies were used to construct radiomic models that relied on the screening features. The logistic regression method was used to construct a composite nomogram that incorporated both the radiomic signature and clinical independent risk indicators., Results: Having an accuracy of 0.82 along with an area under the curve (AUC) of 0.915 [95% confidence interval (CI): 0.806-0.986], the random forest method trained on radiomics characteristics performed better than expected. The predictive accuracy of radiomics prediction models surpassed that of both the clinical nomogram (AUC: 0.75, 95%CI: 0.611-0.899) and the combined nomogram (AUC: 0.869, 95%CI: 0.702-0.986) that integrated clinical parameters and radiomic signature., Conclusion: The MRI-based radiomics model may be an effective tool for preoperative risk grade prediction in EC patients., Competing Interests: Conflict-of-interest statement: The authors declare that they have no competing interests., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

By analyzing the of genetic testing data of patients with renal polycystic kidney disease and their relatives, this study aims to identify unreported novel gene mutation sites associated with autosomal dominant polycystic kidney disease (ADPKD). Structural prediction software was employed to investigate protein structural changes before and after mutations, explore genotype-phenotype correlations, and enrich the ADPKD gene database. In this single-center retrospective study, patients with multiple renal cysts diagnosed from January 2019 to February 2023 at the Zhong Da Hospital Southeast University were included. Genetic and clinical data of patients and their families were collected. Unreported novel gene mutation sites associated with ADPKD were identified. The AlphaFold v2.3.1 software was used to predict protein structures. Changes in protein structure before and after mutations were compared to explore genotype-phenotype correlations and enrich the ADPKD gene database. Twelve mutated genes associated with renal cysts were detected in 52 families. Nineteen novel gene mutation sites associated with ADPKD were identified, including 17 mutations in the PKD1 gene (one splicing mutation, seven frameshift mutations, four nonsense mutations, one whole-codon insertion, and four missense mutations); one ALG9 missense mutation; and one chromosomal structural variation. Truncating mutations in the PKD1 gene were correlated with a more severe clinical phenotype, while non-truncating mutations were associated with greater clinical heterogeneity. Numerous novel gene mutation sites associated with ADPKD remain unreported. Therefore, it is essential to analyze the pathogenicity of these novel mutation sites, establish genotype-phenotype correlations, and enrich the ADPKD gene database.

Sepsis-associated encephalopathy is a diffuse brain dysfunction secondary to infection. It has been established that factors such as age and sex can significantly contribute to the development of sepsis-associated encephalopathy. Our recent study implicated a possible link between adenosine-to-inosine RNA editing and sepsis-associated encephalopathy, yet the dynamics of adenosine-to-inosine RNA editing during sepsis-associated encephalopathy and how it could be influenced by factors such as age, sex and antidepressants remain uninvestigated. Our current study analysed and validated transcriptome-wide changes in adenosine-to-inosine RNA editing in the hippocampus of different septic mouse models. Seventy-four sites in 64 genes showed significant differential RNA editing over time in septic mice induced by caecal ligation and perforation. The differential RNA editing might contribute to the RNA expression regulation of the edited genes, with 42.2% differentially expressed. These differentially edited genes, especially those with missense editing, such as glutamate receptor, ionotropic, kainate 2 ( Grik2 , p.M620V), filamin A ( Flna , p.S2331G) and capicua transcriptional repressor ( Cic , p.E2270G), were mainly involved in abnormal social behaviour and neurodevelopmental and psychiatric disorders. Significant effects of age and sex were also observed on sepsis-associated RNA editing. Further comparison highlighted 40 common differential RNA editing sites that caecal ligation and perforation-induced and lipopolysaccharide-induced septic mouse models shared. Interestingly, these findings demonstrate temporal dynamics of adenosine-to-inosine RNA editing in the mouse hippocampus during sepsis, add to the understanding of age and sex differences in the disease and underscore the role of the epigenetic process in sepsis-associated encephalopathy., Competing Interests: The authors report no competing interests., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Objective: To explore the surgical efficacy of conductive deafness caused by otosclerosis and ossicular malformation with 980 nm fiber laser stapedial floor fenestration. Methods: Data of 58 patients (ears) who were diagnosed with conductive deafness caused by otosclerosis (49 ears) and ossicular malformation (9 ears) treated by 980 nm Diode laser small-fenestra stapedotomy were retrospectively analyzed. Air conduction (AC) thresholds, bone conduction (BC) thresholds, and air-bone gap (ABG) at 0.5, 1, 2, 4 kHz pure tone frequencies were compared before and 3 months after surgery, and the advantages and precautions of 980 nm fiber laser were summarized. Paired t -test (SPSS 26.0 software) was use to analyze the listening data. Results: Fiber optic laser stapes fenestration and artificial stapes implantation were successfully completed in all 57 cases (ears), the hearing of another one patient (ear) with floating malformation of detachment of stapedial floor was lower than that before surgery. Preoperative at 0.5, 1, 2, 4 kHz frequencies of AC thresholds, BC thresholds, and ABG were (65.4±9.7) dB, (27.2±8.9) dB, and (38.2±9.8) dB respectively. Postoperative 3 months at the same frequency of AC thresholds, BC thresholds, and ABG were (42.1±11.3) dB, (26.9±6.6) dB, and (15.2±9.1) dB. Preoperative and postoperative of AC threshold and ABG were statistically significant at 0.5, 1, 2, 4 kHz ( t value was 13.270 and13.948, both P <0.01), and yet the BC threshold was not statistically significant before and after surgery at the same frequency ( t =0.418, P >0.05). Conclusions: 980 nm fiber laser stapes floor fenestration is an effective treatment for conductive deafness caused by otosclerosis and ossicular malformation.

Introduction: The activation of cerebral endothelial cells (CECs) has recently been reported to be the earliest acute neuroinflammation event in the CNS during sepsis-associated encephalopathy (SAE). Importantly, adenosine-to-inosine (A-to-I) RNA editing mediated by ADARs has been associated with SAE, yet its role in acute neuroinflammation in SAE remains unclear., Methods: Our current study systematically analyzed A-to-I RNA editing in cerebral vessels, cerebral endothelial cells (CECs), and microglia sampled during acute neuroinflammation after treatment in a lipopolysaccharide (LPS)-induced SAE mouse model., Results: Our results showed dynamic A-to-I RNA editing activity changes in cerebral vessels during acute neuroinflammation. Differential A-to-I RNA editing (DRE) associated with acute neuroinflammation were identified in these tissue or cells, especially missense editing events such as S367G in antizyme inhibitor 1 ( Azin1 ) and editing events in lincRNAs such as maternally expressed gene 3 ( Meg3 ), AW112010 , and macrophage M2 polarization regulator ( Mm2pr ). Importantly, geranylgeranyl diphosphate synthase 1 ( Ggps1 ) and another three genes were differentially edited across cerebral vessels, CECs, and microglia. Notably, Spearman correlation analysis also revealed dramatic time-dependent DRE during acute neuroinflammation, especially in GTP cyclohydrolase1 ( Gch1 ) and non-coding RNA activated by DNA damage ( Norad ), both with the editing level positively correlated with both post-LPS treatment time and edited gene expression in cerebral vessels and CECs., Discussion: The findings in our current study demonstrate substantial A-to-I RNA editing changes during acute neuroinflammation in SAE, underlining its potential role in the disease., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer QL declared a past co-authorship with the author J-HC to the handling editor. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Li, Liang, Zhang, Li, Wei, Rao, Chen and Jin.)

The gut microbiota has been demonstrated to play a significant role in the pathogenesis of Parkinson's disease (PD). However, conflicting findings regarding specific microbial species have been reported, possibly due to confounding factors within human populations. Herein, our current study investigated the interaction between the gut microbiota and host in a non-human primate (NHP) PD model induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) using a multi-omic approach and a self-controlled design. Our transcriptomic sequencing of peripheral blood leukocytes (PBL) identified key genes involved in pro-inflammatory cytokine dysregulation, mitochondrial function regulation, neuroprotection activation, and neurogenesis associated with PD, such as IL1B, ATP1A3, and SLC5A3. The metabolomic profiles in serum and feces consistently exhibited significant alterations, particularly those closely associated with inflammation, mitochondrial dysfunctions and neurodegeneration in PD, such as TUDCA, ethylmalonic acid, and L-homophenylalanine. Furthermore, fecal metagenome analysis revealed gut dysbiosis associated with PD, characterized by a significant decrease in alpha diversity and altered commensals, particularly species such as Streptococcus, Butyrivibrio, and Clostridium. Additionally, significant correlations were observed between PD-associated microbes and metabolites, such as sphingomyelin and phospholipids. Importantly, PDPC significantly reduced in both PD monkey feces and serum, exhibiting strong correlation with PD-associated genes and microbes, such as SLC5A3 and Butyrivibrio species. Moreover, such multi-omic differential biomarkers were linked to the clinical rating scales of PD monkeys. Our findings provided novel insights into understanding the potential role of key metabolites in the host-microbiota interaction involved in PD pathogenesis., (© 2024. The Author(s).)

An inverse sandwich structure has been computationally predicted for uranium boride and extended to the series of actinide elements (An) from Th to Cm. The electronic structure and chemical bonding of these novel compounds have been analyzed using density functional theory and multireference wave-function based methods. We report the trends in electronic structure and bonding for An 2 B 8 , and found that (d-π)π and (d-p)δ are the most important factors in the stability of An 2 B 8 . The (f-p)δ bond provides extra stabilization for Pa 2 B 8 and U 2 B 8 , owing to the extensive interactions of An-B 8 -An, resulting in a short distance for the Pa-Pa and U-U bonds.

Background: Tissue-engineered heart valves (TEHVs) are promising new heart valve substitutes for valvular heart disease. The Notch signaling pathway plays a critical role in the development of congenital heart valves. Objective: To investigate the role of the Notch signaling pathway in the construction of TEHVs. Methods: The induced endothelial cells, which act as seed cells, were differentiated from adipose-derived stem cells and were treated with Jagged-1 (JAG-1) protein and γ-secretase inhibitor (DAPT, N -[ N -(3,5-difluorophenacetyl)-l-alanyl]-s-phenylglycine t-butyl ester), respectively. Cell phenotypic changes, the expression of proteins relating to the epithelial-mesenchymal transition (EMT), and changes in paxillin expression were detected. Decellularized valve scaffolds were produced from decellularized porcine aortic valves. The seed cells were them inoculated into Matrigel-coated flap scaffolds for complex culture and characterization. Results: JAG-1 significantly reduced apoptosis and promoted the seeded cells' proliferation and migration ability, in contrast to the treatment of DAPT. In addition, the expression of EMT-related proteins, E-cadherin and N-cadherin, was significantly increased after treatment with JAG-1 and was reduced after the application of DAPT. Meanwhile, the adhesive-related expression of paxillin and fibronectin proteins was increased after the activation of Notch1 signaling and vice versa. Of interest, activation of the Notch1 signaling pathway resulted in more closely arranged cells on the valve surface after recellularization. Conclusion: Activation of the JAG-1/Notch1 signaling pathway increased seeded cells' proliferation and migratory ability and promoted the EMT and adhesion of seed cells, which was conducive to binding to the matrix, facilitating accelerated endothelialization of TEHVs.

Background: Metastatic castration-resistant prostate cancer (CRPC), the most refractory prostate cancer, inevitably progresses and becomes unresponsive to hormone therapy, revealing a pressing unmet need for this disease. Novel agents targeting HDAC6 and microtubule dynamics can be a potential anti-CRPC strategy., Methods: Cell proliferation was examined in CRPC PC-3 and DU-145 cells using sulforhodamine B assay and anchorage-dependent colony formation assay. Flow cytometric analysis of propidium iodide staining was used to determine cell-cycle progression. Cell-based tubulin polymerization assay and confocal immunofluorescence microscopic examination determine microtubule assembly/disassembly status. Protein expressions were determined using Western blot analysis., Results: A total of 82 novel derivatives targeting HDAC6 were designed and synthesized, and Compound 25202 stood out, showing the highest efficacy in blocking HDAC6 (IC 50 , 3.5 nM in enzyme assay; IC 50 , 1.0 μM in antiproliferative assay in CRPC cells), superior to tubastatin A (IC 50 , 5.4 μM in antiproliferative assay). The selectivity and superiority of 25202 were validated by examining the acetylation of both α-tubulin and histone H3, detecting cell apoptosis and HDACs enzyme activity assessment. Notably, 25202 but not tubastatin A significantly decreased HDAC6 protein expression. 25202 prolonged mitotic arrest through the detection of cyclin B1 upregulation, Cdk1 activation, mitotic phosphoprotein levels, and Bcl-2 phosphorylation. Compound 25202 did not mimic docetaxel in inducing tubulin polymerization but disrupted microtubule organization. Compound 25202 also increased the phosphorylation of CDC20, BUB1, and BUBR1, indicating the activation of the spindle assembly checkpoint (SAC). Moreover, 25202 profoundly sensitized cisplatin-induced cell death through impairment of cisplatin-evoked DNA damage response and DNA repair in both ATR-Chk1 and ATM-Chk2 pathways., Conclusion: The data suggest that 25202 is a novel selective and potent HDAC6 inhibitor. Compound 25202 blocks HDAC6 activity and interferes microtubule dynamics, leading to SAC activation and mitotic arrest prolongation that eventually cause apoptosis of CRPC cells. Furthermore, 25202 sensitizes cisplatin-induced cell apoptosis through impeding DNA damage repair pathways., (© 2024 Wiley Periodicals LLC.)

Reactivation and infection with cytomegalovirus (CMV) are frequently observed in recipients of solid organ transplants, bone marrow transplants, and individuals with HIV infection. This presents an increasing risk of allograft rejection, opportunistic infection, graft failure, and patient mortality. Among immunocompromised hosts, interstitial pneumonia is the most critical clinical manifestation of CMV infection. Recent studies have demonstrated the potential therapeutic benefits of exosomes derived from mesenchymal stem cells (MSC-exos) in preclinical models of acute lung injury, including pneumonia, ARDS, and sepsis. However, the role of MSC-exos in the pathogenesis of infectious viral diseases, such as CMV pneumonia, remains unclear. In a mouse model of murine CMV-induced pneumonia, we observed that intravenous administration of mouse MSC (mMSC)-exos reduced lung damage, decreased the hyperinflammatory response, and shifted macrophage polarization from the M1 to the M2 phenotype. Treatment with mMSC-exos also significantly reduced the infiltration of inflammatory cells and pulmonary fibrosis. Furthermore, in vitro studies revealed that mMSC-exos reversed the hyperinflammatory phenotype of bone marrow-derived macrophages infected with murine CMV. Mechanistically, mMSC-exos treatment decreased activation of the NF-κB/NLRP3 signaling pathway both in vivo and in vitro. In summary, our findings indicate that mMSC-exo treatment is effective in severe CMV pneumonia by reducing lung inflammation and fibrosis through the NF-κB/NLRP3 signaling pathway, thus providing promising therapeutic potential for clinical CMV infection.

Nonalcoholic fatty liver disease (NAFLD) is one of the common causes of chronic liver disease in the world. The problem of NAFLD had become increasingly prominent. However, its pathogenesis is still indistinct. As we all know, NAFLD begins with the accumulation of triglyceride (TG), leading to fatty degeneration, inflammation and other liver tissues damage. Notably, structure of nucleoporin 85 (NUP85) is related to lipid metabolism and inflammation of liver diseases. In this study, the results of researches indicated that NUP85 played a critical role in NAFLD. Firstly, the expression level of NUP85 in methionine-choline-deficient (MCD)-induced mice increased distinctly, as well as the levels of fat disorder and inflammation. On the contrary, knockdown of NUP85 had the opposite effects. In vitro , AML-12 cells were stimulated with 2 mm free fatty acids (FFA) for 24 h. Results also proved that NUP85 significantly increased in model group, and increased lipid accumulation and inflammation level. Besides, NUP85 protein could interact with C-C motif chemokine receptor 2 (CCR2). Furthermore, when NUP85 protein expressed at an extremely low level, the expression level of CCR2 protein also decreased, accompanied with an inhibition of phosphorylation of phosphoinositol-3 kinase (PI3K)-protein kinase B (AKT) signaling pathway. What is more, trans isomer (ISRIB), a targeted inhibitor of NUP85, could alleviate NAFLD. In summary, our findings suggested that NUP85 functions as an important regulator in NAFLD through modulation of CCR2., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Purpose: Accumulating evidence indicates that mesenchymal stem cells (MSCs)-derived exosomes hold significant potential for the treatment of atherosclerosis. However, large-scale production and organ-specific targeting of exosomes are still challenges for further clinical applications. This study aims to explore the targeted efficiency and therapeutic potential of biomimetic platelet membrane-coated exosome-mimetic nanovesicles (P-ENVs) in atherosclerosis., Methods: To produce exosome-mimetic nanovesicles (ENVs), MSCs were successively extruded through polycarbonate porous membranes. P-ENVs were engineered by fusing MSC-derived ENVs with platelet membranes and characterized using transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), and Western blot. The stability and safety of P-ENVs were also assessed. The targeted efficacy of P-ENVs was evaluated using an in vivo imaging system (IVIS) spectrum imaging system and immunofluorescence. Histological analyses, Oil Red O (ORO) staining, and Western blot were used to investigate the anti-atherosclerotic effectiveness of P-ENVs., Results: Both ENVs and P-ENVs exhibited similar characteristics to exosomes. Subsequent miRNA sequencing of P-ENVs revealed their potential to mitigate atherosclerosis by influencing biological processes related to cholesterol metabolism. In an ApoE -/- mice model, the intravenous administration of P-ENVs exhibited enhanced targeting of atherosclerotic plaques, resulting in a significant reduction in lipid deposition and necrotic core area. Our in vitro experiments showed that P-ENVs promoted cholesterol efflux and reduced total cholesterol content in foam cells. Further analysis revealed that P-ENVs attenuated intracellular cholesterol accumulation by upregulating the expression of the critical cholesterol transporters ABCA1 and ABCG1., Conclusion: This study highlighted the potential of P-ENVs as a novel nano-drug delivery platform for enhancing drug delivery efficiency while concurrently mitigating adverse reactions in atherosclerotic therapy., Competing Interests: None of the authors declare any conflicts of interest., (© 2024 Jiang et al.)

Herbivorous insects employ an array of salivary proteins to aid feeding. However, the mechanisms behind the recruitment and evolution of these genes to mediate plant-insect interactions remain poorly understood. Here, we report a potential horizontal gene transfer (HGT) event from bacteria to an ancestral bug of Eutrichophora. The acquired genes subsequently underwent duplications and evolved through co-option. We annotated them as horizontal-transferred, Eutrichophora-specific salivary protein (HESPs) according to their origin and function. In Riptortus pedestris (Coreoidea), all nine HESPs are secreted into plants during feeding. The RpHESP4 to RpHESP8 are recently duplicated and found to be indispensable for salivary sheath formation. Silencing of RpHESP4-8 increases the difficulty of R. pedestris in probing the soybean, and the treated insects display a decreased survivability. Although silencing the other RpHESPs does not affect the salivary sheath formation, negative effects are also observed. In Pyrrhocoris apterus (Pyrrhocoroidea), five out of six PaHESPs are secretory salivary proteins, with PaHESP3 being critical for insect survival. The PaHESP5, while important for insects, no longer functions as a salivary protein. Our results provide insight into the potential origin of insect saliva and shed light on the evolution of salivary proteins., (© 2024. The Author(s).)

Platelets play a pivotal role in many physiological and pathological processes, with their special targeting/adhering properties towards infarcted myocardium, injured or dysfunctional endothelium, and growing thrombus. Leveraging the site-targeting/adhering property, a variety of platelet-inspired targeting delivery（PITD）designs have been developed, the majority of which are reached by hitchhiking live platelets, cloaking nanoparticles with platelet membranes and mimicking platelet functions. With PITD, drugs or regenerative cells can directly reach targeted sites with minimized systematical distribution thus being of great clinical benefits. Coronary heart disease (CHD) is a major health burden worldwide. Plenty of PITD designs have shown promising outcomes for the treatment of CHD in preclinical models, especially in thrombolysis and post-percutaneous coronary intervention (post-PCI) anti-restenosis. Besides, PITD applications in cardiac protection and atherosclerotic plaque imaging are also under investigation. What's more, the potential benefits of PITD in the field of cell-based therapy are also attracting growing attention since it may resolve the problem of low arriving and retention efficiency, which are also particularly discussed in this review. In brief, our focus is putting on PITD strategies designed for the treatment of CHD, which hopefully can facilitate further optimization of this direction., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Recent studies have revealed that tumor immunotherapy resistance is influenced by ADAR-mediated RNA editing, but its targets remain unelucidated. Our current study identified the poliovirus receptor (PVR) oncogene, which encodes an immune checkpoint in colorectal cancer (CRC), as a potential target for RNA editing. We performed transcriptome sequencing analysis and experimental validation in two Chinese CRC cohorts. PVR and ADAR expressions significantly increased in CRC tumors and showed positive correlations in both cohorts, coupled with upregulated PVR RNA editing in CRC tumors. Manipulation of ADAR expression by over-expression or knockdown substantially changed PVR expression and RNA editing in HTC116 CRC cells. Luciferase reporter and actinomycin D assays further revealed that RNA editing in PVR 3'-UTR could upregulate PVR RNA expression, probably by increasing the RNA stability. By increasing PVR expression, ADAR-mediate RNA editing might contribute to tumor- and immune-related gene functions and pathways in CRC. Moreover, a signature combining PVR RNA editing and expression showed promising predictive performance in CRC diagnosis in both Chinese CRC cohorts. Our findings thus highlight the importance of ADAR-mediated RNA editing in PVR up-regulation in CRC tumors and provide new insight into the application of PVR RNA editing as a novel diagnostic biomarker for CRC., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

We consider the preparation of matrix product states (MPS) on quantum devices via quantum circuits of local gates. We first prove that faithfully preparing translation-invariant normal MPS of N sites requires a circuit depth T=Ω(logN). We then introduce an algorithm based on the renormalization-group transformation to prepare normal MPS with an error ε in depth T=O[log(N/ε)], which is optimal. We also show that measurement and feedback leads to an exponential speedup of the algorithm to T=O[loglog(N/ε)]. Measurements also allow one to prepare arbitrary translation-invariant MPS, including long-range non-normal ones, in the same depth. Finally, the algorithm naturally extends to inhomogeneous MPS.

Background: In this study, we compared the clinical efficacy of endoscope-assisted anterior cervical discectomy and fusion (ACDF) with open ACDF in the treatment of single-segment cervical spondylotic myelopathy., Methods: A retrospective analysis was performed on 52 patients with single-segment cervical spondylotic myelopathy between June 2021 and February 2022, including 33 males and 19 females, with a mean age of 58.42 ± 9.26) years. Among them, 28 patients were treated with endoscope-assisted ACDF (Group A), including 2 cases of C4/5 segment, 16 cases of C5/6 segment, and 10 cases of C6/7 segment; 24 patients were treated with open ACDF (Group B), including 4 cases of C4/5 segment, 11 cases of C5/6 segment, and 9 cases of C6/7 segment. The operation time, intraoperative blood loss, hospital stay, and complications were recorded and compared between the two groups. The Visual Analogue Scale (VAS) and the Japanese Orthopaedic Association (JOA) score were used for clinical evaluation during the follow-up in the 1st month and 3rd month after surgery, and at the final follow-up., Results: The 52 patients were followed up on average for 13.04 months (12-17 months). The operation time in Group A and Group B was (105.18 + 8.66) minutes and (81.88 + 6.05) minutes, the intraoperative blood loss was (84.29 + 13.45) mL and (112.92 + 17.81) mL, and the hospital stay was (6.75 + 1.29) days and (7.63 + 1.41) days, respectively. The difference between the two groups was statistically significant (P < 0.05). The VAS and JOA scores in the 1st month and the 3rd month after surgery and the last follow-up significantly improved in both groups compared with those before surgery (P < 0.05). The VAS and JOA scores of Group A in the 1st month, 3rd month after surgery, and the last follow-up were better than those in Group B (P < 0.05). The complication rate in Group A was 7% (2/28), which was not significantly different from the 17% (4/24) in Group B (P > 0.05)., Conclusion: Both endoscope-assisted ACDF and open ACDF can achieve satisfactory clinical efficacy in the treatment of single-segment cervical spondylotic myelopathy. Although the operation time of endoscope-assisted ACDF is prolonged, it has the advantages of clear vision, thorough decompression, less blood loss, and reduced risk of nerve damage, and is worthy of clinical promotion and application., (© 2024. The Author(s).)

Purpose: The purpose of this study was to identify key genes and their regulatory networks that are conserved in mouse models of age-related macular degeneration (AMD) and human AMD., Methods: Retinal RNA-Seq was performed in laser-induced choroidal neovascularization (CNV) mice at day 3 and day 7 after photocoagulation. Mass spectrometry-based proteomic analysis was performed with retinas collected at day 3. Retinal RNA-Seq data was further compared among mouse models of laser-induced CNV and NaIO3-induced retinal degeneration (RD) and a large AMD cohort., Results: Retinal RNA-Seq revealed upregulated genes and pathways related to innate immunity and inflammation in mice with CNV, with more profound changes at the early stage (day 3). Proteomic analysis further validated these differentially expressed genes and their networks in retinal inflammation during CNV. Notably, the most evident overlap in the retina of mice with laser-induced CNV and NaIO3-induced RD was the upregulation of inflammation-related genes, pointing to a common vital role of retinal inflammation in the early stage for both mouse AMD models. Further comparative transcriptomic analysis of the mouse AMD models and human AMD identified 48 conserved genes mainly involved in inflammation response. Among them, B2M, C3, and SERPING1 were upregulated in all stages of human AMD and the mouse AMD models compared to controls., Conclusions: Our study demonstrates conserved molecular changes related to retinal inflammation in mouse AMD models and human AMD and provides new insight into the translational application of these mouse models in studying AMD mechanisms and treatments.

This study systematically combed the existing evidence of Houyanqing Oral Liquid in the treatment of acute pharyngitis from the &quot;6+1&quot; dimensions of safety, effectiveness, economy, innovation, suitability, accessibility, and characteristics of traditional Chinese medicine(TCM) and carried out qualitative and quantitative analysis of the data from each dimension. The multi-criteria decision analysis(MCDA) model and CSC v2.0 were used to evaluate the clinical value of this drug, so as to provide evidence for the selection of essential drugs in the department of otolaryngology and for medical and health decision-making. The dimensions are graded A, B, C, or D. The adverse reactions of Houyanqing Oral Liquid in the treatment of acute pharyngitis were mainly manifested as abdominal pain, diarrhea, rash, etc., which were relieved after drug withdrawal. In terms of safety, it was considered that Houyanqing Oral Liquid had controllable risk and high safety, which was rated as grade B. Compared with ribavirin aerosol alone, Houyanqing Oral Liquid combined with ribavirin aerosol can significantly improve the total response rate, shorten the time to abatement of fever and di-sappearance of throat pain and mucosal congestion, and alleviate mucosal congestion and cough with sputum. With medium-quality evidence, the effectiveness was rated as grade B. Compared with ribavirin aerosol alone, Houyanqing Oral Liquid combined with ribavirin aerosol had cost-effectiveness advantages in the treatment of acute pharyngitis, and its economy was rated as grade C with the evidence of general quality. For acute pharyngitis, Houyanqing Oral Liquid can shorten the disease course and obviously relieve sore throat. Moreover, it can be used for the treatment of radioactive pharyngitis and oral ulcer, and thus its innovation was rated as grade B. With convenient and simple administration and standard and complete drug information, the suitability of this drug was rated as grade B. Houyanqing Oral Liquid is derived from the folk prescription in Hunan province and has been subjected to real-world studies, and thus the TCM characteristics was rated as grade B. According to the ratings of all the dimensions, the comprehensive value of Houyanqing Oral Liquid in the clinical treatment of acute pharyngitis was determined as grade B, with sufficient evidence and clear results. It is suggested that the results should be conditionally converted into relevant policy of clinical basic drug management according to procedures.

Docosahexaenoic acid (DHA) as one of ω-3 polyunsaturated fatty acids (PUFAs), plays a key role in brain development, and is widely used in food additives and the pharmaceutical industry. Schizochytrium sp. is often considered as a satisfactory strain for DHA industrialization. The aim of this study was to assess the feasibility of phosphopantetheinyl transferase (PPTase) and ω-3 fatty acid desaturase (FAD) for regulating DHA content in Schizochytrium sp. PPTase is essential to activate the polyketide-like synthase (PKS) pathway, which can transfer apo-acyl-carrier protein (apo-ACP) into holo-ACP, and plays a key role in DHA synthesis. Moreover, DHA and docosapentaenoic acid (DPA) are synthesized by the PKS pathway simultaneously, so high DPA synthesis limits the increase of DHA content. In addition, the detailed mechanisms of PKS pathway have not been fully elucidated, so it is difficult to improve DHA content by modifying PKS. However, ω-3 FAD can convert DPA into DHA, and it is the most direct and effective way to increase DHA content and reduce DPA content. Based on this, PPTase was overexpressed to enhance the synthesis of DHA by the PKS pathway, overexpressed ω-3 FAD to convert the co-product of the PKS pathway into DHA, and co-overexpressed PPTase and ω-3 FAD. With these strategies, compared with wild type, the final lipid, and DHA titer were 92.5 and 51.5 g L -1 , which increased by 46.4% and 78.1%, respectively. This study established an efficient DHA production strain, and provided some feasible strategies for industrial DHA production in Schizochytrium sp., (© 2023 Wiley-VCH GmbH.)

Inflammation is implicated in the development of diabetic complications including vascular pathology. Centrosome is known to play a role in cell secretion. We have reported that diabetes can trigger centrosome amplification (CA). Thus, in the present study, we investigated the relationship between CA and the release of proinflammatory cytokines interleukin-1β, tumor necrosis factor-α and interleukin-6 in hCMEC/D3 human endothelial cells treated with advanced glycation end products (AGEs). We found that AGEs induced CA via PLK4 and increased the biosynthesis of the three cytokines via NF-κB. Importantly, treatment of the cells with AGEs also increased the release of the three cytokines. Inhibiting CA by knockdown of polo like kinase 4 (PLK4) attenuated the cytokine release but not their biosynthesis. Knockdown of the cytokines inhibited the CA, while addition of the cytokines individually to the cell culture increased the protein level of PLK4 and CA to a moderate level. Addition of the three cytokines together into the cell culture markedly enhanced the CA, to a level higher than that in the AGEs-treated group. In conclusion, our results provide the direct evidence that the cytokines can induce CA, and suggest that there is a mutual promoting cycle between CA and cytokine release in the treated samples. It is proposed that the cycle of CA-cytokine release is a candidate biological link between diabetes and its complications such as vascular pathologies., Competing Interests: Declaration of competing interest The authors declare no conflict of interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Introduction: The coil handle orientation plays a pivotal role in the therapeutic efficacy of repetitive transcranial magnetic stimulation (rTMS). However, there is currently no consensus on the optimal individualized coil handle orientation, especially for non-motor areas., Case Presentation: The present case reported a short-term effect of functional connectivity (FC)-guided rTMS with coil handle posterior-anterior 45° (PA45°) and posterior-anterior 135° (PA135°) on a patient with insomnia. Notably, in this case, the PA45° orientation was nearly perpendicular to the adjacent sulcus, while the PA135° orientation was almost parallel to it. Local brain activity and functional connectivity were assessed using resting-state functional magnetic resonance imaging (RS-fMRI). Additionally, motor evoked potentials (MEPs) were captured both pre and post-rTMS sessions., Findings: The coil handle orientation PA45° outperformed the PA135° in both RS-fMRI and MEP outcomes. Moreover, a 9-day rTMS treatment led to discernible improvements in symptoms of depression and anxiety, complemented by a modest enhancement in sleep quality., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 International Federation of Clinical Neurophysiology. Published by Elsevier B.V.)

Amnestic mild cognitive impairment (aMCI) is a stage between normal aging and Alzheimer disease (AD) where individuals experience a noticeable decline in memory that is greater than what is expected with normal aging, but dose not meet the clinical criteria for AD. This stage is considered a transitional phase that puts individuals at a high risk for developing AD. It is crucial to intervene during this stage to reduce the changes of AD development. Recently, advanced multimodal magnetic resonance imaging techniques have been used to study the brain structure and functional networks in individuals with aMCI. Through the use of structural magnetic resonance imaging, diffusion tensor imaging, and functional magnetic resonance imaging, abnormalities in certain brain regions have been observed in individuals with aMCI. Specifically, the default mode network, salience network, and executive control network have been found to show abnormalities in both structure and function. This review aims to provide a comprehensive understanding of the brain structure and functional networks associated with aMCI. By analyzing the existing literature on multimodal magnetic resonance imaging and aMCI, this study seeks to uncover potential biomarkers and gain insight into the underlying pathogenesis of aMCI. This knowledge can then guide the development of future treatments and interventions to delay or prevent the progression of aMCI to AD., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Objectives: Over the years, it has been found that colchicine offers substantial benefits in secondary prevention in patients with coronary artery disease (CAD). We studied the effects of colchicine timing because there are no guidelines about when to provide it during the perioperative period for patients with CAD., Methods: Up to January 1, 2023, seven electronic literature databases were screened (including three English databases and four Chinese databases). Randomized controlled trials included only treatment with colchicine in the perioperative period of CAD. The Cochrane Evaluation Tool was used to judge the risk of bias in research. Statistical analysis was performed by Stata 16.0 software., Results: We evaluated twelve studies that found colchicine to be effective in decreasing the occurrence of major adverse cardiac events (MACEs) ( p  < 0.00001), but it also raised the rate of adverse events ( p  = 0.001). Subgroup analysis showed the same benefit in lowering the incidence of MACE with continuous administration of a total daily dose of 0.5 mg postoperatively while minimizing drug-related side effects in the patients ( p  = 0.03). When it comes to preventing surgical stroke occurrences, postoperative administration is more effective ( p  = 0.006). While the effect of simultaneous preoperative and postoperative administration was marginally greater than other periods in reducing postoperative hs-CRP levels ( p  = 0.02)., Conclusion: Colchicine, a traditional anti-inflammatory drug, also reduces the risk of MACE by reducing inflammation after PCI. Administration at different periods had no significant effect on decreasing the occurrence of MACE, but when administered postoperatively, we advise continuous administration with a total daily dose of 0.5 mg to obtain the same benefit while minimizing the drug's side effects. Postoperative administration is the better measure to prevent postoperative stroke events. Due to the effective anti-inflammatory effect of colchicine, we recommend its use as early as possible in the perioperative period and its continued use at low doses in the postoperative period., Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/display&#95;record.php?RecordID=316751, identifier CRD42022316751., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Wei, Lai, Li, Yu, Liu, Hu, Gao and Wu.)

Thoracic aortic aneurysms (TAAs) develop asymptomatically and are characterized by dilatation of the aorta. This is considered a life-threating vascular disease due to the risk of aortic rupture and without effective treatments. The current understanding of the pathogenesis of TAA is still limited, especially for sporadic TAAs without known genetic mutation. Sirtuin 6 (SIRT6) expression was significantly decreased in the tunica media of sporadic human TAA tissues. Genetic knockout of Sirt6 in mouse vascular smooth muscle cells accelerated TAA formation and rupture, reduced survival, and increased vascular inflammation and senescence after angiotensin II infusion. Transcriptome analysis identified interleukin (IL)-1β as a pivotal target of SIRT6, and increased IL-1β levels correlated with vascular inflammation and senescence in human and mouse TAA samples. Chromatin immunoprecipitation revealed that SIRT6 bound to the Il1b promoter to repress expression partly by reducing the H3K9 and H3K56 acetylation. Genetic knockout of Il1b or pharmacological inhibition of IL-1β signaling with the receptor antagonist anakinra rescued Sirt6 deficiency mediated aggravation of vascular inflammation, senescence, TAA formation and survival in mice. The findings reveal that SIRT6 protects against TAA by epigenetically inhibiting vascular inflammation and senescence, providing insight into potential epigenetic strategies for TAA treatment., (© 2023. The Author(s).)

Myopia is one of the most common causes of vision loss globally and is significantly affected by epigenetics. Adenosine-to-inosine (A-to-I RNA) editing is an epigenetic process involved in neurological disorders, yet its role in myopia remains undetermined. We performed a transcriptome-wide analysis of A-to-I RNA editing in the retina of form-deprivation myopia mice. Our study identified 91 A-to-I RNA editing sites in 84 genes associated with myopia. Notably, at least 27 (32.1%) of these genes with myopia-associated RNA editing showed existing evidence to be associated with myopia or related ocular phenotypes in humans or animal models, such as very low-density lipoprotein receptor ( Vldlr ) in retinal neovascularization and hypoxia-induced factor 1 alpha ( Hif1a ). Moreover, functional enrichment showed that RNA editing enriched in FDM was primarily involved in response to fungicides, a potentially druggable process for myopia prevention, and epigenetic regulation. In contrast, RNA editing enriched in controls was mostly involved in post-embryonic eye morphogenesis. Our results demonstrate altered A-to-I RNA editing associated with myopia in an experimental mouse model and warrant further study on its role in myopia development., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Pan, He, Lu, Pan, Wei, Jin, Wang and Chen.)

Background: Alzheimer's disease (AD) is a common, progressive, irreversible, and fatal neurodegenerative disorder with rapidly increasing worldwide incidence. Although much research on magnetic resonance imaging (MRI) of the white matter (WM) in AD has been published, no bibliometric analysis study has investigated this issue. Thus, this study aimed to provide an overview of the current status, hotspots, and trends in MRI of WM in AD., Methods: We searched for records related to MRI studies of WM in AD from 1990 to 2022 in the Web of Science Core Collection (WOSCC) database. CiteSpace (version 5.1.R8) and VOSviewer (version 1.6.19) software were used for bibliometric analyses., Results: A total of 2,199 articles were obtained from this study. From 1990 to 2022, the number of published articles showed exponential growth of y = 4.1374e 0.1294x , with an average of 17.9 articles per year. The top country and institutions were the United States and the University of California Davis, accounting for 44.52 and 5.32% of the total studies, respectively. The most productive journal was Neurology, and the most co-cited journal was Lancet Neurology. Decarli C was the most productive author. The current research frontier trend focuses on the association between small vessel disease and AD, the clinical application and exploration of diffusion MRI, and related markers., Conclusion: This study provides an in-depth overview of publications on MRI of WM in AD, identifying the current research status, hotspots, and frontier trends in the field., Competing Interests: AL was employed by the Sanofi-Aventis China Investment Co., Ltd. W-WZ was employed by the MSD R&D (China) Co., Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Yue, Zhang, Yang, Wang, Sun, Yan, Li, Zhao, Cao, Wang, Wei, Li, Zhu, Yang and Mah.)

Purpose: Helicobacter pylori (HP) infection is an identified risk factor for pediatric chronic gastritis (PCG), but its impact on gastric juice microbiota (GJM) remains to be further elucidated in PCG. This study aimed to analyze and compare the microbial communities and microbial interactive networks of GJM in PCG that clinically tested positive and negative for HP (HP+ and HP-, respectively)., Methods: A total of 45 PCG patients aged from 6 to 16 years were recruited, including 20 HP+ and 25 HP- patients tested by culture and rapid urease test. Gastric juice samples were collected from these PCG patients and subjected to high-throughput amplicon sequencing and subsequent analysis of 16S rRNA genes., Results: While no significant change in alpha diversity, significant differences in beta diversity were observed between HP+ and HP- PCG. At the genus level, Streptococcus, Helicobacter , and Granulicatella were significantly enriched in HP+ PCG, whereas Campylobacter and Absconditabacteriales (SR1) were significantly enriched in HP - PCG. Network analysis showed that Streptococcus was the only genus positively correlated with Helicobacter ( r  = 0.497) in the GJM net work of overall PCG. Moreover, compared to HP- PCG, HP+ PCG showed a reduction in microbial network connectivity in GJM. Netshift analysis identified driver microbes including Streptococcus and other four genera, which substantially contributed to the GJM network transition from HP- PCG to HP+ PCG. Furthermore, Predicted GJM function analysis indicated up-regulated pathways related to the metabolism of nucleotides, carbohydrates, and L-Lysine, the urea cycle, as well as endotoxin peptidoglycan biosynthesis and maturation in HP+ PCG., Conclusion: GJM in HP+ PCG exhibited dramatically altered beta diversity, taxonomic structure, and function, with reduced microbial network connectivity, which could be involved in the disease etiology., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Chen, Xia, Ru, Feng, Tao, Wei, Li, Qian, Lin and Chen.)

Zoledronic acid (ZOL) is a potent antiresorptive agent that increases bone mineral density (BMD) and reduces fracture risk in postmenopausal osteoporosis (PMOP). The anti-osteoporotic effect of ZOL is determined by annual BMD measurement. In most cases, bone turnover markers function as early indicators of therapeutic response, but they fail to reflect long-term effects. We used untargeted metabolomics to characterize time-dependent metabolic shifts in response to ZOL and to screen potential therapeutic markers. In addition, bone marrow RNA-seq was performed to support plasma metabolic profiling. Sixty rats were assigned to sham-operated group (SHAM, n = 21) and ovariectomy group (OVX, n = 39) and received sham operation or bilateral ovariectomy, respectively. After modeling and verification, rats in the OVX group were further divided into normal saline group (NS, n = 15) and ZOL group (ZA, n = 18). Three doses of 100 μg/kg ZOL were administrated to the ZA group every 2 weeks to simulate 3-year ZOL therapy in PMOP. An equal volume of saline was administered to the SHAM and NS groups. Plasma samples were collected at five time points for metabolic profiling. At the end of the study, selected rats were euthanatized for bone marrow RNA-seq. A total number of 163 compound were identified as differential metabolites between the ZA and NS groups, including mevalonate, a critical molecule in target pathway of ZOL. In addition, prolyl hydroxyproline (PHP), leucyl hydroxyproline (LHP), 4-vinylphenol sulfate (4-VPS) were identified as differential metabolites throughout the study. Moreover, 4-VPS negatively correlated with increased vertebral BMD after ZOL administration as time-series analysis revealed. Bone marrow RNA-seq showed that the PI3K-AKT signaling pathway was significantly associated with ZOL-mediated changes in expression (adjusted-p = 0.018). In conclusion, mevalonate, PHP, LHP, and 4-VPS are candidate therapeutic markers of ZOL. The pharmacological effect of ZOL likely occurs through inhibition of the PI3K-AKT signaling pathway., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Li, Wang, Ren, Wei, Hu, Gu, Zhang, Yu and Wang.)