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Quan-Quan Zhuang,1 Zhi-Hang Lin,1 Yan-Cheng Jiang,1 Hao-Hua Deng,2 Shao-Bin He,1,3 Li-Ting Su,4 Xiao-Qiong Shi,2 Wei Chen2 1Department of Pharmacy, Affiliated Quanzhou First Hospital of Fujian Medical University, Quanzhou, 2Department of Pharmaceutical Analysis, School of Pharmacy, Fujian Medical University, Fuzhou, 3Department of Pharmacy, Quanzhou Infectious Disease Hospital, 4Department of Pharmaceutical Analysis, Quanzhou Medical College, Quanzhou, People’s Republic of China Abstract: Dendrite-like cobalt selenide nanostructures were synthesized from cobalt and selenium powder precursors by a solvothermal method in anhydrous ethylenediamine. The as-prepared nanocrystalline cobalt selenide was found to possess peroxidase-like activity that could catalyze the reaction of peroxidase substrates in the presence of H2O2. A spectrophotometric method for uric acid (UA) determination was developed based on the nanocrystalline cobalt selenide-catalyzed coupling reaction between N-ethyl-N-(3-sulfopropyl)-3-methylaniline sodium salt and 4-aminoantipyrine (4-AAP) in the presence of H2O2. Under optimum conditions, the absorbance was proportional to the concentration of UA over the range of 2.0–40 µM with a detection limit of 0.5 µM. The applicability of the proposed method has been validated by determination of UA in human serum samples with satisfactory results. Keywords: enzyme mimics, cobalt selenide, peroxidase-like activity, uric acid, human serum

Traditional antimicrobial-susceptibility testing methodologies, including the isolation and culture of bacteria from urine samples and antibiotic-susceptibility test (AST), are expensive and time-consuming. Therefore, a rapid, user-friendly phenotypic AST is urgently needed to guide treatment strategies. Several novel phenotypic AST platforms based on the physiological characteristics of bacteria obtained directly from clinical urine samples have been proposed as promising methods as rapid AST and appropriate antibiotic treatments. However, inaccurate bacterial quantification can lead to false results when high-accuracy quantitative assays are required using these procedures. Coupling the expression of catalase by pathogens with a chemiluminescence-based analytical method enables a convenient and low-cost operation. Herein, we demonstrate a rapid self-calibrating chemiluminescence sensor that can measure bacterial viability through the variation in catalase activity and its response to hydrogen peroxide after treatment with antibiotics. This rapid nanosensor platform can be utilized to determine the antibiotic susceptibility of uropathogenic Escherichia coli and Klebsiella pneumoniae , which account for 80% of all urinary tract infections, directly from clinical urine samples within 40 min without bacterial quantification. The proposed ultrafast and highly accurate AST can enable the precise guidance of antibiotic prescriptions and shorten the time required for clinical decision-making.

Background: The preservation of islet β-cell function in elderly patients with type 2 diabetes mellitus (T2DM) is a top priority for diabetic control., Aim: To assess the preservation of islet β-cell function among elderly Chinese patients with T2DM after different anti-diabetic treatments., Methods: In this longitudinal observational study, elderly patients with T2DM treated with insulin, oral antidiabetic drugs or a combination of both were enrolled to disclose their islet β-cell function between baseline and follow-up. Islet β-cell function was determined by the plasma Homeostasis Model for β-cell function (HOMA-β), C-peptide and area under the curve (AUC) based on oral glucose tolerance test. Changes in β-cell function (decrement or increment from baseline) between different therapy groups were the outcomes., Results: In total, 745 elderly patients (≥ 60 years) with T2DM [insulin monotherapy, n = 105; oral anti-diabetic drugs (OAD) monotherapy, n = 321; insulin plus OAD, n = 319] had their baseline and follow-up β-cell function assessed during a median observation period of 4.5 years (range, 3.0-7.2 years). Overall, islet β-cell function (HOMA-β, fasting C-peptide, fasting insulin, AUC c-pep , AUC ins , AUC c-pep /AUC glu , AUC ins /AUC glu ) consistently deteriorated over time regardless of the three different antidiabetic treatments. No statistical differences in decrement were observed among the three groups regarding the islet β-cell function indices. All three groups showed an increased ratio of delayed insulin secretion response after 4.5 years of observation., Conclusion: In Chinese elderly patients with T2DM, islet β-cell function progressively declines regardless of insulin supplement or insulin plus OAD treatments., Competing Interests: Conflict-of-interest statement: The authors have declared that no conflict of interests exists., (©The Author(s) 2025. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background and Purpose: Vincamine has extensive biological and pharmaceutical activity. We examined the hepatoprotective effects and mechanisms by which vincamine suppresses hepatic fibrosis., Experimental Approach: Hepatic stellate cells (HSCs), TGF-β stimulated, were cultured with either vincamine, farnesoid X receptor (NR1H4; FXR) agonist or antagonist. Further, C57BL/6 mice were given thioacetamide (TAA) to induce hepatic fibrosis and subsequently treated with vincamine or curcumin., Key Results: Vincamine regulated the deposition of extracellular matrix (ECM), inflammatory factors and S100A4, and up-regulated FXR and TGR5 (GPBA receptor) in activated HSCs, by activating FXR. FXR deficiency blocked vincamine effect on FXR, TGR5, α-smooth muscle actin (α-SMA) and IL1R1 in activated LX-2 cells. Vincamine corrected ECM imbalance, inflammatory secretion and FXR/TGR5 down-regulation in activated LX-2 cells with stimulating medium from LPS-primed THP-1 cells. S100A4 deficiency increased FXR and TGR5, and decreased IL-1β expression in activated THP-1. Further, S100A4 deficiency in activated macrophages could elevate FXR and TGR5 expression in activated LX-2, strengthening the impact of vincamine on α-SMA and IL-1β expression. Further, vincamine reduced serum ALT/AST levels, liver and intestinal histopathological changes, and caused ECM accumulation and protected the intestinal barrier in thioacetamide-induced hepatic fibrosis mice. Vincamine decreased inflammatory factors e.g. caspase 1 and IL-1β, and inhibited the S100A4-mediated FXR-TGR5 pathway., Conclusion and Implications: Vincamine significantly reverses hepatic fibrosis via inhibiting S100A4 involved in the crosstalk between macrophages and HSCs, and by activating the FXR-TGR5 pathway. Targeting the S100A4-mediated FXR dependence on modulating the liver environment may be the key target of vincamine in inhibiting hepatic fibrosis., (© 2025 British Pharmacological Society.)

Background: Despite the fact that an increasing number of studies have focused on developing therapies for acute lung injury, managing acute respiratory distress syndrome (ARDS) remains a challenge in intensive care medicine. Whether the pathology of animal models with acute lung injury in prior studies differed from clinical symptoms of ARDS, resulting in questionable management for human ARDS. To evaluate precisely the therapeutic effect of transplanted stem cells or medications on acute lung injury, we developed an animal model of severe ARDS with lower lung function, capable of keeping the experimental animals survive with consistent reproducibility. Establishing this animal model could help develop the treatment of ARDS with higher efficiency., Results: In this approach, we intratracheally delivered bleomycin (BLM, 5 mg/rat) into rats' left trachea via a needle connected with polyethylene tube, and simultaneously rotated the rats to the left side by 60 degrees. Within seven days after the injury, we found that arterial blood oxygen saturation (SpO 2 ) significantly decreased to 83.7%, partial pressure of arterial oxygen (PaO 2 ) markedly reduced to 65.3 mmHg, partial pressure of arterial carbon dioxide (PaCO 2 ) amplified to 49.2 mmHg, and the respiratory rate increased over time. Morphologically, the surface of the left lung appeared uneven on Day 1, the alveoli of the left lung disappeared on Day 2, and the left lung shrank on Day 7. A histological examination revealed that considerable cell infiltration began on Day 1 and lasted until Day 7, with a larger area of cell infiltration. Serum levels of IL-5, IL-6, IFN-γ, MCP-1, MIP-2, G-CSF, and TNF-α substantially rose on Day 7., Conclusions: This modified approach for BLM-induced lung injury provided a severe, stable, and one-sided (left-lobe) ARDS animal model with consistent reproducibility. The physiological symptoms observed in this severe ARDS animal model are entirely consistent with the characteristics of clinical ARDS. The establishment of this ARDS animal model could help develop treatment for ARDS., Competing Interests: Declarations. Consent for publication: Not applicable. Institutional review board statement: The use of laboratory animals in this study was approved by the Animal Research Committee of the College of Medicine at National Yang Ming Chiao Tung University (IACUC Approval No1090704 and 1101207). Conflicts of interest: All authors declare there is no conflict of interest., (© 2025. The Author(s).)

Introduction: It is well acknowledged that lipids assume a critical role in oocyte maturation and early embryonic metabolism, this study aimed to evaluate the relationship between the lipid composition of plasma and follicular fluid (FF), and the consequences of embryonic development. This study compared the lipidomic profiles of paired plasma and FF samples obtained from sixty-five Chinese women who underwent assisted reproductive technology (ART) treatments., Methods: Non-targeted lipidomics analysis., Result: Results not only indicated similarities in lipid composition between these biofluids, but also revealed a number of unique differences. The biomatrix distinction was found to be primarily driven by lipids belonging to the lysophosphatidylcholines (LPC), phosphatidylethanolamines (PE), ether PE, and triglyceride (TG) classes. In addition, specific species from these subclasses were discovered to be correlated with embryo development outcomes during ART. Notably, the composition of the fatty acyl chains appeared to play a crucial role in these associations. Furthermore, thirteen plasma lipid variables were identified, represented by Phosphatidylcholine 18:014:0 and PE P-18:020:1, which correlated with successful blastocyst formation (BF)., Discussion: The present study demonstrated that FF has a distinctive lipid composition, setting it apart from plasma; and the association observed with embryonic development underscored an important role of lipid composition in the healthy development of oocytes., 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 © 2024 Jiang, Che, Lu, Liu, Ye, Cao, Li, Zhan, Dong, Cheng and O’Neill.)

Background: Berberine, an isoquinoline alkaloid, is known for anti-inflammatory activities. However, the research on the anti-inflammatory mechanism of berberine is not comprehensive. Recently, studies have shown that MrgprB2 (Mas-related G-protein-coupled receptor B2) in mice and MrgprX2 (Mas-related G-protein-coupled receptor X2) in humans play vital roles in inflammation. Therefore, this study aims to investigate whether the anti-inflammatory activity of berberine is related to MrgprB2 receptor., Methods: The anti-inflammatory activity of BH (berberine hydrochloride) was evaluated by hindpaw edema analysis, pathological analysis and RT-qPCR. Transgenic mice (MrgprB2 -/- mice), HEK293T cell transfection, calcium imaging, electrophysiology, molecular docking and other methods were employed to investigate the potential relationship between the anti-inflammatory activity of BH and the MrgprB2 receptor., Results: The results demonstrated that BH significantly alleviated C48/80 (compound 48/80)-induced local inflammation in vivo. This was evidenced by a decrease in paw edema, reduced infiltration of inflammatory cells, inhibition of mast cell activation, and down-regulation of inflammatory factors such as CXCL13 (CXC subfamily 13) and TNF-α (tumor necrosis factor-α). It was also found that knockout of MrgprB2 receptor could block the anti-inflammatory activity of BH in mice. Furthermore, calcium imaging revealed that BH effectively inhibited the activity of MrgprB2 receptor in overexpressed HEK293T cells in vitro. Additionally, it was observed that BH also inhibited MrgprB2-mediated voltage-dependent current changes in mouse peritoneal mast cells. Molecular docking results further indicated that BH had affinity with MrgprX2 protein., Conclusions: The anti-inflammatory mechanism of BH may be partially attributed to the inhibition of MrgprB2 receptor-mediated mast cell activation., 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.)

A contamination analysis was conducted on the soil and crops in the Liu Jia Dian gold mining area of the Pinggu District, Beijing, utilizing the contents and seven-step forms of heavy metals （Hg, Cd, Cr, Pb, and As） in soil and the heavy metal contents in crops at the same location. An assessment of ecological risk caused by heavy metal contamination in the soil and crops was carried out using the enrichment coefficient method and the risk assessment coding method. The study investigated the process of heavy metal absorption and enrichment in the soil-crop system, aiming to establish a scientific foundation for preventing and controlling soil pollution, as well as ensuring the safety of edible crops in the study area. Evidence indicated the presence of soil contamination by heavy metals in the study area, with Cd, Pb, and As being the primary pollutants. Moreover, the distribution of pollution levels could be categorized as severe, moderate, and mild, with proportions of 26.09%, 4.35%, and 10.87%, respectively. The content of each heavy metal decreased following the implementation of environmental governance； however, the ecological risk remains present. Hg, Cr, Pb, and As posed minor ecological risks； however, Cd had a high ecological risk, making it the primary soil ecological risk factor. Fruits, nuts, and cereals in the Pinggu gold mining area remained uncontaminated. Various degrees of contamination were found in melons, rhizomes, and leafy vegetables. The Chinese cabbage, Chinese chive, radish, and eggplant were heavily contaminated, with Cd and Pb being the primary sources of contamination. The accumulation of heavy metals in crops was intricately linked to gold mines and their mining operations. The accumulation of Cd in crops was mainly influenced by the high availability of Cd in soil, whereas the accumulation of Pb was mainly influenced by the high concentration of Pb in the soil. The concentration of heavy metals in the soil and their bioavailability in the Pinggu gold mining area indicated the accumulation of metal elements in crops and impacted the geographical distribution of heavy metal pollution in crops. The physiological characteristics of crops could affect the degree of heavy metal enrichment in the gold mining area. The order of heavy metal accumulation, from highest to lowest, was as follows： leafy vegetables, melons, rhizomes, cereal, fruits, and nuts. Peppers and eggplants were limited in their planting variations for melons, while leeks and cabbages were restricted for leafy vegetables, given the current agricultural planting conditions in the study area.

We present the case of a 60-year-old female patient with no prior history of any systemic disease. She suffered from a prolonged cough that lasted more than 3 months, associated with poor appetite and weight loss of 5 kg. The pathology report of the pre-operative transbronchial needle biopsy was consistent with a neurogenic tumour. Chest computed tomography (CT) revealed a right lower lobe (RLL) mass-like consolidation of 8.67 cm with obstructive pneumonitis and suspicious posterior mediastinal invasion. The tumour was surgically resected with bronchial reconstruction, and the pathological diagnosis was intrabronchial schwannoma located inside the bronchus, a rare tumour that should be included as one of the differential diagnoses of primary bronchial tumours. The possibility of a surgical completed resection should be considered in patients with airway obstruction symptoms., Competing Interests: None declared., (© 2024 The Author(s). Respirology Case Reports published by John Wiley & Sons Australia, Ltd on behalf of The Asian Pacific Society of Respirology.)

Background: Weight loss through lifestyle interventions, notably low-energy diets, offers glycemic benefits in populations with overweight-associated prediabetes. However, >50% of these individuals fail to achieve normoglycemia after weight loss. Circulating lipids hold potential for evaluating dietary impacts and predicting diabetes risk., Objectives: This study sought to identify serum lipids that could serve as evaluative or predictive biomarkers for individual glycemic changes following diet-induced weight loss., Methods: We studied 104 participants with overweight-associated prediabetes, who lost ≥8% weight via a low-energy diet over 8 wk. High-coverage lipidomics was conducted in serum samples before and after the dietary intervention. The lipidomic recalibration was assessed using differential lipid abundance comparisons and partial least squares discriminant analyses. Associations between lipid changes and clinical characteristics were determined by Spearman correlation and Bootstrap Forest of ensemble machine learning model. Baseline lipids, predictive of glycemic parameters changes postweight loss, were assessed using Bootstrap Forest analyses., Results: We quantified 439 serum lipid species and 9 related organic acids. Dietary intervention significantly reduced diacylglycerols, ceramides, lysophospholipids, and ether-linked phosphatidylethanolamine. In contrast, acylcarnitines, short-chain fatty acids, organic acids, and ether-linked phosphatidylcholine increased significantly. Changes in certain lipid species (e.g., saturated and monounsaturated fatty acid-containing glycerolipids, sphingadienine-based very long-chain sphingolipids, and organic acids) were closely associated with clinical glycemic parameters. Six baseline bioactive sphingolipids primarily predicted changes in fasting plasma glucose. In addition, a number of baseline lipid species, mainly diacylglycerols and triglycerides, were predictive of clinical changes in hemoglobin A1c, insulin and homeostasis model assessment of insulin resistance., Conclusions: Newly discovered serum lipidomic alterations and the associated changes in lipid-clinical variables suggest broad metabolic reprogramming related to diet-mediated glycemic control. Novel lipid predictors of glycemic outcomes could facilitate early stratification of individuals with prediabetes who are metabolically less responsive to weight loss, enabling more tailored intervention strategies beyond 1-size-fits-all lifestyle modification advice. The PREVIEW lifestyle intervention study was registered at clinicaltrials.gov as NCT01777893 (https://clinicaltrials.gov/study/NCT01777893)., Competing Interests: Conflict of interest JCB-M is the President and Director of the Glycemic Index Foundation, oversees a glycemic index testing service at The University of Sydney, and is a co-author of books about diet and diabetes. She is a member of the Scientific Advisory Boards of the Novo Foundation and Global Zoe P/L. All other authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work and report no conflicts of interest., (Copyright © 2024 American Society for Nutrition. Published by Elsevier Inc. All rights reserved.)

Three previously undescribed and sixteen known alkaloids were bioguidedly isolated from the bulbs of Narcissus tazetta subsp. chinensis (M.Roem.) Masamura & Yanagih. The structures were elucidated by spectroscopic data, including HRESIMS, NMR, and ECD. Eleven of the isolated alkaloids exhibited immunosuppressive activity on the proliferation of human T cells. (+)-Narciclasine (18) showed the most significantly suppressive activity with an IC 50 value of 14 ± 5 nM. In vitro, (+)-narciclasine (18) blocked NF-κB signal transduction, but did not affect PI3K/AKT signal transduction. What was more, (+)-narciclasine significantly reduced ALT and AST levels and alleviated liver damage induced by ConA in AIH mouse model., Competing Interests: Declaration of competing interest The authors declare no competing financial interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Endocrine therapy has become the fundamental treatment option for hormone receptor-positive (HR + ) and receptor tyrosine-protein kinase erbB-2-negative (HER2 - ) metastatic breast cancer (mBC). While treatments incorporating cyclin-dependent kinase (CDK)4 and 6 inhibitors are more prevalent than ever, comparisons among those regimens are scarce. The aim of the present study was to identify the most effective maintenance treatment for patients with HR + and HER2 - mBC. To this end, databases including PubMed, Embase, Cochrane Library, Scopus and Google Scholar were searched from inception to August, 2023. The endpoints comprised overall survival (OS) and progression free survival (PFS). For dichotomous variants, hazard ratios (HRs) and odds ratios (ORs) were generated, while standard mean difference (SMD) was used for consecutive variants by Bayesian network meta-analysis to make pairwise comparisons among regimens, to determine the optimal therapy. These processes were conducted using Rstudio 4.2.2 orchestrated with STATA 17.0 MP. A total of 16 randomized controlled trials including 7,174 patients with 11 interventions were analyzed. Compared with aromatase inhibitor (AI), palbociclib plus AI (PalboAI) exhibited a significantly longer PFS up to the 36th month of follow-up [HR=1.7; 95% credible interval, 1.36-2.16], including on the 3rd [OR=2.22; 95% confidence interval (CI), 1.10-4.47], 6th (OR=2.39; 95% CI, 1.21-4.69), 12th (OR=1.94; 95% CI, 1.34-2.79), 18th (OR=2.38; 95% CI, 1.65-3.44), 24th (OR=2.39; 95% CI, 1.67-3.43), 30th (OR=2.10; 95% CI, 1.62-2.74) and 36th (OR=2.66; 95% CI, 1.37-5.18) month of follow-up. Additionally, abemaciclib plus fulvestrant exhibited significant effects compared with AI alone between 12 and 36 months. Ribociclib plus fulvestrant, ribociclib plus AI and dalpiciclib plus AI exerted significant effects compared with AI alone between 12 and 30 months. Considering the effect on OS and PFS together with adverse reactions, safety, medical compliance and route of administration, PalboAI was found to be the optimal treatment for HR + /HER2 - mBC. However, additional head-to-head clinical trials are warranted to confirm these findings., Competing Interests: The authors declare that they have no competing interests., (Copyright: © 2024 Jiang et al.)

Background: Left ventricular hypertrophy (LVH) is a critical factor in heart failure and cardiovascular event-related mortality. While the prevalence of LVH in diabetic patients is well-documented, its occurrence and risk factors in non-diabetic populations remain largely unexplored. This study addresses this issue by investigating the independent risk factors of LVH in non-diabetic individuals., Methods: This cross-sectional study, conducted meticulously, utilized data from a robust and comprehensive source, DATADRYAD, in the Sierra Leone database, collected between October 2019 and October 2021, including LVH and various variables. All variables were described and screened using univariate analysis, Spearman correlation, and principal component analysis (PCA). The lipid profile, including total cholesterols (TC), triglycerides (TG), high-density lipoprotein (HDL-C), non-high-density lipoprotein (Non-HDL-C), and low-density lipoprotein cholesterol (LDL-C), TC/HDL-C ratio, TG/HDL-C ratio, Non-HDL-C /HDL-C ratio and LDL-C/HDL-C ratio, which quartiles were treated as categorical variables, with the lowest quartile serving as the reference category. Three adjusted models were constructed to mitigate the influence of other variables. To ensure the robustness of the model, receiver operating characteristic (ROC) curves were used to calculate the cutoff values by analyzing the ROC curves. A sensitivity analysis was performed to validate the findings further., Results: The dataset encompasses information from 2092 individuals. After adjusting for potential factors that could influence the results, we found that TC (OR = 2.773, 95%CI: 1.805-4.26), Non-HDL-C (OR = 2.74, 95%CI: 1.7723-4.236), TC/HDL-C ratio (OR = 2.237, 95%CI: 1.445-3.463), Non-HDL-C/HDL-C ratio (OR = 2.357, 95%CI: 1.548-3.588), TG/HDL-C ratio (OR = 1.513, 95%CI: 1.02-2.245) acts as independent risk factors of LVH. ROC curve analysis revealed the predictive ability of blood lipids for LVH, with Non-HDL-C exhibiting area under the curve (AUC = 0.6109), followed by TC (AUC = 0.6084)., Conclusions: TC, non-HDL-C, TC/HDL-C ratio, Non-HDL-C/HDL-C ratio, and TG/HDL-C ratio were independent risk factors of LVH in non-diabetic people. Non-HDL-C and TC were found to be essential indicators for predicting the prevalence of LVH., (© 2024. The Author(s).)

Electronic band structures in hydrogenated graphene are theoretically investigated by means of first-principle calculations and an effective tight-binding model. It is shown that regularly designed hydrogenation to graphene gives rise to a large band gap about 1 eV. Remarkably, by changing the spatial pattern of the hydrogenation, topologically distinct states can be realized, where the topological nontriviality is detected by C 2 parity indices in bulk and confirmed by the existence of gapless edge/interface states as protected by the mirror and sublattice symmetries. The analysis of the wave functions reveals that the helical edge states in hydrogenated graphene with the appropriate design carry pseudospin currents that are reminiscent of the quantum spin Hall effect. Our work shows the potential of hydrogenated graphene in pseudospin-based device applications., (© 2024. The Author(s).)

Hypertension is a prominent contributor to vascular injury. Deubiquinatase has been implicated in the regulation of hypertension-induced vascular injury. In the present study we investigated the specific role of deubiquinatase YOD1 in hypertension-induced vascular injury. Vascular endothelial endothelial-mesenchymal transition (EndMT) was induced in male WT and YOD1 -/- mice by administration of Ang II (1 μg/kg per minute) via osmotic pump for four weeks. We showed a significantly increased expression of YOD1 in mouse vascular endothelial cells upon Ang II stimulation. Knockout of YOD1 resulted in a notable reduction in EndMT in vascular endothelial cells of Ang II-treated mouse; a similar result was observed in Ang II-treated human umbilical vein endothelial cells (HUVECs). We then conducted LC-MS/MS and co-immunoprecipitation (Co-IP) analyses to verify the binding between YOD1 and EndMT-related proteins, and found that YOD1 directly bound to β-catenin in HUVECs via its ovarian tumor-associated protease (OTU) domain, and histidine at 262 performing deubiquitination to maintain β-catenin protein stability by removing the K48 ubiquitin chain from β-catenin and preventing its proteasome degradation, thereby promoting EndMT of vascular endothelial cells. Oral administration of β-catenin inhibitor MSAB (20 mg/kg, every other day for four weeks) eliminated the protective effect of YOD1 deletion on vascular endothelial injury. In conclusion, we demonstrate a new YOD1-β-catenin axis in regulating Ang II-induced vascular endothelial injury and reveal YOD1 as a deubiquitinating enzyme for β-catenin, suggesting that targeting YOD1 holds promise as a potential therapeutic strategy for treating β-catenin-mediated vascular diseases., (© 2024. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)

Hepatic fibrosis is a compensatory response to chronic liver injury and inflammation, and dietary intervention is recommended as one of the fundamental prevention strategies. Raspberry ketone (RK) is an aromatic compound first isolated from raspberry and widely used to prepare food flavors. The current study investigated the hepatoprotection and potential mechanism of RK against hepatic fibrosis. In vitro , hepatic stellate cell (HSC) activation was stimulated with TGF-β and cultured with RK, farnesoid X receptor (FXR), or peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) agonist or inhibitor, respectively. In vivo , C57BL/6 mice were injected intraperitoneally with thioacetamide (TAA) at 100/200 mg/kg from the first to the fifth week. Mice were intragastrically administrated with RK or Cur once a day from the second to the fifth week. In activated HSCs, RK inhibited extracellular matrix (ECM) accumulation, inflammation, and epithelial-mesenchymal transition (EMT) process. RK both activated FXR/PGC-1α and regulated their crosstalk, which were verified by their inhibitors and agonists. Deficiency of FXR or PGC-1α also attenuated the effect of RK on the reverse of activated HSCs. RK also decreased serum ALT/AST levels, liver histopathological change, ECM accumulation, inflammation, and EMT in mice caused by TAA. Double activation of FXR/PGC-1α might be the key targets for RK against hepatic fibrosis. Above all, these discoveries supported the potential of RK as a novel candidate for the dietary intervention of hepatic fibrosis.

Background: Osteosarcoma primarily affects children and adolescents, with current clinical treatments often resulting in poor prognosis. There has been growing evidence linking programmed cell death (PCD) to the occurrence and progression of tumors. This study aims to enhance the accuracy of OS prognosis assessment by identifying PCD-related prognostic risk genes, constructing a PCD-based OS prognostic risk model, and characterizing the function of genes within this model., Method: We retrieved osteosarcoma patient samples from TARGET and GEO databases, and manually curated literature to summarize 15 forms of programmed cell death. We collated 1621 PCD genes from literature sources as well as databases such as KEGG and GSEA. To construct our model, we integrated ten machine learning methods including Enet, Ridge, RSF, CoxBoost, plsRcox, survivalSVM, Lasso, SuperPC, StepCox, and GBM. The optimal model was chosen based on the average C-index, and named Osteosarcoma Programmed Cell Death Score (OS-PCDS). To validate the predictive performance of our model across different datasets, we employed three independent GEO validation sets. Moreover, we assessed mRNA and protein expression levels of the genes included in our model, and investigated their impact on proliferation, migration, and apoptosis of osteosarcoma cells by gene knockdown experiments., Result: In our extensive analysis, we identified 30 prognostic risk genes associated with programmed cell death (PCD) in osteosarcoma (OS). To assess the predictive power of these genes, we computed the C-index for various combinations. The model that employed the random survival forest (RSF) algorithm demonstrated superior predictive performance, significantly outperforming traditional approaches. This optimal model included five key genes: MTM1, MLH1, CLTCL1, EDIL3, and SQLE. To validate the relevance of these genes, we analyzed their mRNA and protein expression levels, revealing significant disparities between osteosarcoma cells and normal tissue cells. Specifically, the expression levels of these genes were markedly altered in OS cells, suggesting their critical role in tumor progression. Further functional validation was performed through gene knockdown experiments in U2OS cells. Knockdown of three of these genes-CLTCL1, EDIL3, and SQLE-resulted in substantial changes in proliferation rate, migration capacity, and apoptosis rate of osteosarcoma cells. These findings underscore the pivotal roles of these genes in the pathophysiology of osteosarcoma and highlight their potential as therapeutic targets., Conclusion: The five genes constituting the OS-PCDS model-CLTCL1, MTM1, MLH1, EDIL3, and SQLE-were found to significantly impact the proliferation, migration, and apoptosis of osteosarcoma cells, highlighting their potential as key prognostic markers and therapeutic targets. OS-PCDS enables accurate evaluation of the prognosis in patients with osteosarcoma., 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 © 2024 Jiang, Xu, Wang, Ren and Zhang.)

In tuberculosis (TB), chest radiography (CXR) patterns are highly variable, mimicking pneumonia and many other diseases. This study aims to evaluate the efficacy of Google teachable machine, a deep neural network-based image classification tool, to develop algorithm for predicting TB probability of CXRs. The training dataset included 348 TB CXRs and 3806 normal CXRs for training TB detection. We also collected 1150 abnormal CXRs and 627 normal CXRs for training abnormality detection. For external validation, we collected 250 CXRs from our hospital. We also compared the accuracy of the algorithm to five pulmonologists and radiological reports. In external validation, the AI algorithm showed areas under the curve (AUC) of 0.951 and 0.975 in validation dataset 1 and 2. The accuracy of the pulmonologists on validation dataset 2 showed AUC range of 0.936-0.995. When abnormal CXRs other than TB were added, AUC decreased in both human readers (0.843-0.888) and AI algorithm (0.828). When combine human readers with AI algorithm, the AUC further increased to 0.862-0.885. The TB CXR AI algorithm developed by using Google teachable machine in this study is effective, with the accuracy close to experienced clinical physicians, and may be helpful for detecting tuberculosis by CXR., (© 2024. The Author(s).)

Molecular hybridization is a widely employed technique in medicinal chemistry for drug modification, aiming to enhance pharmacological activity and minimize side effects. The combination of an indole ring and imidazole[2,1- b ]thiazole has shown promising potential as a group that exhibits potent anti-inflammatory effects. In this study, we designed and synthesized a series of derivatives comprising indole-2-formamide benzimidazole[2,1- b ]thiazole to evaluate their impact on LPS-induced production of pro-inflammatory cytokines NO, IL-6, and TNF-α release, as well as iron death in RAW264.7 cells. The findings revealed that most compounds effectively inhibited LPS-induced production of pro-inflammatory cytokines NO, IL-6, and TNF-α release in RAW264.7 cells. Compound 13b exhibited the most potent anti-inflammatory activity among the tested compounds. The results of the cytotoxicity assay indicated that compound 13b was nontoxic. Additionally, compound 13b was found to elevate the levels of ROS, MDA, and Fe 2+ , while reducing GSH content, thereby facilitating the iron death process. Consequently, compound 13b showed promise for future development as an anti-inflammatory drug., 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 study., (This journal is © The Royal Society of Chemistry.)

One key challenge in postoperative glioblastoma immunotherapy is to guarantee a potent and durable T-cell response, which is restricted by the immunosuppressive microenvironment within the lymph nodes (LNs). Here, we develop an in situ sprayed exosome-cross-linked gel that acts as an artificial LN structure to directly activate the tumor-infiltrating T cells for prevention of glioma recurrence. Briefly, this gel is generated by a bio-orthogonal reaction between azide-modified chimeric exosomes and alkyne-modified alginate polymers. Particularly, these chimeric exosomes are generated from dendritic cell (DC)-tumor hybrid cells, allowing for direct and robust T-cell activation. The gel structure with chimeric exosomes as cross-linking points avoids the quick clearance by the immune system and thus prolongs the durability of antitumor T-cell immunity. Importantly, this exosome-containing immunotherapeutic gel provides chances for ameliorating functions of antigen-presenting cells (APCs) through accommodating different intracellular-acting adjuvants, such as stimulator of interferon genes (STING) agonists. This further enhances the antitumor T-cell response, resulting in the almost complete elimination of residual lesions after surgery. Our findings provide a promising strategy for postsurgical glioma immunotherapy that warrants further exploration in the clinical arena.

In this study, in order to further search anti-inflammatory drugs with high efficiency and low toxicity, this study took the ring of indoles and imidazole [2,1-b] thiazole as the main skeleton. A total of nine new N-1-substituted derivatives of indole-2-carboxyamide-phenylimidazoles [2,1-b] thiazole (13-20) was synthesized through the processes of cyclization, amino reduction, ester hydrolysis, dehydration condensation and acyl chloride substitution. These derivatives were then tested for their ability to reduce inflammation in RAW 264.7 macrophages. There was a significant majority of these compounds that effectively suppressed the production of NO, IL-6 and TNF-α in RAW 264.7 cells that were stimulated by LPS. One of these compounds, compound 19, was shown to be capable of efficiently lowering the levels of LPS-induced over expression of a number of inflammatory mediators. The inhibition rates for compound 19 were 54.66%, 68.82% and 43.74%, respectively. Additionally, an initial structure-activity relationship evaluation was carried out. The findings indicate that the incorporation of substituted benzyl moieties at the same position provided N-benzylation compounds with a positive anti-inflammatory effect. The electrophilicity of the substituent on the benzyl group had the potential to have an effect on the anti-inflammatory effect, which is something that calls for further investigation.

Background: Evidence shows people living with CHB even with a normal ALT (40U/L as threshold) suffer histological disease and there is still little research to evaluate the potential benefit of antiviral benefits in them., Methods: We retrospectively examined 1352 patients who underwent liver biopsy from 2017 to 2021 and then obtained their 1-year follow-up data to analyze., Results: ALT levels were categorized into high and low, with thresholds set at >29 for males and >15 for females through Youden's Index. The high normal ALT group showed significant histological disease at baseline (56.43% vs 43.82%, p< 0.001), and better HBV DNA clearance from treatment using PSM (p=0.005). Similar results were obtained using 2016 AASLD high normals (male >30, female >19). Further multivariate logistic analysis showed that high normal ALT (both criterias) was an independent predictor of treatment (OR 1.993, 95% CI 1.115-3.560, p=0.020; OR 2.000, 95% CI 1.055-3.793, p=0.034) Both of the models had higher AUC compared with current scoring system, and there was no obvious difference between the two models (AUC:0.8840 vs 0.8835)., Conclusion: Male >30 or female >19 and Male >29 or female>15 are suggested to be better thresholds for normal ALT. Having a high normal ALT in CHB provides a potential benefit in antiviral therapy., 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 © 2024 Cai, Shang, Lin, Jiang, Chen, Xu, Chen, Chen, Cai, Lin, Cai, Lin, Zhang, Yang, Zhang and Lu.)

Angelica dahurica (A. dahurica) has a wide range of pharmacological effects, including analgesic, anti-inflammatory and hepatoprotective effects. In this study, we investigated the effect of A. dahurica extract (AD) and its effective component bergapten (BG) on hepatic fibrosis and potential mechanisms. Hepatic fibrosis was induced by intraperitoneal injection with carbon tetrachloride (CCl 4 ) for 1 week, and mice were administrated with AD or BG by gavage for 1 week before CCl 4 injection. Hepatic stellate cells (HSCs) were stimulated by transforming growth factor-β (TGF-β) and cultured with AD, BG, GW4064 (FXR agonist) or Guggulsterone (FXR inhibitor). In CCl 4 -induced mice, AD significantly decreased serum aminotransferase, reduced excess accumulation of extracellular matrix (ECM), inhibited caspase-1 and IL-1β, and increased FXR expressions. In activated HSCs, AD suppressed the expressions of α-SMA, collagen I, and TIMP-1/MMP-13 ratio and inflammatory factors, functioning as FXR agonist. In CCl 4 -induced mice, BG significantly improved serum transaminase and histopathological changes, reduced ECM excessive deposition, inflammatory response, and activated FXR expression. BG increased FXR expression and inhibited α-SMA and IL-1β expressions in activated HSCs, functioning as GW4064. FXR deficiency significantly attenuated the decreasing effect of BG on α-SMA and IL-1β expressions in LX-2 cells. In conclusion, AD could regulate hepatic fibrosis by regulating ECM excessive deposition and inflammation. Activating FXR signaling by BG might be the potential mechanism of AD against hepatic fibrosis., (© 2024. The Author(s) under exclusive licence to The Japanese Society of Pharmacognosy.)

The analysis of ceramide (Cer) and sphingomyelin (SM) lipid species using liquid chromatography-tandem mass spectrometry (LC-MS/MS) continues to present challenges as their precursor mass and fragmentation can correspond to multiple molecular arrangements. To address this constraint, we developed ReTimeML, a freeware that automates the expected retention times (RTs) for Cer and SM lipid profiles from complex chromatograms. ReTimeML works on the principle that LC-MS/MS experiments have pre-determined RTs from internal standards, calibrators or quality controls used throughout the analysis. Employed as reference RTs, ReTimeML subsequently extrapolates the RTs of unknowns using its machine-learned regression library of mass-to-charge (m/z) versus RT profiles, which does not require model retraining for adaptability on different LC-MS/MS pipelines. We validated ReTimeML RT estimations for various Cer and SM structures across different biologicals, tissues and LC-MS/MS setups, exhibiting a mean variance between 0.23 and 2.43% compared to user annotations. ReTimeML also aided the disambiguation of SM identities from isobar distributions in paired serum-cerebrospinal fluid from healthy volunteers, allowing us to identify a series of non-canonical SMs associated between the two biofluids comprised of a polyunsaturated structure that confers increased stability against catabolic clearance., (© 2024. The Author(s).)

We unveil that the holey graphyne (HGY), a two-dimensional carbon allotrope where benzene rings are connected by two -C≡C- bonds fabricated recently in a bottom-up way, exhibits topological electronic states. Using first-principles calculations and Wannier tight-binding modeling, we discover a higher-order topological invariant associated with C 2 symmetry of the material, and show that the resultant corner modes appear in nanoflakes matching to the structure of precursor reported previously, which are ready for direct experimental observations. In addition, we find that a band inversion between emergent g -like and h -like orbitals gives rise to a nontrivial topology characterized byZ2invariant protected by an energy gap as large as 0.52 eV, manifesting helical edge states mimicking those in the prominent quantum spin Hall effect, which can be accessed experimentally after hydrogenation in HGY. We hope these findings trigger interests towards exploring the topological electronic states in HGY and related future electronics applications., (© 2024 IOP Publishing Ltd.)

Background: Hepatocellular carcinoma (HCC) remains a leading life-threatening health challenge worldwide, with pressing needs for novel therapeutic strategies. Sphingosine kinase 1 (SphK1), a well-established pro-cancer enzyme, is aberrantly overexpressed in a multitude of malignancies, including HCC. Our previous research has shown that genetic ablation of Sphk1 mitigates HCC progression in mice. Therefore, the development of PF-543, a highly selective SphK1 inhibitor, opens a new avenue for HCC treatment. However, the anti-cancer efficacy of PF-543 has not yet been investigated in primary cancer models in vivo, thereby limiting its further translation., Methods: Building upon the identification of the active form of SphK1 as a viable therapeutic target in human HCC specimens, we assessed the capacity of PF-543 in suppressing tumor progression using a diethylnitrosamine-induced mouse model of primary HCC. We further delineated its underlying mechanisms in both HCC and endothelial cells. Key findings were validated in Sphk1 knockout mice and lentiviral-mediated SphK1 knockdown cells., Results: SphK1 activity was found to be elevated in human HCC tissues. Administration of PF-543 effectively abrogated hepatic SphK1 activity and significantly suppressed HCC progression in diethylnitrosamine-treated mice. The primary mechanism of action was through the inhibition of tumor neovascularization, as PF-543 disrupted endothelial cell angiogenesis even in a pro-angiogenic milieu. Mechanistically, PF-543 induced proteasomal degradation of the critical glycolytic enzyme 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3, thus restricting the energy supply essential for tumor angiogenesis. These effects of PF-543 could be reversed upon S1P supplementation in an S1P receptor-dependent manner., Conclusions: This study provides the first in vivo evidence supporting the potential of PF-543 as an effective anti-HCC agent. It also uncovers previously undescribed links between the pro-cancer, pro-angiogenic and pro-glycolytic roles of the SphK1/S1P/S1P receptor axis. Importantly, unlike conventional anti-HCC drugs that target individual pro-angiogenic drivers, PF-543 impairs the PFKFB3-dictated glycolytic energy engine that fuels tumor angiogenesis, representing a novel and potentially safer therapeutic strategy for HCC., (© 2024. The Author(s).)

Functional near-infrared spectroscopy (fNIRS) seems opportune for neurofeedback in robot-assisted rehabilitation training due to its noninvasive, less physical restriction, and no electromagnetic disturbance. Previous research has proved the cross-session reliability of fNIRS responses to non-motor tasks (e.g., visual stimuli) and fine-motor tasks (e.g., finger tapping). However, it is still unknown whether fNIRS responses remain reliable 1) in gross-motor tasks, 2) within a training session, and 3) for different training parameters. Hence, this study aimed to investigate the within-session reliability of fNIRS responses to gross-motor tasks for different training parameters. Ten healthy participants were recruited to conduct right elbow extension-flexion in three robot-assisted modes. The Passive mode was fully motor-actuated, while Active1 and Active2 modes involved active engagement with different resistance levels. FNIRS data of three identical runs were used to assess the within-session reliability in terms of the map- ( R 2 ) and cluster-wise ( R overlap ) spatial reproducibility and the intraclass correlation (ICC) of temporal features. The results revealed good spatial reliability ( R 2 up to 0.69, R overlap up to 0.68) at the subject level. Besides, the within-session temporal reliabilities of Slope, Max/Min, and Mean were between good and excellent ( ICC < 0.86). We also found that the within-session reliability was positively correlated with the intensity of the training mode, except for the temporal reliability of HbO in Active2 mode. Overall, our results demonstrated good within-session reliability of fNIRS responses, suggesting fNIRS as reliable neurofeedback for constructing closed-loop robot-assisted rehabilitation systems.

Astrocytes have countless links with neurons. Previously, astrocytes were only considered a scaffold of neurons; in fact, astrocytes perform a variety of functions, including providing support for neuronal structures and energy metabolism, offering isolation and protection and influencing the formation, function and elimination of synapses. Because of these functions, astrocytes play an critical role in central nervous system (CNS) diseases. The regulation of the secretiory factors, receptors, channels and pathways of astrocytes can effectively inhibit the occurrence and development of CNS diseases, such as neuromyelitis optica (NMO), multiple sclerosis, Alzheimer's disease (AD), Parkinson's disease (PD) and Huntington's disease. The expression of aquaporin 4 in AS is directly related to NMO and indirectly involved in the clearance of Aβ and tau proteins in AD. Connexin 43 has a bidirectional effect on glutamate diffusion at different stages of stroke. Interestingly, astrocytes reduce the occurrence of PD through multiple effects such as secretion of related factors, mitochondrial autophagy and aquaporin 4. Therefore, this review is focused on the structure and function of astrocytes and the correlation between astrocytes and CNS diseases and drug treatment to explore the new functions of astrocytes with the astrocytes as the target. This, in turn, would provide a reference for the development of new drugs to protect neurons and promote the recovery of nerve function., (© 2023 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Protein kinase C delta (PKCδ) is prominently expressed in the nuclei of EGFR-mutant lung cancer cells, and its presence correlates with poor survival of the patients undergoing EGFR inhibitor treatment. The inhibition of PKCδ has emerged as a viable approach to overcoming resistance to EGFR inhibitors. However, clinical-grade PKCδ inhibitors are not available, highlighting the urgent needs for the development of effective drugs that target PKCδ. In this study, we designed and synthesized a series of inhibitors based on the chemical structure of a pan PKC inhibitor sotrastaurin. This was achieved by incorporating a triazole ring group into the original sotrastaurin configuration. Our findings revealed that the sotrastaurin derivative CMU-0101 exhibited an elevated affinity for binding to the ATP-binding site of PKCδ and effectively suppressed nuclear PKCδ in resistant cells in comparison to sotrastaurin. Furthermore, we demonstrated that CMU-0101 synergistically enhanced EGFR TKI gefitinib sensitivity in resistant cells. Altogether, our study provides a promising strategy for designing and synthesizing PKCδ inhibitors with improved efficacy, and suggests CMU-0101 as a potential lead compound to inhibit PKCδ and overcome TKI resistance in lung cancers., Competing Interests: None., (AJCR Copyright © 2023.)

Cultured meat is one of the meat substitutes produced through tissue engineering and other technologies. Large-scale cell culture is the key for cultured meat products to enter the market. Therefore, this study is aimed to explore the effect of long-term passage in vitro on smooth muscle cells (SMCs) and the effect of transforming growth factor-β1 (TGF-β1) on SMCs in the late passage. Multiple passages lead to the decline of the proliferation rate of SMCs in the proliferation stage and the differentiation ability in the differentiation stage. Transcriptome results showed that the ECM pathway and aging-related signaling pathways were significantly up-regulated in the late passage period. TGF-β1 did not promote SMCs of late passage proliferation at the proliferation stage but promoted the gene and protein expression of collagen as the main protein of the extracellular matrix proteins at the differentiation stage. In addition, proteomic analysis revealed that TGF-β1 promoted the expression of cell adhesion molecules which activate the Hippo signaling pathway and the HIF-1 signaling pathway and further promoted the production of collagen-containing extracellular matrix proteins. This could provide ideas for large-scale production of cultured meat products using SMCs.

The fornix is a white matter bundle located in the center of the hippocampaldiencephalic limbic circuit that controls memory and executive functions, yet its genetic architectures and involvement in brain disorders remain largely unknown. We carried out a genome-wide association analysis of 30,832 UK Biobank individuals of the six fornix diffusion magnetic resonance imaging (dMRI) traits. The post-GWAS analysis allowed us to identify causal genetic variants in phenotypes at the single nucleotide polymorphisms (SNP), locus, and gene levels, as well as genetic overlap with brain health-related traits. We further generalized our GWAS in adolescent brain cognitive development (ABCD) cohort. The GWAS identified 63 independent significant variants within 20 genomic loci associated (P < 8.33 × 10 -9 ) with the six fornix dMRI traits. Geminin coiled-coil domain containing (GMNC) and NUAK family SNF1-like kinase 1 (NUAK1) gene were highlighted, which were found in UKB and replicated in ABCD. The heritability of the six traits ranged from 10% to 27%. Gene mapping strategies identified 213 genes, where 11 were supported by all of four methods. Gene-based analyses revealed pathways relating to cell development and differentiation, with astrocytes found to be significantly enriched. Pleiotropy analyses with eight neurological and psychiatric disorders revealed shared variants, especially with schizophrenia under the conjFDR threshold of 0.05. These findings advance our understanding of the complex genetic architectures of fornix and their relevance in neurological and psychiatric disorders., (© 2023. The Author(s).)

The effect of regret on consumers' purchasing behavior is more and more obvious. The limited pre-sale can make retailers with limited production capacity allocate two periods of stock effectively and increase their income. This paper considers the heterogeneous consumers with regret behavior in the market and constructs a model to study the retailer's optimal limited pre-sale strategy. The results show that the high price regret sensitivity negatively affects the higher price of the products in the pre-sale strategy, while the out-of-stock regret sensitivity negatively affects the retailer's profit When the production capacity is relatively low, the proportion of rational consumers is large and the high price regret sensitivity coefficient is small, the retailer should pre-sell at a limited discount and the lowest valuation, and the highest valuation is on sale, otherwise, it should be sold at a price slightly lower than the highest valuation, but when the capacity is very sufficient, the sensitive coefficient of stock-out regret is small and the proportion of rational consumers is small, the retailer should pre-sell at an unlimited premium, and a price slightly lower than the highest valuation of the pre-sale, the lowest valuation of the sale, or should be pre-sold at the highest valuation., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Jiang, Qi. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Cholangiocarcinoma (CCA) is a highly heterogeneous and metastatic malignancy with a poor prognosis even after curative hepatectomy. Studies exploring its pathogenesis and identifying effective therapeutic targets are urgently needed. In this study, we found that TANK-binding kinase 1 (TBK1), a serine/threonine-protein kinase, showed a dynamic increase during the different stages of murine spontaneous CCA carcinogenesis (hyperplasia, dysplasia, and CCA). TBK1 was upregulated in human tissues, including intrahepatic (n = 182) and extrahepatic (n = 40) CCA tissues, compared with nontumor tissues, and the elevated expression of TBK1 was positively correlated with larger tumour diameter, lymph node metastasis, and advanced TNM stage. Functional studies indicated that TBK1 promoted CCA growth and metastasis both in vitro and in vivo. TBK1 directly interacts with β-catenin, promoting its phosphorylation at the S552 site and its nuclear translocation, which further activates EMT-related transcriptional reprogramming. GSK-8612, a TBK1 inhibitor or a kinase-inactivating mutation, effectively suppresses the above processes. In addition, we found that low-density lipoprotein receptor (LDLR), which mediates the endocytosis of cholesterol, was upregulated in CCA. Therefore, we designed a cholesterol-conjugated DNA/RNA heteroduplex oligonucleotide targeting TBK1 (Cho-TBK1-HDO), which could accumulate in CCA cells via LDLR, reduce the TBK1 mRNA level and inhibit intrahepatic metastasis of CCA. Besides, in the experimental group of 182 ICC patients, high TBK1 expression combined with high nuclear β-catenin expression predicted a worse prognosis. In summary, TBK1 might serve as a potential prognostic biomarker and therapeutic target for patients with CCA., (© 2023. The Author(s).)

Skin-derived precursor Schwann cells have been reported to play a protective role in the central nervous system. The neuroprotective effects of skin-derived precursor Schwann cells may be attributable to the release of growth factors that nourish host cells. In this study, we first established a cellular model of Parkinson's disease using 6-hydroxydopamine. When SH-SY5Y cells were pretreated with conditioned medium from skin-derived precursor Schwann cells, their activity was greatly increased. The addition of insulin-like growth factor-2 neutralizing antibody markedly attenuated the neuroprotective effects of skin-derived precursor Schwann cells. We also found that insulin-like growth factor-2 levels in the peripheral blood were greatly increased in patients with Parkinson's disease and in a mouse model of Parkinson's disease. Next, we pretreated cell models of Parkinson's disease with insulin-like growth factor-2 and administered insulin-like growth factor-2 intranasally to a mouse model of Parkinson's disease induced by 6-hydroxydopamine and found that the level of tyrosine hydroxylase, a marker of dopamine neurons, was markedly restored, α-synuclein aggregation decreased, and insulin-like growth factor-2 receptor down-regulation was alleviated. Finally, in vitro experiments showed that insulin-like growth factor-2 activated the phosphatidylinositol 3 kinase (PI3K)/AKT pathway. These findings suggest that the neuroprotective effects of skin-derived precursor Schwann cells on the central nervous system were achieved through insulin-like growth factor-2, and that insulin-like growth factor-2 may play a neuroprotective role through the insulin-like growth factor-2 receptor/PI3K/AKT pathway. Therefore, insulin-like growth factor-2 may be an useful target for Parkinson's disease treatment., Competing Interests: None

This study focuses on modifying the surface of an AA 5052-H32 aluminum alloy using plasma treatment. Discharge power, exposure time, and working gas were adjusted as process parameters to improve the adhesion between the aluminum alloy and glass fiber-reinforced thermoplastic (GFRTP) polycarbonate composite. The surface composition and morphology of the aluminum alloy sheet were analyzed by X-ray photoelectron spectroscopy and scanning electron microscopy, and surface roughness and wettability were evaluated using a surface roughness-measuring instrument and contact angle goniometry, respectively. The bonding performance of GFRTP/aluminum alloy was also assessed. The surface of the aluminum alloy was subjected to chemical treatment prior to plasma treatment. The results revealed that nitrogen plasma treatment led to a substantial increase (25%) in bonding strength due to the synergistic effect of rough surface mechanical bonding and chemical bonding through functional groups between the aluminum alloy and GFRTP. However, the improvement in surface wettability by plasma treatment is time dependent and may gradually diminish over time due to the re-adsorption of hydrocarbon contamination from the surrounding air.

Background: The cerebellum is recognized as being involved in neurocognitive and motor functions with communication with extra-cerebellar regions relying on the white matter integrity of the cerebellar peduncles. However, the genetic determinants of cerebellar white matter integrity remain largely unknown., Methods: We conducted a genome-wide association analysis of cerebellar white matter microstructure using diffusion tensor imaging data from 25,415 individuals from UK Biobank. The integrity of cerebellar white matter microstructure was measured as fractional anisotropy (FA) and mean diffusivity (MD). Identification of independent genomic loci, functional annotation, and tissue and cell-type analysis were conducted with FUMA. The linkage disequilibrium score regression (LDSC) was used to calculate genetic correlations between cerebellar white matter microstructure and regional brain volumes and brain-related traits. Furthermore, the conditional/conjunctional false discovery rate (condFDR/conjFDR) framework was employed to identify the shared genetic basis between cerebellar white matter microstructure and common brain disorders., Results: We identified 11 genetic loci (P < 8.3 × 10 -9 ) and 86 genes associated with cerebellar white matter microstructure. Further functional enrichment analysis implicated the involvement of GABAergic neurons and cholinergic pathways. Significant polygenetic overlap between cerebellar white matter tracts and their anatomically connected or adjacent brain regions was detected. In addition, we report the overall genetic correlation and specific loci shared between cerebellar white matter microstructural integrity and brain-related traits, including movement, cognitive, psychiatric, and cerebrovascular categories., Conclusions: Collectively, this study represents a step forward in understanding the genetics of cerebellar white matter microstructure and its shared genetic etiology with common brain disorders., Competing Interests: Declaration of Competing Interest Authors declare that they have no competing interests., (Copyright © 2023. Published by Elsevier Inc.)

Purpose: To report the efficacy and safety of postoperative adjuvant hepatic arterial infusion chemotherapy (HAIC) with 5-fluorouracil and oxaliplatin (FOLFOX) in hepatocellular carcinoma (HCC) patients with microvascular invasion (MVI)., Patients and Methods: In this randomized, open-label, multicenter trial, histologically confirmed HCC patients with MVI were randomly assigned (1:1) to receive adjuvant FOLFOX-HAIC (treatment group) or routine follow-up (control group). The primary end point was disease-free survival (DFS) by intention-to-treat (ITT) analysis while secondary end points were overall survival, recurrence rate, and safety., Results: Between June 2016 and August 2021, a total of 315 patients (ITT population) at five centers were randomly assigned to the treatment group (n = 157) or the control group (n = 158). In the ITT population, the median DFS was 20.3 months (95% CI, 10.4 to 30.3) in the treatment group versus 10.0 months (95% CI, 6.8 to 13.2) in the control group (hazard ratio, 0.59; 95% CI, 0.43 to 0.81; P = .001). The overall survival rates at 1 year, 2 years, and 3 years were 93.8% (95% CI, 89.8 to 98.1), 86.4% (95% CI, 80.0 to 93.2), and 80.4% (95% CI, 71.9 to 89.9) for the treatment group and 92.0% (95% CI, 87.6 to 96.7), 86.0% (95% CI, 79.9 to 92.6), and 74.9% (95% CI, 65.5 to 85.7) for the control group (hazard ratio, 0.64; 95% CI, 0.36 to 1.14; P = .130), respectively. The recurrence rates were 40.1% (63/157) in the treatment group and 55.7% (88/158) in the control group. Majority of the adverse events were grade 0-1 (83.8%), with no treatment-related death in both groups., Conclusion: Postoperative adjuvant HAIC with FOLFOX significantly improved the DFS benefits with acceptable toxicities in HCC patients with MVI.

The amygdala is a crucial interconnecting structure in the brain that performs several regulatory functions, yet its genetic architectures and involvement in brain disorders remain largely unknown. We carried out the first multivariate genome-wide association study (GWAS) of amygdala subfield volumes in 27,866 UK Biobank individuals. The whole amygdala was segmented into nine nuclei groups using Bayesian amygdala segmentation. The post-GWAS analysis allowed us to identify causal genetic variants in phenotypes at the SNP, locus, and gene levels, as well as genetic overlap with brain health-related traits. We further generalized our GWAS in Adolescent Brain Cognitive Development (ABCD) cohort. The multivariate GWAS identified 98 independent significant variants within 32 genomic loci associated (P < 5 × 10 -8 ) with amygdala volume and its nine nuclei. The univariate GWAS identified significant hits for eight of the ten volumes, tagging 14 independent genomic loci. Overall, 13 of the 14 loci identified in the univariate GWAS were replicated in the multivariate GWAS. The generalization in ABCD cohort supported the GWAS results with the 12q23.2 (RNA gene RP11-210L7.1) being discovered. All of these imaging phenotypes are heritable, with heritability ranging from 15% to 27%. Gene-based analyses revealed pathways relating to cell differentiation/development and ion transporter/homeostasis, with the astrocytes found to be significantly enriched. Pleiotropy analyses revealed shared variants with neurological and psychiatric disorders under the conjFDR threshold of 0.05. These findings advance our understanding of the complex genetic architectures of amygdala and their relevance in neurological and psychiatric disorders., (© 2023. The Author(s).)

Precise design of low-cost, efficient and definite electrocatalysts is the key to sustainable renewable energy. Herein, this work develops a targeted-anchored and subsequent spontaneous-redox strategy to synthesize nickel-iron layered double hydroxide (LDH) nanosheets anchored with monodispersed platinum (Pt) sites (Pt@LDH). Intermediate metal-organic frameworks (MOF)/LDH heterostructure not only provides numerous confine points to guarantee the stability of Pt sites, but also excites the spontaneous reduction for Pt II . Electronic structure, charge transfer ability and reaction kinetics of Pt@LDH can be effectively facilitated by the monodispersed Pt moieties. As a result, the optimized Pt@LDH that with the 5% ultra-low content Pt exhibits the significant increment in electrochemical water splitting performance in alkaline media, which only afford low overpotentials of 58 mV at 10 mA cm -2 for hydrogen evolution reaction (HER) and 239 mV at 10 mA cm -2 for oxygen evolution reaction (OER), respectively. In a real device, Pt@LDH can drive an overall water-splitting at low cell voltage of 1.49 V at 10 mA cm -2 , which can be superior to most reported similar LDH-based catalysts. Moreover, the versatility of the method is extended to other MOF precursors and noble metals for the design of ultrathin LDH supported monodispersed noble metal electrocatalysts promoting research interest in material design., (© 2023 Wiley-VCH GmbH.)

Background: Various inhaled bronchodilators have been associated with cardiovascular safety concerns. This study aimed to investigate the long-term impact of chronic obstructive pulmonary disease (COPD) and the safety of COPD medications in patients after their first acute myocardial infarction (AMI)., Methods: This nationwide cohort study was conducted using data from the Taiwan National Health Insurance Research Database. Patients hospitalized between 2000 and 2012 with a primary diagnosis of first AMI were included and divided into three cohorts (AMI, ST-elevation myocardial infarction [STEMI], and non-STEMI [NSTEMI]). Each cohort was propensity score matched (1:1) with patients without COPD. A Cox proportional hazards regression model was used to estimate hazard ratios (HRs) with 95% CIs., Results: A total of 186 112 patients with AMI were enrolled, and COPD was diagnosed in 13 065 (7%) patients. Kaplan-Meier curves showed that patients with COPD had a higher mortality risk than those without COPD in all cohorts (AMI, STEMI, and NSTEMI). The HR of mortality in AMI, STEMI, and NSTEMI patients with COPD was 1.12 (95% CI, 1.09-1.14), 1.20 (95% CI, 1.14-1.25), and 1.07 (95% CI, 1.04-1.10), respectively. Short-acting inhaled bronchodilators and corticosteroids increased mortality risk in all three cohorts. However, long-acting inhaled bronchodilators reduced mortality risk in patients with AMI (long-acting beta-agonist [LABA]: HR, 0.87; 95% CI, 0.81-0.94; long-acting muscarinic antagonist [LAMA]: HR, 0.82; 95% CI, 0.69-0.96) and NSTEMI (LABA: HR, 0.89; 95% CI, 0.83-0.97; LAMA: HR, 0.80; 95% CI, 0.68-0.96)., Conclusion: This study demonstrated that AMI patients with COPD had higher mortality rates than those without COPD. Using inhaled short-acting bronchodilators and corticosteroids reduced survival, whereas long-acting bronchodilators provided survival benefits in AMI and NSTEMI patients. Therefore, appropriate COPD medication for acute AMI is crucial., Competing Interests: Conflicts of interest: The authors declare that they have no conflicts of interest related to the subject matter or materials discussed in this article., (Copyright © 2022, the Chinese Medical Association.)

Bimanual coordination is common in human daily life, whereas current research focused mainly on decoding unimanual movement from electroencephalogram (EEG) signals. Here we developed a brain-computer interface (BCI) paradigm of task-oriented bimanual movements to decode coordinated directions from movement-related cortical potentials (MRCPs) of EEG. Eight healthy subjects participated in the target-reaching task, including (1) performing leftward, midward, and rightward bimanual movements, and (2) performing leftward and rightward unimanual movements. A combined deep learning model of convolution neural network and bidirectional long short-term memory network was proposed to classify movement directions from EEG. Results showed that the average peak classification accuracy for three coordinated directions of bimanual movements reached 73.39 ± 6.35 %. The binary classification accuracies achieved 80.24 ± 6.25 , 82.62 ± 7.82 , and 86.28 ± 5.50 % for leftward versus midward, rightward versus midward and leftward versus rightward, respectively. We also compared the binary classification (leftward versus rightward) of bimanual, left-hand, and right-hand movements, and accuracies achieved 86.28 ± 5.50 %, 75.67 ± 7.18 %, and 77.79 ± 5.65 %, respectively. The results indicated the feasibility of decoding human coordinated directions of task-oriented bimanual movements from EEG.

Brain-computer interface (BCI) systems based on spontaneous electroencephalography (EEG) hold the promise to implement human voluntary control of lower-extremity powered exoskeletons. However, current EEG-BCI paradigms do not consider the cooperation of upper and lower limbs during walking, which is inconsistent with natural human stepping patterns. To deal with this problem, this study proposed a stepping-matched human EEG-BCI paradigm that involved actions of both unilateral lower and contralateral upper limbs (also referred to as compound-limbs movement). Experiments were conducted in motor execution (ME) and motor imagery (MI) conditions to validate the feasibility. Common spatial pattern (CSP) proposed subject-specific CSP (SSCSP), and filter-bank CSP (FBCSP) methods were applied for feature extraction, respectively. The best average classification results based on SSCSP indicated that the accuracies of compound-limbs paradigms in ME and MI conditions achieved 89.02% ± 12.84% and 73.70% ± 12.47%, respectively. Although they were 2.03% and 5.68% lower than those of the single-upper-limb mode that does not match human stepping patterns, they were 24.30% and 11.02% higher than those of the single-lower-limb mode. These findings indicated that the proposed compound-limbs EEG-BCI paradigm is feasible for decoding human stepping intention and thus provides a potential way for natural human control of walking assistance devices.

While many voluntary movements involve bimanual coordination, few attempts have been made to simultaneously decode the trajectory of bimanual movements from electroencephalogram (EEG) signals. In this study, we proposed a novel bimanual brain-computer interface (BCI) paradigm to reconstruct the continuous trajectory of both hands during coordinated movements from EEG. The protocol required human subjects to complete a bimanual reaching task to the left, middle, or right target while EEG data were collected. A multi-task deep learning model combining the EEGNet and long short-term memory network (LSTM) was proposed to decode bimanual trajectories, including position and velocity. Decoding performance was evaluated in terms of the correlation coefficient (CC) and normalized root mean square error (NRMSE) between decoded and real trajectories. Experimental results from 13 human subjects showed that the grand-averaged combined CC values achieved 0.54 and 0.42 for position and velocity decoding, respectively. The corresponding combined NRMSE values were 0.22 and 0.23. Both CC and NRMSE were significantly superior to the chance level (p<0.05). Comparative experiments also indicated that the proposed model significantly outperformed some other commonly-used methods in terms of CC and NRMSE for continuous trajectory decoding. These findings demonstrated the feasibility of simultaneously decoding bimanual trajectory from EEG, indicating the potential of bimanual control for coordinated tasks.

The treatment of drug-resistant bacterial infections attributed to the overuse of antibiotics still remains a serious challenge globally. Herein, zwitterionic charge switchable meso-silica/polypeptide hybrid nanoparticles (MSPNs) were prepared for the synergistic chemo-photodynamic therapy in the treatment of drug-resistant bacterial infections. Subsequently, azithromycin (AZT) and methylene blue (MB) were loaded in the MSPNs to form the combined chemo-photodynamic therapeutic nanoparticles (MSPNs-AZT/MB) for the treatment of methicillin-resistant Staphylococcus aureus (MRSA). Remarkably, the as-prepared MSPNs-AZT/MB exhibited a negative surface charge of -5.2 mV at physiological pH while switching into positive surface charge of 24.7 mv in an acidic environment, leading to enhanced binding with bacterial surface. The lipase-triggered AZT release up to 77.9 % was achieved, and the loaded MB demonstrated efficient singlet oxygen ( 1 O 2 ) generation for photodynamic therapy. The in vitro experimental results displayed an excellent antibacterial effect against MRSA in both planktonic and biofilm phenotypes. Additionally, the as-prepared MSPNs-AZT/MB exhibited synergistic and enhanced antibacterial infection effect up to 94 % comparing to monotherapy in a mice model. Considering the above advantages, the as-prepared combined chemo-photodynamic therapeutic nanoparticles showed promising biocompatibility and clinical potential for the efficient therapy of drug-resistant bacteria., (Copyright © 2022 Elsevier B.V. All rights reserved.)

The purpose of the present article is to identify intrinsic genes across general hypertension (HT), hypertension with left ventricular remodeling (HT-LVR), and uncontrolled hypertension (UN-HT). In total, four microarray datasets (GSE24752, GSE75360, GSE74144, and GSE71994) were downloaded from the GEO database and were used to identify differentially expressed genes (DEGs), respectively. Furthermore, gene set enrichment analysis (GSEA) was utilized to screen for significantly enriched biological pathways across the four datasets above, respectively. Furthermore, weighted gene co-expression network analysis (WGCNA) and functional enrichment analysis were applied to screen out gene modules of interest and potential biological functions, respectively. Finally, a Metascape-based multiple gene list meta-analysis was used to investigate intrinsic genes at different stages of the progression of hypertension. A total of 75 DEGs (63 upregulated genes and 12 downregulated genes, GSE24752) and 23 DEGs (2 upregulated genes and 21 downregulated genes, GSE74144) were identified. However, there were few DEGs identified in GSE75360, GSE71994, and part of the GSE74144 datasets. GSEA and functional enrichment of gene module of interest have indicated that "Heme metabolism," "TNF alpha/NFkB," and "interferon alpha response signaling," and MYC target v1/v2 were enriched significantly in different stages of hypertension progression. Significantly, findings from the multiple gene list meta-analysis suggested that FBXW4 and other 13 genes were unique to the hypertension group, and TRIM11 and other 40 genes were mainly involved in hypertension with the left ventricular remodeling group, while the other 18 genes including F13A1 significantly enriched in uncontrolled hypertension. Collectively, the precise switch of the "immune-metabolic-inflammatory" loop pathway was the most significant hallmark across different stages of hypertension, thereby providing a potential therapeutic target for uncontrolled hypertension treatment., 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 © 2022 Yu, Gu, Jiang and Zhang.)

Acanthoic acid (AA) is a pimaradiene diterpene isolated from the root bark of Acanthopanax koreanum Nakai (Araliaceae) with a wide range of pharmacological activities, including anti-cancer, anti-inflammatory, anti-diabetes, liver protection, gastrointestinal protection, and cardiovascular protection. In addition, AA promotes its pharmacological effects by targeting liver X receptors (LXRs), nuclear factor-kappa B (NF-κB), Toll-Like Receptor 4 (TLR4) and IL-1 receptor-associated kinase (IRAK) signaling pathways, or AMP-activated protein kinase (AMPK) signaling pathway, etc. Also, some studies focus on the structural modification of AA to improve its pharmacological activities. The review summarizes the pharmacological activities, molecular mechanism, and the structural modification of AA, which might supply information for the development of AA in the future., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Autophagy has been shown to play an important role in Parkinson's disease. We hypothesized that skin-derived precursor cells exhibit neuroprotective effects in Parkinson's disease through affecting autophagy. In this study, 6-hydroxydopamine-damaged SH-SY5Y cells were pretreated with a culture medium containing skin-derived precursors differentiated into Schwann cells (SKP-SCs). The results showed that the SKP-SC culture medium remarkably enhanced the activity of SH-SY5Y cells damaged by 6-hydroxydopamine, reduced excessive autophagy, increased tyrosine hydroxylase expression, reduced α-synuclein expression, reduced the autophagosome number, and activated the PI3K/AKT/mTOR pathway. Autophagy activator rapamycin inhibited the effects of SKP-SCs, and autophagy inhibitor 3-methyladenine had the opposite effect. These findings confirm that SKP-SCs modulate the PI3K/AKT/mTOR pathway to inhibit autophagy, thereby exhibiting a neuroprotective effect in a cellular model of Parkinson's disease. This study was approved by the Animal Ethics Committee of Laboratory Animal Center of Nantong University (approval No. S20181009-205) on October 9, 2018., Competing Interests: None

The present study focused on the potential mechanism of betulin (BT), a pentacyclic triterpenoid isolated from the bark of white birch ( Betula pubescens ), against chronic alcohol-induced lipid accumulation and metaflammation. AML-12 and RAW 264.7 cells were administered ethanol (EtOH), lipopolysaccharide (LPS) or BT. Male C57BL/6 mice were fed Lieber-DeCarli liquid diets containing 5% EtOH for 4 weeks, followed by single EtOH gavage on the last day and simultaneous treatment with BT (20 or 50 mg/kg) by oral gavage once per day. In vitro , MTT showed that 0-25 mM EtOH and 0-25 μM BT had no toxic effect on AML-12 cells. BT could regulate sterolregulatory-element-binding protein 1 (SREBP1), lipin1/2, P2X7 receptor (P2X7r) and NOD-like receptor family, pyrin domains-containing protein 3 (NLRP3) expressions again EtOH-stimulation. Oil Red O staining also indicated that BT significantly reduced lipid accumulation in EtOH-stimulated AML-12 cells. Lipin1/2 deficiency indicated that BT might mediate lipin1/2 to regulate SREBP1 and P2X7r expression and further alleviate lipid accumulation and inflammation. In vivo , BT significantly alleviated histopathological changes, reduced serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and triglyceride (TG) levels, and regulated lipin1/2, SREBP1, peroxisome proliferator activated receptor α/γ (PPARα/γ) and PGC-1α expression compared with the EtOH group. BT reduced the secretion of inflammatory factors and blocked the P2X7r-NLRP3 signaling pathway. Collectively, BT attenuated lipid accumulation and metaflammation by regulating the lipin1/2-mediated P2X7r signaling pathway.