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Shanshan Liu, Ju Li, Zhongyuan Zhang, Deqian Meng, Kai Wang Department of Rheumatology and Immunology, The Affiliated Huaian No. 1 People’s Hospital of Nanjing Medical University, Huaian, 223001, People’s Republic of ChinaCorrespondence: Kai Wang, Department of Rheumatology and Immunology, The affiliated Huaian No.1 People’s Hospital of Nanjing Medical University, Huaian, 223001, People’s Republic of China, Tel/Fax +86-17551710317, Email morrosun@hotmail.comObjective: To evaluate belimumabf’s efficacy in refractory lupus nephritis (LN) patients and identify predictive serum biomarkers for treatment response.Methods: In this single-arm retrospective study, we assessed clinical responses in LN patients at baseline and six months after initiating belimumab. Serum cytokines (IL-2, IL-4, IL-6, IL-10, TNF-α, IFN-γ) were quantified using multiplex magnetic bead flow immunoassay before and after treatment.Results: Fourteen patients with various subtypes of refractory LN participated in the study: seven with class III and V LN, three with type V alone, two with class III, and two with class IV+V and V LN. Post six months of belimumab therapy, all participants exhibited a reduction in the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI)-2K scores from their respective baseline values. Notably, most patients showed a decrease in the dosage of prednisone, levels of 24-hour urinary protein, immunoglobulins, erythrocyte sedimentation rate (ESR), and anti-double-stranded DNA antibody IgM, along with serum levels of IL-4, IL-6, IL-10, and IFN-γ. Meanwhile, levels of C3, C4, IL-2, and TNF-α were observed to increase. Of the participants, nine (64.29%) achieved a complete renal response, one (7.14%) showed a partial response, and four (28.57%) exhibited no response. Significantly, higher baseline serum IFN-γ levels were found in patients who did not achieve complete renal response (CR) compared to those who did (p = 0.009). Receiver operating characteristic (ROC) curve analysis demonstrated that baseline IFN-γ levels had an area under curve (AUC) of 0.96 (0.70– 1.00), with a sensitivity of 0.89 and a specificity of 1.00 (p < 0.001).Conclusion: Belimumab shows potential efficacy in treating refractory LN. Baseline serum IFN-γ levels may predict response to belimumab therapy, potentially enabling more targeted treatment approaches for this challenging condition.Keywords: refractory lupus nephritis, belimumab, treatment, biomarker, IFN-&#x03B3

Yanan Yang,1,&ast; Shuoye Yang,1,2,&ast; Beibei Zhang,1 Jinpeng Wang,1 Di Meng,1 Lan Cui,1,2 Lu Zhang1,2 1School of Biological Engineering, Henan University of Technology, Zhengzhou, People’s Republic of China; 2Key Laboratory of Functional Molecules for Biomedical Research, Zhengzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Shuoye Yang, School of Biological Engineering, Henan University of Technology, Lianhua Street, Gaoxin District, Zhengzhou, 450001, People’s Republic of China, Tel/Fax: +86-371-67756513, Email yangshuoyehaut@163.comIntroduction: RNA interference (RNAi) stands as a widely employed gene interference technology, with small interfering RNA (siRNA) emerging as a promising tool for cancer treatment. However, the inherent limitations of siRNA, such as easy degradation and low bioavailability, hamper its efficacy in cancer therapy. To address these challenges, this study focused on the development of a nanocarrier system (HLM-N@DOX/R) capable of delivering both siRNA and doxorubicin for the treatment of breast cancer.Methods: The study involved a comprehensive investigation into various characteristics of the nanocarrier, including shape, diameter, Fourier transform infrared (FT-IR) spectroscopy, X-ray photoelectron spectroscopy (XPS), encapsulation efficiency, and drug loading. Subsequently, in vitro and in vivo studies were conducted on cytotoxicity, cellular uptake, cellular immunofluorescence, lysosome escape, and mouse tumor models to evaluate the efficacy of the nanocarrier in reversing tumor multidrug resistance and anti-tumor effects.Results: The results showed that HLM-N@DOX/R had a high encapsulation efficiency and drug loading capacity, and exhibited pH/redox dual responsive drug release characteristics. In vitro and in vivo studies showed that HLM-N@DOX/R inhibited the expression of P-gp by 80%, inhibited MDR tumor growth by 71% and eliminated P protein mediated multidrug resistance.Conclusion: In summary, HLM-N holds tremendous potential as an effective and targeted co-delivery system for DOX and P-gp siRNA, offering a promising strategy for overcoming MDR in breast cancer.Keywords: mesoporous silica nanoparticles, multidrug resistance, small interfering RNA, doxorubicin, hybrid nanoparticles

Decheng Meng,1 Fengxia Zhang,2 Wenfei Yu,1 Xin Zhang,1 Guoliang Yin,1 Pengpeng Liang,3 Yanan Feng,1 Suwen Chen,1 Hongshuai Liu1 1The First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, 250011, People’s Republic of China; 2Department of Neurology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, 250011, People’s Republic of China; 3Shenzhen Hospital, Shanghai University of Traditional Chinese Medicine, Shenzhen, 518001, People’s Republic of ChinaCorrespondence: Fengxia Zhang, Department of Neurology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, 250011, People’s Republic of China, Tel +86-131-5317-5246, Email fxzhang0987@163.comAbstract: Non-alcoholic fatty liver disease(NAFLD) is an umbrella term for a range of diseases ranging from hepatic fat accumulation and steatosis to non-alcoholic steatohepatitis (NASH) in the absence of excessive alcohol consumption and other definite liver damage factors. The incidence of NAFLD has increased significantly in recent years and will continue to grow in the coming decades. NAFLD has become a huge health problem and economic burden. SIRT1 is a member of Sirtuins, a group of highly conserved histone deacetylases regulated by NAD+, and plays a vital role in regulating cholesterol and lipid metabolism, improving oxidative stress, inflammation, and insulin resistance through deacetylating some downstream transcription factors and thus improving NAFLD. Although there are no currently approved drugs for treating NAFLD and some unresolved limitations in developing SIRT1 activators, SIRT1 holds promise as a proper therapeutic target for NAFLD and other metabolic diseases. In recent years, natural products have played an increasingly important role in drug development due to their safety and efficacy. It has been discovered that some natural products may be able to prevent and treat NAFLD by targeting SIRT1 and its related pathways. This paper reviews the mechanism of SIRT1 in the improvement of NALFD and the natural products that regulate NAFLD through SIRT1 and its associated pathways, and discusses the potential of SIRT1 as a therapeutic target for treating NAFLD and the effectiveness of these related natural products as clinical drugs or dietary supplements. These works may provide some new ideas and directions for finding new therapeutic targets for NAFLD and the development of anti-NAFLD drugs with good pharmacodynamic properties. Keywords: NAFLD, SIRT1, natural products, FFA, TG

Rui Liu, Dandan Shi, Lu Guo, Shan Xiao, Mengmeng Shang, Xiao Sun, Dong Meng, Yading Zhao, Xiaoxuan Wang, Jie Li Department of Ultrasound, Qilu Hospital of Shandong University, Jinan, Shandong, 250012, People’s Republic of ChinaCorrespondence: Jie Li, Department of Ultrasound, Qilu Hospital of Shandong University, Jinan, Shandong, 250012, People’s Republic of China, Email jieli@email.sdu.edu.cnIntroduction: Triple-negative breast cancer (TNBC) is known to be the most aggressive form of breast cancer. Due to its high recurrence and mortality rates, the treatment of TNBC is a significant challenge for the medical community. Besides, ferroptosis is an emerging regulatory cell death that may provide new insights into the treatment of TNBC. As a central inhibitor of the ferroptosis process, the selenoenzyme glutathione peroxidase 4 (GPX4) is its classical therapeutic target. However, inhibition of GPX4 expression is quite detrimental to normal tissues. Ultrasound contrast agents, as an emerging visualization precision treatment, may provide a solution to the existing problem.Methods: In this study, nanodroplets (NDs) carrying simvastatin (SIM) were constructed using the homogeneous/emulsification method. Then, the characterization of SIM-NDs was systematically evaluated. Meanwhile, in this study, the ability of SIM-NDs combined with ultrasound-targeted microbubble disruption (UTMD) to initiate ferroptosis and its respective mechanisms of ferroptosis induction were verified. Finally, the antitumor activity of SIM-NDs was investigated in vitro and in vivo using MDA-MB-231 cells and TNBC animal models.Results: SIM-NDs exhibited excellent pH- and ultrasound-responsive drug release and noticeable ultrasonographic imaging ability, also showing good biocompatibility and biosafety. UTMD could promote increased intracellular reactive oxygen species and consume intracellular glutathione. However, SIM-NDs were efficiently internalized into cells under ultrasound irradiation, followed by the rapid release of SIM, which inhibited intracellular mevalonate production, and synergistically downregulated GPX4 expression, thereby promoting ferroptosis. Moreover, this combined treatment demonstrated strong antitumor ability in vitro and in vivo.Conclusion: The combination of UTMD and SIM-NDs presents a promising avenue for harnessing ferroptosis in the treatment of malignant tumors.Graphical Abstract: Keywords: ultrasound-targeted microbubble disruption, nanodroplets, ferroptosis, glutathione peroxidase 4, theranostics, lipid peroxidation

Kai Wang, Yian Tian, Shanshan Liu, Zhongyuan Zhang, Leilei Shen, Deqian Meng, Ju Li Department of Rheumatology, the Affiliated Huaian No.1 People’s Hospital of Nanjing Medical University, Huaian, 223001, People’s Republic of ChinaCorrespondence: Ju Li; Deqian Meng, Department of Rheumatology, the affiliated Huaian No.1 People’s Hospital of Nanjing Medical University, Huaian, 223001, People’s Republic of China, Email liju198461@163.com; deqianmeng2016njmc@163.comBackground: Rapidly progressive interstitial lung disease (RP-ILD) is a significant complication that determines the prognosis of dermatomyositis (DM). Early RP-ILD diagnosis can improve screening and diagnostic efficiency and provide meaningful guidance to carry out early and aggressive treatment.Methods: A retrospective screening of 284 patients with DM was performed. Clinical and laboratory characteristics of the patients were recorded. The risk factors of RP-ILD in DM patients were screened by logistic regression (LR) and machine learning methods, and the prediction models of RP-ILD were developed by machine learning methods, namely least absolute shrinkage and selection operator (LASSO), random forest (RF), and extreme gradient boosting (XGBoost).Results: According to the result of univariate LR, disease duration is a protective factor for RP-ILD, and ESR, CRP, anti-Ro-52 antibody and anti-MDA5 antibody are risk factors for RP-ILD. The top 10 important variables of the 3 machine learning models were intersected to obtain common important variables, and there were 5 common important variables, namely disease duration, LDH, CRP, anti-Ro-52 antibody and anti-MDA5 antibody. The AUC of LASSO, RF and XGBoost test set were 0.661, 0.667 and 0.867, respectively. We further validated the performance of these three models on validation set, and the results showed that, the AUC of LASSO, RF and XGBoost were 0.764, 0.727 and 0.909, respectively. Based on the results of the models, XGBoost is the optimal model in this study.Conclusion: Disease duration, LDH, CRP, anti-Ro-52 antibody and anti-MDA5 antibody are vital risk factors for RP-ILD in DM. The prediction model constructed using XGBoost can be used for risk identification and early intervention in DM patients with RP-ILD and practical application.Keywords: dermatomyositis, interstitial lung disease, risk factor, predictive model, logistic regression, least absolute shrinkage and selection operator, random forest, extreme gradient boosting

Ling Lu,1,&ast; Qiaoyan Liang,2,&ast; Xinyi Zhang,3 Yumeng Xu,3 Dehua Meng,4 Zhaofeng Liang3 1Child Healthcare Department, the Fourth Affiliated Hospital of Jiangsu University, Zhenjiang, People’s Republic of China; 2Health Care Department, People’s Liberation Army Navy No. 971 Hospital, Qingdao, People’s Republic of China; 3School of Medicine, Jiangsu University, Zhenjiang, People’s Republic of China; 4Department of Allergy, Dongtai People’s Hospital, Yancheng, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zhaofeng Liang, School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang, Jiangsu, 212013, People’s Republic of China, Email liangzhaofeng@ujs.edu.cn Dehua Meng, Department of Allergy, Dongtai People’s Hospital, 02 Fukang West Road, Yancheng, Jiangsu, 224200, People’s Republic of China, Email 2798184241@qq.comAbstract: Gastric cancer (GC) is one of the most common malignant cancers that seriously affect human health. Autophagy is a highly conserved self-defense mechanism found to plays an important role in the occurrence, progression, drug resistance, and prognosis of GC. Noncoding RNAs (ncRNAs) play a critical role in the occurrence and development of a variety of diseases including GC. In recent years, increasing attention has been given to research on autophagy-related ncRNAs, such as miRNA, lncRNA, and circRNA in GC. Herein, we briefly summarize the roles, functions, and the research progress of autophagy and autophagy-related ncRNAs in GC with a focus on the potential application in GC tumorigenesis, development, prognosis, and drug resistance. We also discussed prospects of clinical application, future research direction, and challenges in future research of autophagy-related ncRNAs.Keywords: gastric cancer, autophagy, noncoding RNA, function

Zijuan Ma,1,2 Yanqiang Tao,3 Huilin Chen,4 Yifan Zhang,1,2 Ye Pan,1,2 Dongjing Meng,1,2 Fang Fan1,2 1School of Psychology, Center for Studies of Psychological Application, and Guangdong Key Laboratory of Mental Health and Cognitive Science, South China Normal University, Guangzhou, People’s Republic of China; 2Key Laboratory of Brain, Cognition and Education Sciences, Ministry of Education, Guangzhou, People’s Republic of China; 3Beijing Key Laboratory of Applied Experimental Psychology, Faculty of Psychology, Beijing Normal University, Beijing, People’s Republic of China; 4Department of Psychology, University of Bath, Bath, UKCorrespondence: Fang Fan, Email fangfan@scnu.edu.cnPurpose: Sleep inertia (SI) is the transitional state accompanied by compromised cognitive and physical performance and sleepiness. Network analysis offers a potential new framework to conceptualize a complex network of symptom–symptom interactions, and the network structure is analyzed to reveal the core characteristics. However, no previous study examined the network structure of SI symptoms. Thus, this study aimed to elucidate characteristics and compare sex differences of SI symptom networks in the general population.Materials and Methods: A total of 1491 participants from China were recruited from 30 May to 17 June, 2021. SI symptoms were assessed by using the Sleep Inertia Questionnaire (SIQ). The network structures were estimated and compared using network analytic methods in the R version 4.1.1.Results: Centrality properties analysis of the expected influence suggested that symptoms of “Feel sleepy”, “Groggy, fuzzy or hazy mind”, and “Dread starting your day” exerted greatest influences. The weighted adjacency matrix revealed that the “Dread starting your day” and “Anxious about the upcoming day” edge showed the strongest connection (edge weight value = 0.70). The network comparison test found no significant difference in network global strength (p=0.928), distribution of edge weights (p=0.194) and individual edge weights (all p values > 0.05 after Holm–Bonferroni corrections) between males and females.Conclusion: Symptoms of “Feel sleepy”, “Groggy, fuzzy or hazy mind”, and “Dread starting your day” were central in the SI symptom network. Intervention, such as the artificial dawn and change in body temperature, for symptoms of “Feel sleepy”, “Groggy, fuzzy or hazy mind”, and “Dread starting your day” might be crucial to hasten the dissipation of SI in the general population who may need to perform tasks upon waking.Keywords: sleep inertia, Sleep Inertia Questionnaire, network analysis, general population

Yong Shi,1,&ast; Deru Meng,1,&ast; Shuanghu Wang,1 Peiwu Geng,1 Tao Xu,2 Quan Zhou,1 Yunfang Zhou,1 Wanshu Li,3 Xugao Chen4 1Comprehensive Breast Health Center, Department of Thyroid and Breast Surgery, The Sixth Affiliated Hospital of Wenzhou Medical University, The People’s Hospital of Lishui, Lishui, 323000, People’s Republic of China; 2Department of Pharmacy, Ningbo First Hospital, Ningbo, 315010, Zhejiang, People’s Republic of China; 3Department of Pharmacy, Ningbo Municipal Hospital of Traditional Chinese Medicine, Ningbo, 315010, Zhejiang, People’s Republic of China; 4Department of Radiology, The Sixth Affiliated Hospital of Wenzhou Medical University, The People’s Hospital of Lishui, Lishui, 323000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xugao ChenDepartment of Radiology, The Sixth Affiliated Hospital of Wenzhou Medical University, The People’s Hospital of Lishui, Lishui, 323000, People’s Republic of ChinaTel/Fax +86578-2780081Email lishui001@163.comWanshu LiDepartment of Pharmacy, Ningbo Municipal Hospital of Traditional Chinese Medicine, Ningbo, 315010, Zhejiang, People’s Republic of ChinaTel/Fax +86574-87089100Email wanshu_lws@126.comPurpose: Avitinib is the first third-generation epithelial growth factor receptor (EGFR) inhibitor independently developed in China and is mainly used for treating non-small cell lung cancer. However, pharmacokinetic details are limited. This study explored the in vivo and in vitro effects of avitinib on cytochrome CYP450 enzymes metabolic activity.Methods: A rapid and sensitive ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed and validated for determining six probe substrates and their metabolites. Avitinib influence on activity levels of CYP isozymes was examined in vitro using human and rat liver microsomes (HLMs/RLMs). For in vivo studies, rats were pretreated with 30 mg/kg avitinib once daily for 7 days (avitinib multiple-doses group), 30 mg/kg avitinib on day 7 (avitinib single-dose group), or an equivalent amount of CMC-Na once daily for 7 days (control group), followed by intragastrical administration of the probe substrates (1 mg/kg tolbutamide and 10 mg/kg phenacetin, bupropion, chlorzoxazone, dextromethorphan, and midazolam). Plasma pharmacokinetics and IC50 values of the probe substrates were then compared. Pharmacokinetic parameters were determined using non-compartmental analysis implemented in a pharmacokinetic program.Results: In vitro experiments revealed different inhibitory effects of avitinib on the six probe substrates with various IC50 values (bupropion, 6.39/22.64 μM; phenacetin, 15.79/48.36 μM; chlorzoxazone, 23.15/57.09 μM; midazolam, 27.64/59.6 μM; tolbutamide, 42.18/6.91 μM; dextromethorphan, 44.39/56.57 μM, in RLMs and HLMs respectively). In vivo analysis revealed significant differences (P < 0.05) in distinct pharmacokinetic parameters (AUC(0-t), AUC (0-∞), Cmax, MRT(0-t), MRT (0-∞), and CLz/F) for the six probe substrates after avitinib pretreatment.Conclusion: A sensitive and reliable UPLC-MS/MS method was established to determine the concentration of six probe substrates in rat plasma. Avitinib had inhibitory effects on CYP450 enzymes, especially cyp2b1, cyp1a2 in RLMs, CYP2C9 in HLMs, and cyp1a2, cyp2b1, cyp2d1, and cyp2e1 in vivo. Our data recommend caution when avitinib was taken simultaneously with drugs metabolized by CYP450 enzymes.Keywords: cytochrome, EGFR inhibitor, UPLC-MS/MS, rat liver microsome, drug-drug interaction

Dexin Meng,1,&ast; Ying Zhao,2,3,&ast; Jing Guo,2,3 Huiying Xu,4 Yiming Fu,2,3 Xiaohan Ma,2,3 Liwei Zhu,2,3 Li Mu2,3 1Department of Physiology, Jiamusi University, Jiamusi, People’s Republic of China; 2Research Center of Brain and Cognitive Neuroscience, Liaoning Normal University, Dalian, Liaoning Province, People’s Republic of China; 3Key Laboratory of Brain and Cognitive Neuroscience, Liaoning Province, Dalian, Liaoning Province, People’s Republic of China; 4School of Clinical Medicine, Changchun University of Chinese Medicine, Changchun, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Li MuResearch Center of Brain and Cognitive Neuroscience, Liaoning Normal University, No. 850 Huanghe Road, Shahekou District, Dalian, 116029, Liaoning Province, People’s Republic of ChinaEmail mul@lnnu.edu.cnIntroduction: Bedtime procrastination (BP) has a close relationship with one’s chronotype, from a biological perspective on time. However, it remains unknown whether there is an association between BP and psychological time. Therefore, the aim of the present study was to evaluate the relationship between time perspective (TP) and BP and the effect of TP on the relationship between BP and chronotype by examining a sample of college students pre- and post-COVID-19 outbreak.Methods: A total of 628 Chinese students (267 in pre-outbreak and 361 in post-outbreak) validly completed the Chinese version of the Bedtime Procrastination Scale, the Zimbardo Time Perspective Inventory (ZTPI), and the Morningness–Eveningness Questionnaire.Results: Students with more BP behaviors exhibited greater deviation from a balanced TP, especially after the COVID-19 outbreak. Hierarchical regression analyses revealed that the past-negative and future orientations, as operationalized by the ZTPI, contributed independently to BP behaviors. The structural equation modeling analyses further demonstrated that morningness was significantly related to a more future-oriented TP, which in turn decreased BP in pre- and post-COVID-19 outbreak samples, while morningness was associated with a less past-negative-oriented TP, which in turn decreased BP only in the post-COVID-19 outbreak sample.Conclusion: This study indicated that TP in students with BP predominantly focused on future orientation and that TP can mediate the relationship between chronotype and BP behaviors. However, the COVID-19 pandemic may disrupt the time flow and change the role of chronotype–TP in BP. These findings explain how individual differences in TP are associated with BP, which may be helpful in designing effective interventions to avoid BP, from the viewpoint of time perspective therapy.Keywords: bedtime procrastination, deviation from balanced time perspective, future time perspective, morningness, past negative time perspective, COVID-19

Xinxin Liu, Dandan Shi, Lu Guo, Xiaoying Zhou, Mengmeng Shang, Xiao Sun, Dong Meng, Yading Zhao, Jie Li Department of Ultrasound, Qilu Hospital of Shandong University, Jinan, People’s Republic of ChinaCorrespondence: Jie LiDepartment of Ultrasound, Qilu Hospital of Shandong University, Wenhua Western Road, Jinan 107#, People’s Republic of ChinaTel/Fax +86-531-82166101Email jieli301@163.comPurpose: To synthesize echogenic chitosan/perfluorohexane nanodroplets (CNDs) for DKK-2 gene delivering in a spatiotemporally controlled manner in vitro.Methods: The characteristics, contrast-enhanced ultrasound imaging, DNA binding and DNase protection capacity, DKK-2 gene transfection and effects on LNCaP cells of these CNDs were investigated.Results: The obtained CNDs showed positive surface charges and could attract the genetic cargo with negative surface charges to form nanocomplexes. Agarose gel electrophoresis confirmed binding of the CNDs and pDNA. DKK-2 pDNA-loaded CNDs, in combination with ultrasound, ruptured and released DKK-2 pDNA, entering LNCaP cells through nano-scale pores in the cell membrane, which further reduced the proliferation of LNCaP cells.Conclusion: These stable and safe CNDs may be a promising choice to achieve efficient ultrasound-mediated gene delivery to specific tissues in a spatiotemporally controlled manner.Keywords: nanodroplets, chitosan, DKK-2, ultrasonic gene transfer, prostate cancer

Feifei Chen,1,* Hui Jiang,1,* Jia Xu,1 Shuanghu Wang,1 Deru Meng,1 Peiwu Geng,1 Dapeng Dai,2 Quan Zhou,1 Yunfang Zhou1 1The Laboratory of Clinical Pharmacy, The Sixth Affiliated Hospital of Wenzhou Medical University, The People’s Hospital of Lishui, Lishui, Zhejiang 323000, People’s Republic of China; 2The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Beijing Hospital, National Center of Gerontology, National Health Commission, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing 100730, People’s Republic of China*These authors contributed equally to this work.Correspondence: Yunfang Zhou; Quan ZhouThe Laboratory of Clinical Pharmacy, The Sixth Affiliated Hospital of Wenzhou Medical University, The People’s Hospital of Lishui, Lishui, Zhejiang 323000, People’s Republic of ChinaTel/Fax +86 578 2780081Email zyf2808@lsu.edu.cn; zhouquan1991@lsu.edu.cnPurpose: The purpose of the present study was to investigate the effects of vonoprazan on the pharmacokinetics of venlafaxine in vitro and in vivo.Methods: The mechanism underlying the inhibitory effect of vonoprazan on venlafaxine was investigated using rat liver microsomes. In vitro, the inhibition was evaluated by determining the production of O-desmethylvenlafaxine. Eighteen male Sprague–Dawley rats were randomly divided into three groups: control group, vonoprazan (5 mg/kg) group, and vonoprazan (20 mg/kg) group. A single dose of 20 mg/kg venlafaxine was administrated to rats orally without or with vonoprazan. Plasma was prepared from blood samples collected via the tail vein at different time points and concentrations of venlafaxine and its metabolite, O-desmethylvenlafaxine, were determined by ultra-performance liquid chromatography-tandem mass spectrometry.Results: We observed that vonoprazan could significantly decrease the amount of O-desmethylvenlafaxine (IC50 = 5.544 μM). Vonoprazan inhibited the metabolism of venlafaxine by a mixed inhibition, combining competitive and non-competitive inhibitory mechanisms. Compared with that in the control group (without vonoprazan), the pharmacokinetic parameters of venlafaxine and its metabolite, O-desmethylvenlafaxine, were significantly increased in both 5 and 20 mg/kg vonoprazan groups, with an increase in MRO-desmethylvenlafaxine.Conclusion: Vonoprazan significantly alters the pharmacokinetics of venlafaxine in vitro and in vivo. Further investigations should be conducted to check these effects in humans. Therapeutic drug monitoring of venlafaxine in individuals undergoing venlafaxine maintenance therapy is recommended when vonoprazan is used concomitantly.Keywords: gastroduodenal ulcer, gastroesophageal reflux disease, proton pump inhibitors, vonoprazan fumarate

Delong Li,1 Debin Meng,1,2 Rungui Niu1 1Department of Special Geriatrics, Shanxi Cancer Hospital, Taiyuan, Shanxi, People’s Republic of China; 2Department of General Surgery, Shanxi Cancer Hospital, Taiyuan, Shanxi, People’s Republic of ChinaCorrespondence: Debin MengDepartment of Special Geriatrics, Shanxi Cancer Hospital, No. 3 Worker Street of Xinghualing District, Taiyuan City, Shanxi Province, People’s Republic of ChinaEmail debinmengsx@sina.comIntroduction: Non-small lung cancer (NSCLC) is one of the most common malignant tumors in the world. Chemoresistance is the main reason of adverse effects leading to the death of patients; thus, it is important to discover the potential target of chemotherapeutic resistance.Methods: The expression of differentially expressed miRNA was detected in BEAS-2B, A549 and A549/cisplatin (DDP) by qRT-PCR. Transmission electron microscopy (TEM) and exosome biomarkers were used to validate the extracted exosome. Cells incubated with miR-613 enriched exosomes were used to detect the function of exo-miR-613 in vitro. Then, exo-miR-613 was injected to mice treated with DDP to investigate the function role of exo-miR-613 in vivo.Results: Comparing to BEAS-2B, the expression of miR-613 inA549 was significantly reduced, which was more obvious in A549/DDP. After incubated with exo-miR-613 and corresponding exo-negative control (NC), we found overexpression of miR-613 remarkably increased the inhibition of cell proliferation induced by cisplatin. Exo-miR-613 fused into cells to significantly enhance the inhibited effect of DDP on the proliferation, migration and showed a promotion on cell apoptosis and DNA damage. The in vivo study showed that exo-miR-613 significantly inhibited the tumor growth, and promote the sensitivity to DDP, probably by down-regulating the expressions of GJA1, TBP and EIF-4E in tumor cells and tissues.Conclusion: Exo-miR-613 reversed chemoresistance to DDP in NSCLC cell to involve in the process of tumor progression, and might be a potential therapeutic strategy for NSCLC.Keywords: exosome, miRNA, non-small cell lung cancer, cisplatin, chemoresistance, apoptosis

Jiquan Shen,1,* Bo Wang,1,* Shuanghu Wang,2,3 Feifei Chen,2 Deru Meng,2 Hui Jiang,2 Yunfang Zhou,2 Peiwu Geng,2 Quan Zhou,2 Bin Liu1 1Department of Orthopaedics, The Sixth Affiliated Hospital of Wenzhou Medical University, The People’s Hospital of Lishui, Lishui, Zhejiang 323000, People’s Republic of China; 2The Laboratory of Clinical Pharmacy, The Sixth Affiliated Hospital of Wenzhou Medical University, The People’s Hospital of Lishui, Lishui, Zhejiang 323000, People’s Republic of China; 3School of Pharmaceutical Science, Guangdong Provincial Key Laboratory of New Drug Screening, Southern Medical University, Guangzhou 510515, People’s Republic of China*These authors contributed equally to this workCorrespondence: Quan ZhouThe Laboratory of Clinical Pharmacy, The Sixth Affiliated Hospital of Wenzhou Medical University, The People’s Hospital of Lishui, Lishui 323000, Zhejiang, People’s Republic of ChinaTel/Fax +86 578 278 0081Email zhouquan1991@lsu.edu.cnBin LiuDepartment of Orthopaedics, The Sixth Affiliated Hospital of Wenzhou Medical University, The People’s Hospital of Lishui, Lishui 323000, Zhejiang, People’s Republic of ChinaEmail doctorliubin@163.comPurpose: The purpose of this study was to examine the effects of voriconazole on the pharmacokinetics of vonoprazan.Methods: Fifteen Sprague-Dawley rats were randomly divided into three groups: five rats in each group, including control group, single-dose group (a single dose of 30 mg/kg of voriconazole), and multiple-dose group (multiple doses of 30 mg/(kg•day) per dose of voriconazole). Each group of rats was given an oral dose of 10 mg/kg vonoprazan 30 min after the administration of voriconazole or vehicle. After the oral administration of vonoprazan, 50 μL of blood was collected into 1.5-mL heparinized tubes via the caudal vein. The concentration of vonoprazan in plasma was quantified by ultra-performance liquid chromatography/tandem mass spectrometry. Both in vitro effects of voriconazole on vonoprazan and the mechanism of the observed inhibition were studied in rat liver microsomes.Results: When orally administered, voriconazole increased the area under the plasma concentration–time curve (AUC), prolonged the elimination half-life (t1/2), and decreased the clearance (CL) of vonoprazan; there was no significant difference between the single-dose and multiple-dose groups. Voriconazole inhibited the metabolism of vonoprazan at an IC50 of 2.93 μM and showed mixed inhibition. The results of the in vivo experiments were consistent with those of the in vitro experiments.Conclusion: Our findings provide the evidence of drug–drug interactions between voriconazole and vonoprazan that could occur with pre-administration of voriconazole. Thus, clinicians should pay attention to the resulting changes in pharmacokinetic parameters and accordingly, adjust the dose of vonoprazan in clinical settings.Keywords: cytochrome P450, drug–drug interaction, pharmacokinetic, proton pump inhibitor

Xiao Sun,1 Lu Guo,1 Mengmeng Shang,1 Dandan Shi,1 Ping Liang,2 Xuanxuan Jing,1 Dong Meng,1 Xinxin Liu,1 Xiaoying Zhou,1 Yading Zhao,1 Jie Li1 1Department of Ultrasound, Qilu Hospital of Shandong University, Jinan, People’s Republic of China; 2Department of Interventional Ultrasound, Chinese PLA General Hospital, Beijing, People’s Republic of ChinaCorrespondence: Jie LiDepartment of Ultrasound, Qilu Hospital of Shandong University, Wenhua Western Road, 107#, Jinan Tel/Fax +86-531-82166101Email jieli301@163.comPurpose: To synthesize and evaluate a novel folate-conjugated ultrasonic nanobubble (HA-FOL-NB) loading low-molecular-weight hyaluronic acid (LMW-HA) for specific tumor-associated macrophages (TAMs) targeting and reeducation.Methods: The characteristics, cytotoxicity, contrast-enhanced ultrasound imaging (CEUS), and targeting ability to TAMs of HA-FOL-NBs were investigated. The TAMs reprogramming function of HA-FOL-NBs combining ultrasound targeted nanobubble destruction was assessed as well.Results: HA-FOL-NBs (about 342 nm) showed remarkable contrast enhancement images, and higher targeting ability due to the folate to folate receptor interactions. Combined with ultrasound targeted nanobubble destruction, HA-FOL-NBs could specifically deliver LMW-HA into TAMs, thus exhibited stronger reeducation effect compared with free LMW-HA.Conclusion: These folate-conjugated and LMW-HA-loaded nanobubbles, with targeted CEUS imaging and TAMs reeducation, are expected to be a potential approach for tumor therapy based on TAMs, especially folate receptor-positive ones.Keywords: ultrasound contrast agent, ultrasonic nanobubble, tumor-associated macrophage, tumor microenvironment, contrast-enhanced ultrasound imaging

Mengmeng Shang,1 Xiao Sun,1 Lu Guo,1 Dandan Shi,1 Ping Liang,2 Dong Meng,1 Xiaoying Zhou,1 Xinxin Liu,1 Yading Zhao,1 Jie Li1 1Department of Ultrasound, Qilu Hospital of Shandong University, Jinan 250012, People’s Republic of China; 2Department of Interventional Ultrasound, Chinese PLA General Hospital, Beijing 100853, People’s Republic of ChinaCorrespondence: Jie LiDepartment of Ultrasound, Qilu Hospital of Shandong University, 107 Wenhua Xi Road, Jinan 250012, People’s Republic of ChinaTel +86-531-82166101Fax +86-531-86927544Email jieli301@163.comBackground: Synergistic chemoradiotherapy (CRT) has become a primary effective curative approach for many solid cancers. However, CRT is still associated with several obstacles, including the increases in side effects and systemic toxicity. Incorporating nanocarriers into CRT is a new and exciting approach to solve these obstacles. The purpose of the present study was to design a unique pH- and ultrasound-responsive perfluoropentane-encapsulated, paclitaxel (PTX)-loaded carboxymethyl chitosan nanodroplets (NDs) for combined imaging and synergistic CRT.Materials and Methods: The NDs were prepared by a homogenization/emulsion method. Their physicochemical properties, echogenicity and biocompatibility were evaluated. PTX-loaded NDs with a high loading efficiency and encapsulation efficiency were prepared and their pH-responsive drug release profile was determined by dialysis sack method. Then, PC3 cells were exposed to (1) PTX (4 μg/mL), (2) NDs (30 μg/mL), (3) PTX-loaded NDs (34 μg/mL), (4) RT (6 Gy), (5) RT (10 Gy), (6) combination of PTX (4 μg/mL), ultrasound (0.5 W/cm2, 30 s) and RT (6 Gy), (7) combination of NDs (30 μg/mL), ultrasound (0.5 W/cm2, 30 s) and RT (6Gy), (8) combination of PTX-loaded NDs (30 μg/mL), ultrasound (0.5 W/cm2, 30 s) and RT (6 Gy). 24 hrs later, CCK-8 assay, flow cytometry and migration assay were carried out to evaluate their therapeutic effects in CRT.Results: The desired NDs were successfully prepared, which were with round, spherical shapes, relatively smooth surfaces, core-shell structures and uniform in sizes (< 300 nm with PDI< 0.3 when at pH≧6.0). The NDs exhibited good abilities in pH-dependent charge conversion, biocompatibility and ultrasound contrast echogenicity. The in vitro drug release from PTX-loaded NDs (the highest loading efficiency and encapsulation efficiency were 20.35% and 91.58%) was pH dependent and exhibited an initial burst followed by a sustained drug release. The results of the CCK-8 assay, flow cytometry and migration assay all showed PTX-loaded NDs combined ultrasound and RT significantly enhanced cell responses in CRT.Conclusion: The pH- and ultrasound-responsive PTX-loaded NDs, which exhibited a high echogenicity, drug delivery ability and radiosensitization ability, could be a feasible option for combined imaging and novel enhancing approach in synergistic CRT.Keywords: nanodroplets, ultrasound contrast agents, chemoradiotherapy, radiosensitizer, paclitaxel, chitosan

Yongwei Hao,1,* Lei Wang,1,2,* Bingxiang Zhang,1 Dong Li,1 Dehui Meng,1 Jinjin Shi,1 Hongling Zhang,1 Zhenzhong Zhang,1 Yun Zhang11School of Pharmaceutical Sciences, 2School of Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou, People’s Republic of China *These authors contributed equally to this work Abstract: The aim of this study was to construct redox- and pH-responsive degradable manganese dioxide (MnO2) nanosheets for cancer theranostic application. The small MnO2 nanosheets were synthesized, and then functionalized by hyaluronic acid (HA), demonstrating excellent stability and tumor-targeting ability. Cisplatin (cis-diamminedichloroplatinum [CDDP]) was absorbed by the nanosheets through a physical action, which was designed as MnO2/HA/CDDP. The prepared MnO2/HA/CDDP formulation was able to efficiently deliver CDDP to tumor cells in vitro and in vivo, resulting in improved therapeutic efficiency. Subsequently, they were triggered by lower pH and higher level of reduced glutathione to generate Mn2+, enabling magnetic resonance imaging. The smart multifunctional system combining efficient magnetic resonance imaging and chemotherapy has the potential to be used as a tumor-targeting theranostic nanomedicine.Keywords: manganese dioxide nanosheets, hyaluronic acid, magnetic resonance imaging, theranostic application

We report the pulsed-laser deposition of epitaxial double-perovskite Bi2FeCrO6(BFCO) films on the (001)-, (110), and (111)-oriented single-crystal SrTiO3 substrates. All of the BFCO films with various orientations show the 1/2 1/2 1/2 and 3/2 3/2 3/2 superlattice-diffraction peaks. The intensity ratios between the 1/2 1/2 1/2-superlattice and the main 111-diffraction peak can be tailored by simply adjusting the laser repetition rate and substrate temperature, reaching up to 4.4%. However, both optical absorption spectra and magnetic measurements evidence that the strong superlattice peaks are not correlated with the B-site Fe3+/Cr3+ cation ordering. Instead, the epitaxial (111)-oriented Bi2FeCrO6 films show an enhanced remanent polarization of 92 μC/cm2 at 10 K, much larger than the predicted values by density-functional theory calculations. Positive-up-negative-down (PUND) measurements with a time interval of 10 μs further support these observations. Therefore, our experimental results reveal that the strong superlattice peaks may come from A- or B-site cation shifts along the pseudo-cubic [111] direction, which further enhance the ferroelectric polarization of the BFCO thin films.

To explore variation in the meat metabolites of two goat breeds, metabolomics analysis of the mutton samples of Jining Gray and Lubei White goat breeds was performed using mass spectrometry (LC-MS). The profile revealed a total of 2,599 metabolites in the mutton samples. The significantly higher (p < 0.05) metabolites included methionyl asparagine (p = 0.017), hydrocarbons, tryptophylhistidine, L-glutamine, D-glutamine, and indole acrylic acid in the longissimus dorsi muscle of Jining Gray goats compared to Lubei White goats. The essential amino acids, such as histidine, phenylalanine, and L-tyrosine were significantly higher in the mutton of the Lubei White goats compared to that of the Jining Gray goats. The contents of 2-hydroxycinnamic acid (p = 0.027) and nicotinamide (p = 0.002) in Lubei White goat were also significantly high. Taken together, the data showed that the meat profile of the Lubei White and Jining Gray goats significantly varied. The data would be helpful in further studying the meat traits in the two goat breeds. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Multicause-of-death methods were used to analyze mortality and leading causes of death associated with polymyalgia rheumatica (PMR) in the United States from 1999 to 2020. MATERIALS AND METHODS: We analyzed mortality data from the Centers for Disease Control and Prevention (CDC) Data analysis system and selected death certificates that listed PMR as the cause of death based on the International Statistical Classification of Diseases and Related Health Problems (ICD-10) category code. Relevant mortality rates, number of deaths and historical trends were analyzed. The number of PMR-related deaths and age-standardized mortality rate (ASMR) trend charts were made using Excel 2010 version and trend lines were added. RESULTS: Over the last 22 years, the total number of PMR-related deaths in the United States was 15,421 women (89.8%), a ratio of about 1:9 men to women. When PMR is listed as the underlying cause of death, the ASMR for women and men (per 100,000 people) is approximately 1.8-5.1:1, and when it is listed as the non-underlying cause of death, it is 1.8-3.3:1. PMR deaths are more frequent in individuals aged 70 years and above, with patients aged 80 years and above being most affected. Among different ethnicities, the highest number of deaths was found in Caucasians, followed by Black or African American. When it comes to causes of death, heart disease still ranks first, followed by cancer. In addition, we also found that when PMR combined with malignant tumors as a multiple cause of death, the number of female deaths was higher than that of male deaths, the overall number of deaths of both showed an upward trend, and the overall ASMR of both showed a downward trend. CONCLUSIONS: In the past 22 years, we have observed a low mortality rate of PMR in the United States. However, for patients with PMR, especially elderly women, medical workers should be vigilant and pay attention to whether they are combined with other complications, such as malignant neoplasms, and make timely diagnosis and treatment to further reduce the mortality rate of patients with PMR. [ABSTRACT FROM AUTHOR]

Vasculitis is the inflammation of blood vessels caused by autoimmunity and/or autoinflammation, and its etiology and pathogenesis remain largely unknown. The Janus kinase (JAK) and Signal transduction Transcription Activator (STAT) signal transduction pathways are a group of molecules involved in the major pathways by which many cytokines exert and integrate their functions, and their dysregulation has been implicated in the pathogenesis of a variety of autoimmune diseases. However, current data supporting the role of the JAK/ STAT pathway in the development of vasculitis is limited. In terms of treatment, glucocorticoids and immunosuppressants have been the standard therapy. However, because of the huge burden of treatment side effects, people have long waited for new treatment options. JAK inhibitors reduce the production of multiple cytokines and inhibit inflammation by targeting the JAK/STAT pathway, and have the advantage of rapidly acting in oral formulations, reducing glucocorticoid dependence and associated adverse events, especially in refractory cases. Therefore, JAK inhibitors are expected to be a promising drug for the treatment of vasculitis. [ABSTRACT FROM AUTHOR]

Summary: We conducted a systematic review of the literature reporting phenylephrine‐induced changes in blood pressure, cardiac output, cerebral blood flow and cerebral tissue oxygen saturation as measured by near‐infrared spectroscopy in humans. We used the proportion change of the group mean values reported by the original studies in our analysis. Phenylephrine elevates blood pressure whilst concurrently inducing a reduction in cardiac output. Furthermore, despite increasing cerebral blood flow, it decreases cerebral tissue oxygen saturation. The extent of phenylephrine's influence on cardiac output (r = ‐0.54 and p = 0.09 in awake humans; r = ‐0.55 and p = 0.007 in anaesthetised humans), cerebral blood flow (r = 0.65 and p = 0.002 in awake humans; r = 0.80 and p = 0.003 in anaesthetised humans) and cerebral tissue oxygen saturation (r = ‐0.72 and p = 0.03 in awake humans; r = ‐0.24 and p = 0.48 in anaesthetised humans) appears closely linked to the magnitude of phenylephrine‐induced blood pressure changes. When comparing the effects of phenylephrine in awake and anaesthetised humans, we found no evidence of a significant difference in cardiac output, cerebral blood flow or cerebral tissue oxygen saturation. There was also no evidence of a significant difference in effect on systemic and cerebral circulations whether phenylephrine was given by bolus or infusion. We explore the underlying mechanisms driving the phenylephrine‐induced cardiac output reduction, cerebral blood flow increase and cerebral tissue oxygen saturation decrease. Individualised treatment approaches, close monitoring and consideration of potential risks and benefits remain vital to the safe and effective use of phenylephrine in acute care. [ABSTRACT FROM AUTHOR]

Abstract Effective antibacterial therapy while accelerating the repair of bone defects is crucial for the treatment of osteomyelitis. Inspired by the protective mechanism of Andrias davidianus, we constructed an antibacterial hydrogel scaffold with excellent rigidity and long-term slow-release activity. While retaining the toughness of the skin secretion of Andrias davidianus (SSAD), the rigidity of the hydrogel material is increased by incorporating hydroxyapatite to meet the demands of bone-defect-filling materials. It also exerted antibacterial effects via the slow-release of vancomycin from local osteomyelitis lesions. Notably, the hydrogel can also carry a high stable recombinant miR-214-3p inhibitor (MSA-anti214). By the delivery of nano vector polyvinylamine, the long-term slow-release of MSA-anti214 is achieved to promote bone repair, making this composite hydrogel a potential SSAD-based osteomyelitis alleviator (SOA). In vitro and vivo results verified that the SOA effectively eliminated Staphylococcus aureus and repaired bone defects, ultimately mitigating the progression of osteomyelitis. This composite hydrogel extends the economic application prospects of A. davidianus and has provided new insights for the treatment of osteomyelitis. The study also explored new insights for the bone filling materials of bone defection and other skeletal system diseases.

Abstract Objectives To quantitatively investigate the anatomy of the anterior talofibular ligament (ATFL) and calcaneofibular ligament (CFL) for surgical reconstruction procedures in chronic ankle instability (CAI). Methods 3D MRI was performed on five fresh-frozen cadaveric ankles using six different spatial resolutions (0.3 × 0.3 × 0.3 mm3, 0.45 × 0.45 × 0.45 mm3, 0.6 × 0.6 × 0.6 mm3, 0.75 × 0.75 × 0.75 mm3, 0.9 × 0.9 × 0.9 mm3, 1.05 × 1.05 × 1.05 mm3). After comparing the MRI results with cadaver dissection, a resolution of 0.45 × 0.45 × 0.45 mm³ was selected for bilateral ankles MRI on 24 volunteers. Classification of the ATFL and four distances of surgically relevant bony landmarkers were analyzed (distance 1 and 3, the fibular origin of the ATFL and CFL to the tip of fibula, respectively; distance 2, the talar insertion of the ATFL to the bare zone of talus; distance 4, the calcaneal insertion of the CFL to the peroneal tubercle). Results In subjective evaluation, the interobserver ICC was 0.95 (95% confidence interval (CI): 0.94–0.97) between two readers. The spatial resolution of 0.3 × 0.3 × 0.3 mm3 and 0.45 × 0.45 × 0.45 mm3 received highest subjective score on average and demonstrated highest consistency with autopsy measurements in objective evaluation. Measurements on the 48 volunteer ankles, distance 1 in type I and II were 12.65 ± 2.08 mm, 13.43 ± 2.06 mm (superior-banded in Type II) and 7.69 ± 2.56 mm (inferior-banded in Type II) (means ± SD), respectively. Distance 2 in type I and II were 10.90 ± 2.24 mm, 11.07 ± 2.66 mm (superior-banded in Type II), and 18.44 ± 3.28 mm (inferior-banded in Type II), respectively. Distance 3 and 4 were 4.71 ± 1.04 mm and 14.35 ± 2.22 mm, respectively. Conclusion We demonstrated the feasibility of quantifying the distances between bony landmarkers for surgical reconstruction surgery in CAI using high-resolution 3D MRI. Critical relevance statement High-resolution 3D MRI examination may have a guiding effect on the preoperative evaluation of chronic ankle instability patients. Key Points Spatial resolutions of 0.3 × 0.3 × 0.3 mm3 and 0.45 × 0.45 × 0.45 mm3 demonstrated highest consistency with autopsy measurements. The spatial resolution of 0.45 × 0.45 × 0.45 mm3 was conformed more to clinical needs. 3D MRI can assist surgeons in developing preoperative plans for chronic ankle instability. Graphical Abstract

Abstract The brown planthopper (BPH) is one of the most problematic pests affecting rice (Oryza sativa L.) yields in Asia. Breeding rice varieties containing resistance genes is the most economical and effective means of controlling BPH. In this study, the key factors in resistance to BPH were investigated between the high-resistance rice variety “R26” and the susceptible variety “TN1” using RNA-sequencing. We identified 9527 differentially expressed genes (DEGs) between the rice varieties under BPH-induced stress. Weighted time-course gene co-expression network analysis (WGCNA) indicated that the increased expression of genes is associated with plant hormones, MAPK signaling pathway and biosynthesis of other secondary metabolites, which were involved in disease resistance. A connection network identified a hub gene, OsREM4.1 (BGIOSGA024059), that may affect rice resistance to the BPH. Knocking out OsREM4.1 in rice can lead to a decrease in callose, making it less resistant to BPH. Overall, the expression of differentially expressed genes varies among rice varieties with different resistance in BPH invasion. Inaddition, R26 enhances resistance to BPH by upregulating genes and secondary metabolites related to stress resistance and plant immunity. In summary, our study provides valuable insights into the genome-wide expression profile of DEGs in rice under BPH invasion through high-throughput sequencing, and further suggests that R26 can be used to develop high resistance rice lines in BPH resistant breeding programs.

Objective To investigate the molecular mechanism of polysaccharides from Atractylodes macrocephala koidz.(PAM) to treat severe pneumonia. Methods Sixty male SD rats were randomly divided into control group, model group (inoculation of Klebsiella pneumonia by tracheal puncture), positive control group (levofloxacin, 18 mg/kg), PAM low-dose group (50 mg/kg) and PAM high-dose group (200 mg/kg) with 12 in each. After occurrence of severe pneumonia, the rats were orally administered the medicine once daily for 7 day. The lung tissue underwent histopathological examination using HE staining microscopy to find the pathological alterations and evaluate the extent of injury. Wet/dry ratio of lung tissue was measured by weighing method. The leukocytes and neutrophils counts in peripheral blood were determined by hematology analyzer. The level of tumor necrosis factor-α(TNF-α), interleukin-1β(IL-1β) and IL-6 in serum and bronchoalveolar lavage fluid (BALF) was detected by enzyme-linked immunosorbent assay. The expression of proteins related to the Toll-like receptor 4 (TLR4) / myeloid differentiation factor 88 (MyD88)/nuclear factor-κB(NF-κB) signaling pathway in lung tissues was detected using Western blot analysis. Results Compared with the control group, lung injury score and wet/dry ratio, the number of leukocytes and neutrophils in peripheral blood, the level of TNF-α, IL-1β and IL-6 in serum and in BALF,protein expression of TLR4 and MyD88 and the phosphorylation level of NF-κB p56 in lung tissues from model group were all significantly increased(P＜0.05). The lung injury of rats in each levofloxacin treatment group exhibited significant improvement compared to the model group. Among them, the number of leukocytes and neutrophils in peripheral blood of rats in PAM high-dose group decreased significantly(P＜0.05); The level of TNF-α, IL-1β and IL-6 in serum and BALF, the protein expression of TLR4 and MyD88 and the phosphorylation level of NF-κB p56 in lung tissue were significantly decreased(P＜0.05). Conclusions The administration of PAM exerts a specific protective effect against Klebsiella pneumoniae-induced pneumonia in rats, potentially suppress inflammatory response through modulation of the TLR4/MyD88/NF-κB signaling pathway.

Abstract Background Renal cell carcinoma (RCC) is a type of cancer that can develop at any point in adulthood, spanning the range of age-related changes that occur in the body. However, the specific molecular mechanisms underlying the connections between age and genetic mutations in RCC have not been extensively investigated. Methods Clinical and genetic data from patients diagnosed with RCC were collected from two prominent medical centers in China as well as the TCGA dataset. The patients were categorized into two groups based on their prognosticated age: young adults (YAs) and older adults (OAs). Univariate and multivariate analysis were employed to evaluate the relationships between age and genetic mutations. Furthermore, a mediation analysis was conducted to assess the association between age and overall survival, with genetic disparities serving as a mediator. Results Our analysis revealed significant differences in clinical presentation between YAs and OAs with RCC, including histopathological types, histopathological tumor stage, and sarcomatoid differentiation. YAs were found to have lower mutation burden and significantly mutated genes (SMGs) of RCC. However, we did not observe any significant differences between the two groups in terms of 10 canonical oncogenic signaling pathways-related genes mutation, telomerase-related genes (TRGs) mutation, copy number changes, and genetic mutations associated with clinically actionable targeted drugs. Importantly, we demonstrate superior survival outcomes in YAs, and we confirmed the mediating effect of genetic disparities on these survival outcome differences between YAs and OAs. Conclusion Our findings reveal previously unrecognized associations between age and the molecular underpinnings of RCC. These associations may serve as valuable insights to guide precision diagnostics and treatments for RCC.

Permanent magnet synchronous motors (PMSMs) are widely utilized in the field of manufacturing and production due to their notable advantages such as simple structure, stable operation, high efficiency, and diverse configurations. Operating under conditions with variable speeds and load fluctuations, PMSMs inevitably experience various faults, including bearing faults, eccentricity faults, demagnetization faults, and interturn short-circuit faults. An overview of common fault types in PMSMs is provided in this paper and the existing researches on signal-based condition monitoring methods in the field of automation for the detection and diagnosis of electrical and mechanical faults are summarized. Subsequently, diagnostic methods are summarized, and their strengths and limitations are analyzed, discussing the pros and cons of different signal processing approaches in application. Finally, considering the current state of research, the challenges and future directions in the monitoring and diagnosis of PMSM faults are discussed.

Abstract The gas vesicle (GV) is like a hollow nanoparticle consisting of an internal gas and a protein shell, which mainly consists of hydrophobic gas vesicle protein A (GvpA) and GvpC attached to the surface. GVs, first discovered in cyanobacteria, are mainly produced by photosynthetic bacteria (PSB) and halophilic archaea. After being modified and engineered, GVs can be utilized as contrast agents, delivery carriers, and immunological boosters for disease prevention, diagnosis, and treatment with good results due to their tiny size, strong stability and non-toxicity advantages. Many diagnostic and therapeutic approaches based on GV are currently under development. In this review, we discuss the source, function, physical and chemical properties of GV, focus on the current application progress of GV, and put forward the possible application prospect and development direction of GV in the future.

Abstract Background Trans-radial (TRA) access has become increasingly prevalent in neurointervention. Nonetheless, mediastinal hematoma after TRA is an infrequent yet grave complication associated with a notably elevated mortality rate. While our review found no reported mediastinal hematoma cases managed conservatively within neuro-interventional literature, similar complications are documented in cardiac and vascular interventional radiology, indicating its potential occurrence across disciplines. Case Presentation Carotid computed tomography angiography (CTA) showed calcified plaques with stenosis (Left: Severe, Right: Moderate) in the bilateral internal carotid arteries (ICAs) of an 81-year-old male presented with paroxysmal weakness in the right upper limb. Dual antiplatelet therapy with aspirin and clopidogrel was administered. On day 7, DSA of the bilateral ICAs was performed via TRA. Post-DSA, the patient experienced transient loss of consciousness, chest tightness, and other symptoms without ECG or MRI abnormalities. Hemoglobin level decreased from 110 g/L to 92 g/L. Iodinated contrast-induced laryngeal edema was suspected, and the patient was treated with intravenous methylprednisolone. Neck CT indicated a possible mediastinal hemorrhage, which chest CTA confirmed. The patient’s treatment plan involved discontinuing antiplatelet medication as a precautionary measure against the potential occurrence of an ischemic stroke instead of the utilization of a covered stent graft and surgical intervention. Serial CTs revealed hematoma absorption. Discharge CT showed a reduced hematoma volume of 35 × 45 mm. Conclusions This case underscores the need for timely identification and precise manipulation of guidewires and guide-catheters through trans-radial access. The critical components of successful neuro-interventional techniques include timely examination, rapid identification, proper therapy, and diligent monitoring.

Abstract In situ exploration of the dynamic structure evolution of catalysts plays a key role in revealing reaction mechanisms and designing efficient catalysts. In this work, PtCu/MgO catalysts, synthesized via the co-impregnation method, outperforms monometallic Pt/MgO and Cu/MgO. Utilizing quasi/in-situ characterization techniques, it is discovered that there is an obvious structural evolution over PtCu/MgO from Pt x Cu y O z oxide cluster to PtCu alloy with surface CuO x species under different redox and CO oxidation reaction conditions. The synergistic effect between PtCu alloy and CuO x species enables good CO oxidation activity through the regulation of CO adsorption and O2 dissociation. At low temperatures, CO oxidation is predominantly catalyzed by surface CuO x species via the Mars-van Krevelen mechanism, in which CuO x can provide abundant active oxygen species. As the reaction temperature increases, both surface CuO x species and PtCu alloy collaborate to activate gaseous oxygen, facilitating CO oxidation mainly through the Langmuir-Hinshelwood mechanism.

Objective·To investigate the potential causal relationship between type 1 diabetes and colorectal cancer by using Mendelian randomization (MR).Methods·Two-sample bidirectional MR was used to investigate the causal relationship between type 1 diabetes and colorectal cancer. All research data were collected from the IEU Open GWAS Project database. The dataset of type 1 diabetes included 9 266 cases and 15 574 controls, with correlation analysis in 12 783 129 single nucleotide polymorphisms (SNPs); the dataset of colorectal cancer included 5 657 cases and 372 016 controls, with correlation analysis in 29 999 696 SNPs. The instrumental variables SNPs were screened. The results derived from the inverse-variance weighted (IVW) method were used as the main indicator of effect. The results derived from other four methods, namely MR-Egger regression, weighted median, simple mode, and weighted mode, were used as reference. Sensitivity was analyzed with the leave-one-out method. Heterogeneity was analyzed with Cochran's Q test by using both IVW and MR-Egger methods. Pleiotropy was analyzed with MR-pleiotropy function, and Steiger test was used for directional research. The colocation analysis was used to find out whether the causal relationship between type 1 diabetes and colorectal cancer was caused by the same SNP. The genetic correlation between 2 diseases was analyzed by using the linkage disequilibrium score regression (LDSC). All tests were analyzed by using R language software (version 4.3.1).Results·After being screened, a total of 33 instrumental variables (SNPs) were used. The heterogeneity test results showed that there was heterogeneity among the SNPs (IVW and MR-Egger: P0.05). Steiger test showed that the effect of type 1 diabetes on colorectal cancer was not interfered with by the reverse effect. Reverse MR analysis showed no causal effect of colorectal cancer on type 1 diabetes (P>0.05). The results of colocalization analysis showed that the probability of H4 hypothesis was 45.7%, and the causal relationship between the 2 diseases was not caused by the same SNP in the gene sequences. LDSC analysis demonstrated that there was no genetic correlation between the two diseases.Conclusion·Type 1 diabetes may promote colorectal cancer, but colorectal cancer has no effect on type 1 diabetes.

Abstract Background Ketone β-hydroxybutyrate (BHB) has been reported to prevent tumor cell proliferation and improve drug resistance. However, the effectiveness of BHB in oxaliplatin (Oxa)-resistant colorectal cancer (CRC) and the underlying mechanism still require further proof. Methods CRC-Oxa-resistant strains were established by increasing concentrations of CRC cells to Oxa. CRC-Oxa cell proliferation, apoptosis, invasion, migration, and epithelial-mesenchymal transition (EMT) were checked following BHB intervention in vitro. The subcutaneous and metastasis models were established to assess the effects of BHB on the growth and metastasis of CRC-Oxa in vivo. Eight Oxa responders and seven nonresponders with CRC were enrolled in the study. Then, the serum BHB level and H3K79me, H3K27ac, H3K14ac, and H3K9me levels in tissues were detected. DOT1L (H3K79me methyltransferase) gene knockdown or GNE-049 (H3K27ac inhibitor) use was applied to analyze further whether BHB reversed CRC-Oxa resistance via H3K79 demethylation and/or H3K27 deacetylation in vivo and in vitro. Results Following BHB intervention based on Oxa, the proliferation, migration, invasion, and EMT of CRC-Oxa cells and the growth and metastasis of transplanted tumors in mice were suppressed. Clinical analysis revealed that the differential change in BHB level was associated with drug resistance and was decreased in drug-resistant patient serum. The H3K79me, H3K27ac, and H3K14ac expressions in CRC were negatively correlated with BHB. Furthermore, results indicated that H3K79me inhibition may lead to BHB target deletion, resulting in its inability to function. Conclusions β-hydroxybutyrate resensitized CRC cells to Oxa by suppressing H3K79 methylation in vitro and in vivo.