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Personalized treatment of well-differentiated gastric neuroendocrine tumors based on clinicopathological classification and grading:A multicenter retrospective study

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Chinese Medical Journal 2024年第6期137卷 720-728页

作者： ju huang Huimin Liu Dekun Yang Tianming Xu Jing Wang Jingnan Li Department of Gastroenterology Peking Union Medical College HospitalChinese Academy of Medical SciencesPeking Union Medical CollegeBeijing 100730China Key Laboratory of Gut Microbiota Translational Medicine Research Chinese Academy of Medical SciencesBeijing 100730China Department of Gastroenterology Affiliated Yantai Yuhuangding Hospital of Qingdao University Medical CollegeYantaiShandong 264000China Department of Gastroenterology Beijing Zhong-Neng-Jian HospitalBeijing 102401China

Background:The incidence of well-differentiated gastric neuroendocrine tumors(G-NET)is increasing annually,and while they have a good prognosis and low mortality rate,their high recurrence rate makes treatment options controversial.This study aims to determine the relationship between individualized treatment plans and the recurrence of G-NET.Methods:We performed a multicenter,retrospective study of 94 patients with highly differentiated G-NET and treated at Peking Union Medical College Hospital,Yantai Yuhuangding Hospital,and Beijing Zhong-Neng-Jian Hospital from November 2015 to September 2023.Risk factors for recurrence of G-NETs were investigated using chi-squared test and multifactorial logistic regression analysis.Results:After a median follow-up of 49 months,the overall recurrence rate among the 94 G-NET patients was 14%(13/94).The recurrence rates of endoscopic mucosal resection(EMR),endoscopic submucosal dissection(ESD),somatostatin analog(SSA)therapy,and surgery were 43%(6/14),10%(5/49),5%(1/22),and 11%(1/9),respectively.Post-treatment recurrence rates were significantly different(P=0.014)among four treatments(EMR,ESD,SSA,and surgery),and further subgroup comparisons revealed lower recurrence rates in the ESD and SSA groups than in the EMR group.From the second month onward,SSA therapy considerably reduced the gastrin levels from 1081.0(571.5,2472.8)pg/mL to 461.5(255.3,795.0)pg/mL(Z=-3.521,P<0.001).Both chi-squared test and multifactorial logistic regression analysis suggested that among the clinicopathological parameters studied,only the pre-treatment gastrin level(P=0.018 and 0.005)and the type of treatment(P=0.014 and 0.017)were significantly associated with G-NET recurrence.Conclusions:Individualized treatment strategies may reduce the risk of relapse after G-NET treatment.Long-term SSA therapy may be a secure and efficacious treatment option for type 1 G-NET with more than six lesions,and it substantially decreases the incidence of post-treatment recurrence.

关键词： Well-differentiated G-NET Serum gastrin Personalized treatment Endoscopic submucosal dissection Endoscopic mucosal resection Somatostatin analog therapy Surgical resection Recurrence

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Multiple regulatory roles of the transfer RNA-derived small RNAs in cancers

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Genes & Diseases 2024年第2期11卷 597-613页

作者： Yu Zhang Xinliang Gu Yang Li Yuejiao huang Shaoqing ju Medical School of Nantong University Nantong UniversityNantongJiangsu 226001China Department of Laboratory Medicine Affiliated Hospital of Nantong UniversityNantongJiangsu 226001China Research Center of Clinical Medicine Affiliated Hospital of Nantong UniversityNantongJiangsu 226001China Department of Medical Oncology Affiliated Hospital of Nantong UniversityNantongJiangsu 226001China

With the development of sequencing technology,transfer RNA(tRNA)-derived small RNAs(tsRNAs)have received extensive attention as a new type of small noncoding RNAs.Based on the differences in the cleavage sites of nucleases on tRNAs,tsRNAs can be divided into two categories,tRNA halves(tiRNAs)and tRNA-derived fragments(tRFs),each with specific subcellular localizations.Additionally,the biogenesis of tsRNAs is tissue-specific and can be regulated by tRNA modifications.In this review,we first elaborated on the classification and biogenesis of tsRNAs.After summarizing the latest mechanisms of tsRNAs,including transcriptional gene silencing,post-transcriptional gene silencing,nascent RNA silencing,translation regulation,rRNA regulation,and reverse transcription regulation,we explored the representative biological functions of tsRNAs in tumors.Furthermore,this review summarized the clinical value of tsRNAs in cancers,thus providing theoretical support for their potential as novel biomarkers and therapeutic targets.

关键词： Biogenesis Biological function Cancer Mechanism Therapeutic strategy tsRNAs

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Transfer RNA-derived fragment tRF-23-Q99P9P9NDD promotes progression of gastric cancer by targeting ACADSB

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Journal of Zhejiang University-Science B(Biomedicine & Biotechnology) 2024年第5期25卷 438-450页

作者： Yu ZHANG Xinliang GU Yang LI Xun LI Yuejiao huang Shaoqing ju Medical School of Nantong University Nantong UniversityNantong 226001China Department of Laboratory Medicine Affiliated Hospital of Nantong UniversityNantong 226001China Research Center of Clinical Medicine Afiliated Hospital of Nantong UniversityNantong 226001China Department of Medical Oncology Afiliated Hospital of Nantong UniversityNantong 226001China

Gastric cancer(GC)is one of the most common gastrointestinal tumors.As a newly discovered type of non-coding RNAs,transfer RNA(tRNA)-derived small RNAs(tsRNAs)play a dual biological role in cancer.Our previous studies have demonstrated the potential of tRF-23-Q99P9P9NDD as a diagnostic and prognostic biomarker for GC.In this work,we confirmed for the first time that tRF-23-Q99P9P9NDD can promote the proliferation,migration,and invasion of GC cells in vitro.The dual luciferase reporter gene assay confirmed that tRF-23-Q99P9P9NDD could bind to the 3'untranslated region(UTR)site of acyl-coenzyme A dehydrogenase short/branched chain(ACADSB).In addition,ACADSB could rescue the effect of tRF-23-Q99P9P9NDD on GC cells.Next,we used Gene Ontology(GO),the Kyoto Encyclopedia of Genes and Genomes(KEGG),and Gene Set Enrichment Analysis(GSEA)to find that downregulated ACADSB in GC may promote lipid accumulation by inhibiting fatty acid catabolism and ferroptosis.Finally,we verified the correlation between ACADSB and 12 ferroptosis genes at the transcriptional level,as well as the changes in reactive oxygen species(ROS)levels by flow cytometry.In summary,this study proposes that tRF-23-Q99P9P9NDD may affect GC lipid metabolism and ferroptosis by targeting ACADSB,thereby promoting GC progression.It provides a theoretical basis for the diagnostic and prognostic monitoring value of GC and opens upnew possibilities for treatment.

关键词： Transfer RNA(tRNA)-derived small RNA(tsRNA) Gastric cancer(GC) Acyl-coenzyme A dehydrogenase short/branched chain(ACADSB) Molecular mechanism Treatment Ferroptosis

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Diamond-Like Carbon Depositing on the Surface of Polylactide Membrane for Prevention of Adhesion Formation During Tendon Repair

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Nano-Micro Letters 2024年第9期16卷 478-499页

作者： Yao Xiao Zaijin Tao Yufeng ju Xiaolu huang Xinshu Zhang Xiaonan Liu Pavel A.Volotovski Chao huang Hongqi Chen Yaozhong Zhang Shen Liu Department of Orthopaedics Shanghai Jiao Tong University School of Medicine Affiliated Sixth People’s Hospital600 Yishan RdShanghai 200233People’s Republic of China Shanghai Tongji Hospital 389 Xincun RdShanghai 200065People’s Republic of China Key Laboratory for Thin Film and Microfabrication of Ministry of Education Research Institute of Micro/Nano Science and TechnologyShanghai Jiao Tong UniversityShanghai 200240People’s Republic of China Orthopedic Trauma Department Belarus Republic Scientific and Practical Center for Traumatology and OrthopedicsKizhevatova str.60/4220024 MinskBelarus Shanghai Haohai Biological Technology Limited Liability Company 1386 Hongqiao RdShanghai 200336People’s Republic of China Department of General Surgery Shanghai Jiao Tong University School of Medicine Affiliated Sixth People’s Hospital600 Yishan RdShanghai 200233People’s Republic of China Shanghai Key Laboratory for High Temperature Materials and Precision Forming School of Materials Science and EngineeringShanghai Jiao Tong UniversityShanghai 200240People’s Republic of China

Post-traumatic peritendinous adhesion presents a significant challenge in clinical medicine.This study proposes the use of diamond-like carbon(DLC)deposited on polylactic acid(PLA)membranes as a biophysical mechanism for anti-adhesion barrier to encase ruptured tendons in tendon-injured rats.The results indicate that PLA/DLC composite membrane exhibits more efficient anti-adhesion effect than PLA membrane,with histological score decreasing from 3.12±0.27 to 2.20±0.22 and anti-adhesion effectiveness increasing from 21.61%to 44.72%.Mechanistically,the abundant C=O bond functional groups on the surface of DLC can reduce reactive oxygen species level effectively;thus,the phosphorylation of NF-κB and M1 polarization of macrophages are inhibited.Consequently,excessive inflammatory response augmented by M1 macrophage-originated cytokines including interleukin-6(IL-6),interleukin-1β(IL-1β),and tumor necrosis factor-α(TNF-α)is largely reduced.For biocompatibility evaluation,PLA/DLC membrane is slowly absorbed within tissue and displays prolonged barrier effects compared to traditional PLA membranes.Further studies show the DLC depositing decelerates the release of degradation product lactic acid and its induction of macrophage M2 polarization by interfering esterase and PLA ester bonds,which further delays the fibrosis process.It was found that the PLA/DLC membrane possess an efficient biophysical mechanism for treatment of peritendinous adhesion.

关键词： Diamond-like carbon Reactive oxygen species scavenging Foreign body reaction Biodegradation Antioxidant Peritendinous adhesion

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dECM restores macrophage immune homeostasis and alleviates iron overload to promote DTPI healing

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Regenerative Biomaterials 2024年第2期3卷 100-113页

作者： ju Zhang Ruijuan Si Yu Gao Hui Shan Qi Su Zujian Feng Pingsheng huang Deling Kong Weiwei Wang Tianjin Key Laboratory of Biomaterial Research Institute of Biomedical EngineeringChinese Academy of Medical Sciences and Peking Union Medical CollegeTianjin300192China School of Nursing Qingdao UniversityNingde RoadShinan DistrictQingdaoShandong266071China Cancer Hospital of Tianjin Medical University North Huanhu West RoadTianjinChina The Affliated Hospital of Qingdao University 16 Jjiangsu RoadShinan DistrictQingdaoChina 5NankaiUniver aniin300071.China

Due to its highly insidious and rapid progression,deep tissue pressure injury(DTPI)is a clinical challenge.Our previous study found that DTPI may be a skeletal muscle injury dominated by macrophage immune dysfunction due to excessive iron accu-mulation.Decellularized extracellular matrix(dECM)hydrogel promotes skeletal muscle injury repair.However,its role in po-larizing macrophages and regulating iron metabolism in DTPI remains unclear.Here,porcine dECM hydrogel was prepared,and its therapeutic function and mechanism in repairing DTPI were investigated.The stimulus of dECM hydrogel toward RAW264.7 cells resulted in a significantly higher percentage of CD2o6+macrophages and notably decreased intracellular divalent iron levels.In mice DTPI model,dECM hydrogel treatment promoted M1 to M2 macrophage conversion,improved iron metabolism and reduced oxidative stress in the early stage of DTPI.In the remodeling phase,the dECM hydrogel remarkably enhanced revascularization and accelerated skeletal muscle repair.Furthermore,the immunomodulation of dEcM hydrogels in vivo was mainly involved in the P13k/Akt signaling pathway,as revealed by GO and KEGG pathway analysis,which may ameliorate the iron deposition and promote the healing of DTPI.Our findings indicate that dECM hydrogel is promising in skeletal muscle repair,inflammation resolution and tissue injury healing by effectively restoring macrophage immune homeostasis and normalizing iron metabolism.

关键词： Deep tissue pressure injury hydrogel immunomodulation tissue repair

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Integrated neural tracing and in-situ barcoded sequencing reveals the logic of SCN efferent circuits in regulating circadian behaviors

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Science China(Life Sciences) 2024年第3期67卷 518-528页

作者： Meimei Liao Xinwei Gao Chen Chen Qi Li Qingchun Guo He huang Erquan Zhang Dapeng ju College of Biological Sciences China Agriculture UniversityBeijing 100193China National Institute of Biological Sciences(NIBS) Beijing 102206China Chinese Institute for Brain Research Beijing 102206China School of Biomedical Engineering Capital Medical UniversityBeijing 100069China Department of Anesthesiology The Second Affiliated HospitalChongqing Medical UniversityChongqing 401336China Tsinghua Institute of Multidisciplinary Biomedical Research Tsinghua UniversityBeijing 102206China

The circadian clock coordinates rhythms in numerous physiological processes to maintain organismal homeostasis. Since the suprachiasmatic nucleus(SCN) is widely accepted as the circadian pacemaker, it is critical to understand the neural mechanisms by which rhythmic information is transferred from the SCN to peripheral clocks. Here, we present the first comprehensive map of SCN efferent connections and suggest a molecular logic underlying these projections. The SCN projects broadly to most major regions of the brain, rather than solely to the hypothalamus and thalamus. The efferent projections from different subtypes of SCN neurons vary in distance and intensity, and blocking synaptic transmission of these circuits affects circadian rhythms in locomotion and feeding to different extents. We also developed a barcoding system to integrate retrograde tracing with in-situ sequencing, allowing us to link circuit anatomy and spatial patterns of gene expression. Analyses using this system revealed that brain regions functioning downstream of the SCN receive input from multiple neuropeptidergic cell types within the SCN, and that individual SCN neurons generally project to a single downstream brain region.This map of SCN efferent connections provides a critical foundation for future investigations into the neural circuits underlying SCNmediated rhythms in physiology. Further, our new barcoded tracing method provides a tool for revealing the molecular logic of neuronal circuits within heterogeneous brain regions.

关键词： circadian rhythms SCN output circuit neural tracing barcoded GFP in situ sequencing

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Ten- year follow- up investigation of stroke risk in systemic lupus erythematosus

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Stroke & Vascular Neurology 2024年第1期9卷 1-7页

作者： Jin-An huang Ching-Heng Lin Ming-ju Wu Yi-Hsing Chen Kuo-Cheng Chang Chung-Wei Hou Division of Neurology Neurological InstituteTaichung Veterans General HospitalTaichungTaiwan Department of Health Business Administration Hungkuang UniversityTaichungTaiwan Department of Medical Research Taichung Veterans General HospitalTaichungTaiwan Division of Nephrology Department of Internal MedicineTaichung Veterans General HospitalTaichungTaiwan School of Medicine Chung Shan Medical UniversityTaichungTaiwan College of Medicine National Chung Hsing UniversityTaichungTaiwan Division of Allergy Immunology and RheumatologyDepartment of Internal MedicineTaichung Veterans General HospitalTaichungTaiwan School of Medicine National Yang-Ming Chiao Tung UniversityTaichungTaiwan

Background and purpose To analyse the long-term risk of ischaemic stroke and the clinical effects of antithrombotics on the risk of haemorrhagic stroke in patients with systemic lupus erythematosus(SLE).Methods A retrospective cohort study was conducted using a population-based database taken from Taiwan National Health Insurance Research Database.Patients with SLE between 2000 and 2008 were registered and matched with two controls by the index date,age,gender and Charlson Comorbidity Index(CCI).These subjects were followed until either stroke event or 31 December 2013.Adjusted HRs(aHRs)for strokes were estimated with Cox regression models,and the cumulative incidence of ischaemic stroke was analysed by log-rank test and Kaplan-Meier survival analysis.Results In total,8310 patients with SLE and 16620 patients without SLE were included.In general,patients with SLE had higher rates of ischaemic stroke(5.4%vs 3.3%)and haemorrhagic stroke(1.5%vs 0.6%)than in controls.In multivariate analysis adjusted to age,gender,CCI,urbanisation level and antithrombotics uses,aHRs of all strokes,ischaemic stroke and haemorrhagic stroke were 1.73(95%CI:1.54 to 1.94),1.65(95%CI:1.45 to 1.87)and 2.24(95%CI:1.71 to 2.95),respectively,in patients with SLE.Patients with SLE were significantly more likely to suffer ischaemic stroke than patients without SLE,even 10 years after SLE diagnosis(6.12%vs 3.50%,p<0.001).Antiplatelet use increased the risk of haemorrhagic stroke in SLE group(aHR=1.74,95%CI:1.18 to 2.57).Conclusions Patients with SLE are at greater risk of developing ischaemic stroke that lasts for 10 years.Antiplatelets should be carefully administered to prevent cardiovascular events in patients with SLE due to the risk of haemorrhagic stroke.

关键词： erythematosus diagnosis likely

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Chinese herbal medicine decreases incidence of hepatocellular carcinoma in diabetes mellitus patients with regular insulin management

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World Journal of Gastrointestinal Oncology 2024年第3期16卷 716-731页

作者： Hsiang-Chun Lai ju-Chien Cheng Hei-Tung Yip Long-Bin Jeng Sheng-Teng huang Graduate Institute of Chinese Medicine School of Chinese MedicineCollege of Chinese MedicineChina Medical UniversityTaichung 404328TaiwanChina Department of Medical Laboratory Science and Biotechnology China Medical UniversityTaichung 404TaiwanChina Management Office for Health Data China Medical University HospitalTaichung 404327TaiwanChina Organ Transplantation Center China Medical University HospitalTaichung 40447TaiwanChina Department of Chinese Medicine China Medical University HospitalSchool of Chinese MedicineChina Medical UniversityTaichung 40447TaiwanChina

BACKGROUND Type 2 diabetes mellitus(DM)is an independent risk factor for hepatocellular carcinoma(HCC),while insulin is a potent mitogen.Identifying a new therapeutic modality for preventing insulin users from developing HCC is a critical goal for researchers.AIM To investigate whether regular herbal medicine use can decrease HCC risk in DM patients with regular insulin control.METHODS We used data acquired from the Taiwan,Chinaese National Health Insurance research database between 2000 and 2017.We identified patients with DM who were prescribed insulin for>3 months.The herb user group was further defined as patients prescribed herbal medication for DM for>3 months per annum during RESULTS We initially enrolled 657144 DM patients with regular insulin use from 2000 to 2017.Among these,46849 patients had used a herbal treatment for DM,and 140547 patients were included as the matched control group.The baseline variables were similar between the herb users and nonusers.DM patients with regular herb use had a 12%decreased risk of HCC compared with the control group[adjusted hazard ratio(aHR)=0.88,95%CI=0.80–0.97].The cumulative incidence of HCC in the herb users was significantly lower than that of the nonusers.Patients with a herb use of>5 years cumulatively exhibited a protective effect against development of HCC(aHR=0.82,Phuang Qi)plus Salvia miltiorrhiza Bunge(Dan Shen),and Astragalus propinquus(huang Qi)plus Trichosanthes kirilowii Maxim.(Tian Hua Fen)were the most frequent combination of single herbs.Meanwhile,Ji Sheng Shen Qi Wan plus Dan Shen was the most frequent combination of herbs and formulas.CONCLUSION This large-scale retrospective cohort study reveals that herbal medicine may decrease HCC risk by 12%i

关键词： Hepatocellular carcinoma Diabetes mellitus Insulin Herb Taiwan,Chinaese National health insurance research database

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Machine learning-based comparison of factors influencing estimated glomerular filtration rate in Chinese women with or without nonalcoholic fatty liver

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World Journal of Clinical Cases 2024年第15期12卷 2506-2521页

作者： I-Chien Chen Lin-ju Chou Shih-Chen huang Ta-Wei Chu Shang-Sen Lee Department of Nursing Kaohsiung Armed Forces General HospitalKaohsiung 802Taiwan Department of Obstetrics and Gynecology Tri-Service General HospitalNational Defense Medical CenterTaipei 114Taiwan Chief Executive Officer's Office MJ Health Research FoundationTaipei 114Taiwan Department of Urology Taichung Tzu Chi HospitalBuddhist Tzu Chi Medical FoundationTaichung 427Taiwan School of Medicine Tzu Chi UniversityHualian 970Taiwan Department of Urology Tri-Service General HospitalNational Defense Medical CenterTaipei 114Taiwan

BACKGROUND The prevalence of non-alcoholic fatty liver(NAFLD)has increased recently.Subjects with NAFLD are known to have higher chance for renal function impairment.Many past studies used traditional multiple linear regression(MLR)to identify risk factors for decreased estimated glomerular filtration rate(eGFR).However,medical research is increasingly relying on emerging machine learning(Mach-L)methods.The present study enrolled healthy women to identify factors affecting eGFR in subjects with and without NAFLD(NAFLD+,NAFLD-)and to rank their importance.AIM To uses three different Mach-L methods to identify key impact factors for eGFR in healthy women with and without NAFLD.METHODS A total of 65535 healthy female study participants were enrolled from the Taiwan MJ cohort,accounting for 32 independent variables including demographic,biochemistry and lifestyle parameters(independent variables),while eGFR was used as the dependent variable.Aside from MLR,three Mach-L methods were applied,including stochastic gradient boosting,eXtreme gradient boosting and elastic net.Errors of estimation were used to define method accuracy,where smaller degree of error indicated better model performance.RESULTS Income,albumin,eGFR,High density lipoprotein-Cholesterol,phosphorus,forced expiratory volume in one second(FEV1),and sleep time were all lower in the NAFLD+group,while other factors were all significantly higher except for smoking area.Mach-L had lower estimation errors,thus outperforming MLR.In Model 1,age,uric acid(UA),FEV1,plasma calcium level(Ca),plasma albumin level(Alb)and T-bilirubin were the most important factors in the NAFLD+group,as opposed to age,UA,FEV1,Alb,lactic dehydrogenase(LDH)and Ca for the NAFLD-group.Given the importance percentage was much higher than the 2nd important factor,we built Model 2 by removing age.CONCLUSION The eGFR were lower in the NAFLD+group compared to the NAFLD-group,with age being was the most important impact factor in both groups of healthy Chinese women,followed by LDH,UA,FEV1 and

关键词： Non-alcoholic fatty liver Estimated glomerular filtration rate Machine learning Chinese women

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Bayesian Estimation and Model Selection for the Spatiotemporal Autoregressive Model with Autoregressive Conditional Heteroscedasticity Errors

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应用数学学报:英文版 2023年第4期39卷 972-989页

作者： Bing SU Fu-kang ZHU ju huang Department of Statistics&Actuarial Science University of Hong KongHong Kong 999077China School of Mathematics Jilin UniversityChangchun 130012China National Energy Administration Information Center Beijing 100045China

The spatial and spatiotemporal autoregressive conditional heteroscedasticity(STARCH) models receive increasing attention. In this paper, we introduce a spatiotemporal autoregressive(STAR) model with STARCH errors, which can capture the spatiotemporal dependence in mean and variance simultaneously. The Bayesian estimation and model selection are considered for our model. By Monte Carlo simulations, it is shown that the Bayesian estimator performs better than the corresponding maximum-likelihood estimator, and the Bayesian model selection can select out the true model in most times. Finally, two empirical examples are given to illustrate the superiority of our models in fitting those data.

关键词： autoregressive conditional heteroscedasticity model Bayesian estimation model selection spatial ARCH model spatial panel model spatiotemporal model

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