1.Sesquiterpene ZH-13 from Aquilariae Lignum Resinatum Improves Neuroinflammation by Regulating JNK Phosphorylation
Ziyu YIN ; Yun GAO ; Junjiao WANG ; Weigang XUE ; Xueping PANG ; Huiting LIU ; Yunfang ZHAO ; Huixia HUO ; Jun LI ; Jiao ZHENG
Chinese Journal of Experimental Traditional Medical Formulae 2025;31(1):139-145
		                        		
		                        			
		                        			ObjectiveTo study the pharmacological substances and mechanisms through which sesquiterpene ZH-13 from Aquilariae Lignum Resinatum improves neuroinflammation. MethodsBV-2 microglial cells were stimulated with lipopolysaccharide (LPS) to induce neuroinflammation. The cells were divided into the normal group, the model group, and the ZH-13 low- and high-dose treatment groups (10, 20 μmol·L-1). The model group was treated with 1 μmol·L-1 LPS. Cell viability was assessed using the cell proliferation and activity assay (CCK-8 kit). Nitric oxide (NO) release in the cell supernatant was measured using a nitric oxide kit (Griess method). The mRNA expression levels of interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), inducible nitric oxide synthase (iNOS), and interleukin-6 (IL-6) were detected by real-time fluorescence quantitative polymerase chain reaction (Real-time PCR). The phosphorylation of mitogen-activated protein kinase (MAPK) pathway proteins was assessed by Western blot. ResultsCompared with the model group, ZH-13 dose-dependently reduced NO release from BV-2 cells under LPS stimulation (P<0.05, P<0.01). In the 20 μmol·L-1 ZH-13 treatment group, the mRNA expression levels of IL-1β, TNF-α, iNOS, and IL-6 were significantly reduced compared to the model group (P<0.05, P<0.01). In both the low- and high-dose ZH-13 groups, the expression of the inflammatory factor TNF-α and the phosphorylation of c-Jun N-terminal kinase (JNK) in the upstream MAPK pathway were significantly reduced (P<0.05). After stimulation with the JNK agonist anisomycin (Ani), both low- and high-dose ZH-13 treatment groups showed reduced phosphorylation of JNK proteins compared to the Ani-treated group (P<0.01). ConclusionThe sesquiterpene compound ZH-13 from Aquilariae Lignum Resinatum significantly ameliorates LPS-induced neuroinflammatory responses in BV-2 cells by inhibiting excessive JNK phosphorylation and reducing TNF-α expression. These findings elucidate the pharmacological substances and mechanisms underlying the sedative and calming effects of Aquilariae Lignum Resinatum. 
		                        		
		                        		
		                        		
		                        	
2.Association between moderate to vigorous intensity physical activity and sedentary behavior among primary and secondary school students and their parents
YAO Zifeng, YE Rongrong, CHEN Jiade, XU Peng, HUANG Yanhong, LI Lixia, LI Hongjuan, GAO Yanhui
Chinese Journal of School Health 2025;46(1):68-72
		                        		
		                        			Objective:
		                        			To explore the associations of moderate to vigorous intensity physical activity (MVPA) and sedentary behavior (SB) among primary and secondary school students and their parents, so as to provide a scientific basis for formulating targeted physical activity promotion strategies for children and adolescents.
		                        		
		                        			Methods:
		                        			From 2021 to 2022, basic information and  24 h  movement behaviors of 2 484 pairs of students and their parents were collected from five primary and secondary schools in Haizhu District, Guangzhou City, with a convenient sampling combining with cluster sampling method. Component regression models were constructed to analyze the relationship between parental MVPA, SB and primary and secondary school students  MVPA and SB, and a component isochronous substitution model was used to explore the effects of mutual substitution between parental MVPA, residual components (time use components other than SB during the 24 h period), and SB on the behavioral activities of MVPA and SB in primary and secondary school students.
		                        		
		                        			Results:
		                        			Parental MVPA and SB of students in grade 1 to 3 were positively correlated with both students  MVPA and SB ( β=0.06, 0.12, P <0.01). The component isochronous substitution model showed that substituting 10 and 20 minutes of MVPA for SB by parents in grade 1 to 3 was associated with an increase in MVPA of students, and substituting 10 and 20 minutes of residual ingredients for SB was associated with a decrease in SB of students, with mean changes of 0.8 (95% CI =0.4-1.2) and 1.4 (95% CI =0.7-2.2) and -1.4 (95% CI =-1.7 to -1.1) and -2.9 (95% CI =-3.4 to -2.3)( P <0.05). No statistically significant associations were observed between parents of students in grades 4 to 6 and 7 to 9 and students  physical activity and sedentary behaviour ( P >0.05).
		                        		
		                        			Conclusions
		                        			Parents of students in grades 1 to 3 increases MVPA and decrease SB are beneficial to increase MVPA and decrease SB of students. Parents could promote physical activity among primary and secondary school students, and the intervention gateway should be advanced, with the low grades as the optimal intervention period.
		                        		
		                        		
		                        		
		                        	
3.Association of physical activity and sugar sweetened beverage consumption with psychological sub health among middle school students in Bao an District, Shenzhen
Chinese Journal of School Health 2025;46(1):102-105
		                        		
		                        			Objective:
		                        			To explore the association of physical activity and sugar sweetened beverage consumption with psychological sub health among middle school students in Bao an District, Shenzhen, so as to provide a reference for adolescent mental health promotion.
		                        		
		                        			Methods:
		                        			A questionnaire survey was conducted in November 2024 by a stratified cluster random sampling method to select 6 926 junior and senior middle school students from 5 middle schools in Shenzhen. The questionnaire from Youth Risk Behavior Surveillance System was used to assess the consumption of sugar sweetened beverages, and physical activity Rating Scale was used to assess the level of physical activity, and Brief Instrument on Psychological Health of Youths was used to evaluate the psychological sub health status. The  Chi -square test was used to analyze the differences in the detection rates of psychological sub health among different groups of middle school students, and a multivariate Logistic regression model was established to analyze the effects of physical activity and sugar sweetened beverage consumption and their combined effects on the psychological sub health of middle school students.
		                        		
		                        			Results:
		                        			The detection rate of psychological sub health among middle school students in Bao an District, Shenzhen was 18.93%. Multivariate Logistic regression analysis showed that, after controlling for confounding factors such as gender, school stage, family residence, family economic status, parental literacy, academic stress and number of friends, lack of physical activity or excessive sugar sweetened beverage consumption were associated with increased risks of psychological sub health among middle school students ( OR =1.36, 1.45); and the highest risk of psychological sub health was found in middle school students who were lack of physical activity and excessive sugar sweetened beverage consumption ( OR =2.59) ( P <0.01). Further analysis by school stages showed that junior high school students with sufficient physical activity and excessive intake of sugary drinks ( ROR =2.10), lack of physical activity and excessive intake of sugary drinks ( ROR =2.31) were at higher risks of psychological sub health than senior high school students( P <0.05).
		                        		
		                        			Conclusions
		                        			Insufficient physical activity and excessive sugar sweetened beverage consumption are closely associated with an increased risk of psychological sub health among middle school students. Effective interventions should be targeted to reduce the risk of psychological sub health problems among middle school students.
		                        		
		                        		
		                        		
		                        	
4.Trends in incidence and mortality of acute myocardial infarction in Xiaoshan District, Hangzhou City from 2017 to 2023
Yuanyuan GAO ; Fenjuan WANG ; Dongfei WANG ; Yurong LI ; Yuanyuan JIANG ; Fangfang ZHAO ; Duanduan XIAO ; Junying LIN
Shanghai Journal of Preventive Medicine 2025;37(3):249-254
		                        		
		                        			
		                        			ObjectiveTo analyze the incidence rate and mortality of acute myocardial infarction (AMI) and their changing trends among the registered residents in Xiaoshan District, Hangzhou City from 2017 to 2023, so as to provide references for formulating policies related to AMI prevention. MethodsThe morbidity and mortality data of AMI among the registered residents in Xiaoshan District from 2017 to 2023 were collected through the Hangzhou Chronic Disease and Death Cause Monitoring System. Software such as Excel 2019, SPSS 25.0 and Joinpoint 4.9.1.0 were used to calculate the incidence rate, mortality, and average annual percentage change (AAPC) of AMI. ResultsFrom 2017 to 2023, the average annual crude incidence rate, age-standardized incidence rate using China standard population (ASIRC), and the age-standardized incidence rate using World standard population (ASIRW) of AMI in Xiaoshan District were 48.25/100 000, 29.14/100 000, and 21.64/100 000, respectively, and, from which the AAPCs were 5.495%, 6.010%, and 6.533%, respectively, all showing an upward trend. The average annual crude mortality rate, the age-standardized mortality rate using China standard population (ASMRC), and the age-standardized mortality rate using World standard population (ASMRW) were 11.76/100 000, 6.52/100 000, and 4.71/100 000, respectively, from which the AAPCs were -9.669%, -10.433% and -9.615%, respectively, all showing a downward trend. The average annual crude incidence rate of AMI was higher in males (65.87/100 000) than that in females (31.31/100 000). Moreover, the average annual crude mortality rate of AMI was higher in males (14.08/100 000) than that in females (9.52/100 000), and the difference was statistically significant (all P<0.001) .After age grouping, the crude incidence rate of AMI among the residents aged 35-, 45-, 55-, and 65- years in Xiaoshan District from 2017 to 2023 showed an upward trend over time, with AAPCs of 16.993%, 17.149%, 8.523%, and 5.002%, respectively. While the crude mortality rate in residents aged 35-, 75-, and 85-102 years showed an decreasing trend over time, with AAPCs of -23.977%, -15.467%, and -17.415%, respectively, but there was no statistically significant difference in the trends in incidence rate and mortality of other age groups (all P>0.05). ConclusionThe situation of AMI prevention and control among the registered residents in Xiaoshan District is not optimistic, and targeted measures should be strengthened for the male residents aged ≥35 years old. 
		                        		
		                        		
		                        		
		                        	
5.Application of artificial intelligence in pulmonary nodule analysis and lung segment resection planning for standardized training in thoracic surgery
Chao GAO ; Xiaoyun ZHOU ; Chao GUO ; Hongsheng LIU ; Shanqing LI ; Naixin LIANG
Chinese Journal of Clinical Thoracic and Cardiovascular Surgery 2025;32(04):469-472
		                        		
		                        			
		                        			Objective To explore the application of artificial intelligence (AI) in the standardized training of thoracic surgery residents, specifically in enhancing clinical skills and anatomical understanding through AI-assisted lung nodule identification and lung segment anatomy teaching. Methods Thoracic surgery residents undergoing standardized training at Peking Union Medical College Hospital from September 2023 to September 2024 were selected. They were randomly assigned to a trial group and a control group using a random number table. The trial group used AI-assisted three-dimensional reconstruction technology for lung nodule identification, while the control group used conventional chest CT images. After basic teaching and self-practice, the ability to identify lung nodules on the same patient CT images was evaluated, and feedback was collected through questionnaires. Results A total of 72 residents participated in the study, including 30 (41.7%) males and 42 (58.3%) females, with an average age of (24.0±3.0) years. The trial group showed significantly better overall diagnostic accuracy for lung nodules (91.9% vs. 73.3%) and lung segment identification (100.0% vs. 83.70%) compared to the control group, and the reading time was significantly shorter [ (118.5±10.5) s vs. (332.1±20.2) s, P<0.01]. Questionnaire results indicated that 94.4% of the residents had a positive attitude toward AI technology, and 91.7% believed that it improved diagnostic accuracy. Conclusion AI-assisted teaching significantly improves thoracic surgery residents’ ability to read images and clinical thinking, providing a new direction for the reform of standardized training.
		                        		
		                        		
		                        		
		                        	
6.Regulation of Immune Function by Exercise-induced Metabolic Remodeling
Hui-Guo WANG ; Gao-Yuan YANG ; Xian-Yan XIE ; Yu WANG ; Zi-Yan LI ; Lin ZHU
Progress in Biochemistry and Biophysics 2025;52(6):1574-1586
		                        		
		                        			
		                        			Exercise-induced metabolic remodeling is a fundamental adaptive process whereby the body reorganizes systemic and cellular metabolism to meet the dynamic energy demands posed by physical activity. Emerging evidence reveals that such remodeling not only enhances energy homeostasis but also profoundly influences immune function through complex molecular interactions involving glucose, lipid, and protein metabolism. This review presents an in-depth synthesis of recent advances, elucidating how exercise modulates immune regulation via metabolic reprogramming, highlighting key molecular mechanisms, immune-metabolic signaling axes, and the authors’ academic perspective on the integrated “exercise-metabolism-immunity” network. In the domain of glucose metabolism, regular exercise improves insulin sensitivity and reduces hyperglycemia, thereby attenuating glucose toxicity-induced immune dysfunction. It suppresses the formation of advanced glycation end-products (AGEs) and interrupts the AGEs-RAGE-inflammation positive feedback loop in innate and adaptive immune cells. Importantly, exercise-induced lactate, traditionally viewed as a metabolic byproduct, is now recognized as an active immunomodulatory molecule. At high concentrations, lactate can suppress immune function through pH-mediated effects and GPR81 receptor activation. At physiological levels, it supports regulatory T cell survival, promotes macrophage M2 polarization, and modulates gene expression via histone lactylation. Additionally, key metabolic regulators such as AMPK and mTOR coordinate immune cell energy balance and phenotype; exercise activates the AMPK-mTOR axis to favor anti-inflammatory immune cell profiles. Simultaneously, hypoxia-inducible factor-1α (HIF-1α) is transiently activated during exercise, driving glycolytic reprogramming in T cells and macrophages, and shaping the immune landscape. In lipid metabolism, exercise alleviates adipose tissue inflammation by reducing fat mass and reshaping the immune microenvironment. It promotes the polarization of adipose tissue macrophages from a pro-inflammatory M1 phenotype to an anti-inflammatory M2 phenotype. Moreover, exercise alters the secretion profile of adipokines—raising adiponectin levels while reducing leptin and resistin—thereby influencing systemic immune balance. At the circulatory level, exercise improves lipid profiles by lowering pro-inflammatory free fatty acids (particularly saturated fatty acids) and triglycerides, while enhancing high-density lipoprotein (HDL) function, which has immunoregulatory properties such as endotoxin neutralization and macrophage cholesterol efflux. Regarding protein metabolism, exercise triggers the expression of heat shock proteins (HSPs) that act as intracellular chaperones and extracellular immune signals. Exercise also promotes the secretion of myokines (e.g., IL-6, IL-15, irisin, FGF21) from skeletal muscle, which modulate immune responses, facilitate T cell and macrophage function, and support immunological memory. Furthermore, exercise reshapes amino acid metabolism, particularly of glutamine, arginine, and branched-chain amino acids (BCAAs), thereby influencing immune cell proliferation, biosynthesis, and signaling. Leucine-mTORC1 signaling plays a key role in T cell fate, while arginine metabolism governs macrophage polarization and T cell activation. In summary, this review underscores the complex, bidirectional relationship between exercise and immune function, orchestrated through metabolic remodeling. Future research should focus on causative links among specific metabolites, signaling pathways, and immune phenotypes, as well as explore the epigenetic consequences of exercise-induced metabolic shifts. This integrated perspective advances understanding of exercise as a non-pharmacological intervention for immune regulation and offers theoretical foundations for individualized exercise prescriptions in health and disease contexts. 
		                        		
		                        		
		                        		
		                        	
7.Improvement effects and mechanism of total secondary ginsenosides on hypertrophic changes in cardiomyocytes
Bin LI ; Jia LI ; Zhongjie YUAN ; Mingjun ZHU ; Shiyang XIE ; Yuan GAO ; Rui YU ; Xinlu WANG
China Pharmacy 2025;36(12):1430-1435
		                        		
		                        			
		                        			OBJECTIVE To investigate the ameliorative effects and potential mechanism of total secondary ginsenosides (TSG) on hypertrophic changes of primary cardiomyocytes stimulated by angiotensin Ⅱ (Ang Ⅱ). METHODS Primary cardiomyocytes were isolated from the hearts of neonatal SD rats and divided into the following groups: control group, AngⅡ group (2 µmol/L), TSG group (7.5 µg/mL), PFK-015 group [6-phosphofructo-2-kinase/fructose-2, 6-bisphosphatase 3 (PFKFB3) inhibitor, 10 nmol/L], and TSG+PFK-015 group (TSG 7.5 µg/mL+PFK-015 10 nmol/L). The surface area, protein synthesis, energy metabolism-related indicators [free fatty acid (FFA), coenzyme A (CoA), acetyl coenzyme A (acetyl-CoA)], and the expressions of glycolysis-related factors [hypoxia-inducible factor 1α (HIF-1α), glucose transporter protein 4 (GLUT-4), lactate dehydrogenase A (LDHA), pyruvate dehydrogenase kinase 1 (PDK1) and PFKFB3] in primary cardiomyocytes of each group were measured. RESULTS Compared with the control group, the surface area of primary cardiomyocytes and protein synthesis were significantly increased, the content of FFA, protein and mRNA expressions of HIF-1α, LDHA, PDK1 and PFKFB3 were significantly increased or up-regulated in the AngⅡ group, while the contents of CoA and acetyl-CoA, the protein and mRNA expressions of GLUT-4 were significantly decreased or down-regulated (P<0.05). Compared with the AngⅡ group, both TSG group and PFK-015 group showed significant improvements in these indexes, with the TSG+PFK-015 group generally demonstrating superior effects compared to either treatment alone (P<0.05). CONCLUSIONS TSG can reduce the surface area of AngⅡ-induced primary cardiomyocytes, decrease protein synthesis, and inhibit their hypertrophic changes. These effects may be related to improving energy metabolism and the inhibition of glycolysis activity.
		                        		
		                        		
		                        		
		                        	
8.Risk factors of ineffective eradication therapy of adult Helicobacter pylori infection:a meta-analysis
Zhifeng TANG ; Guoming GAO ; Shuoquan LI ; Agang QU ; Lixia GOU
China Pharmacy 2025;36(12):1525-1529
		                        		
		                        			
		                        			OBJECTIVE To systematically evaluate the risk factors for ineffective eradication therapy of adult Helicobacter pylori (Hp) infection. METHODS Retrieved from PubMed,Web of Science, the Cochrane Library, Embase, CNKI, VIP and Wanfang Data, cohort studies and case-control studies on the eradication therapy for Hp infection in adult patients were searched from Jan. 2000 to Jul. 2024. After screening literature, extracting data, and evaluating the quality of literature, RevMan 5.3 software was used for meta-analysis, and sensitivity analysis and publication bias analysis were also performed. RESULTS A total of 19 articles were included, all of which were cohort studies, involving 9 931 patients in total. Among them, 1 929 patients were ineffective in eradication therapy, with the ineffective rates ranging from 8.02% to 33.33%. Meta-analysis showed that age<50 years [OR=1.33, 95%CI (1.12,1.57), P<0.001], body mass index (BMI)>25 kg/m2 [OR=1.87, 95%CI (1.35, 2.59), P= 0.000 2], a history of smoking [OR=1.62, 95%CI(1.35, 1.95), P<0.001], a history of drinking [OR=1.93, 95%CI(1.47, 2.54), P<0.001], living in a rural area [OR=1.74, 95%CI(1.41, 2.15), P<0.001], having non-peptic ulcer [OR=3.45, 95%CI (1.75, 6.67), P=0.000 3], a family members’ infection history [OR=4.72, 95%CI(3.32, 6.74), P<0.001], poor treatment compliance [OR=4.89, 95%CI (3.07, 7.79), P<0.001], amoxicillin resistance [OR=3.42, 95%CI (1.95, 6.00), P<0.001] and clarithromycin resistance [OR=8.14, 95%CI(5.00, 13.24), P<0.001] had significant impacts on ineffective eradication therapy of Hp infection in adults. Sensitivity analysis and publication bias analysis showed that the result of this study was robust and reliable. CONCLUSIONS Age<50 years, BMI>25 kg/m, a history of smoking, a history of drinking, living in a rural area, having non-peptic ulcer, a family members’ infection history, poor treatment compliance, amoxicillin resistance and clarithromycin resistance are risk factors for failure of Hp infection eradication therapy in adults.
		                        		
		                        		
		                        		
		                        	
9.Research progress on oxidative stress mechanism and traditional Chinese medicine intervention in varicocele-induced infertility
Shengnan LI ; Hongyan CHEN ; Tengfei CHEN ; Boxian GAO ; Chongfu ZHONG
China Pharmacy 2025;36(12):1536-1541
		                        		
		                        			
		                        			Varicocele-induced infertility (VCI) is a common andrological disease in clinical practice. Oxidative stress represents the primary mechanism through which varicocele causes male infertility. Traditional Chinese medicine (TCM) treatment, characterized by its multi-target, multi-component, multi-system, and multi-pathway actions, has achieved favorable outcomes in the field of VCI treatment. This paper summarizes the underlying oxidative stress mechanism of VCI and the relevant signaling pathways involved. By reviewing the current research status on how monomers, active fractions, compound formulas, and related preparations of TCM can intervene in oxidative stress through the regulation of these signaling pathways to improve VCI, it is found that the nuclear factor-erythroid 2-related factor 2 (Nrf2) signaling pathway, the mitogen-activated protein kinase (MAPK) signaling pathway, and the hypoxia-inducible factor-1α (HIF-1α) signaling pathway are closely related to the development of VCI. TCM monomers and active fractions (flavonoids from Cuscutae Semen, polysaccharides from Astragali Radix, curcumin, ginsenoside Rg1, hyperin and echinacoside), as well as compound formulas and related preparations of TCM (modified Dahuang zhechong granules, Shengjing huoxue formula, modified Tianxiong san, Tongjingling, Bushen huoxue formula, Mailuoshutong pill, Zishen yutai pill, Danhong tongjing formula) can alleviate oxidative stress, reduce lipid peroxidation damage, improve mitochondrial dysfunction, decrease sperm DNA fragmentation, and inhibit apoptosis by activating the Nrf2 signaling pathways and inhibiting the MAPK and HIF-1α signaling pathways, thereby improving reproductive function.
		                        		
		                        		
		                        		
		                        	
10.The Regulatory Role of Glucose Transporter 1 on the Function of Human Umbilical Vein Endothelial Cells Under Ischemia-hypoxic Conditions
Meiling LI ; Siqi GAO ; Zhefu LIU ; Huanyan LIAO ; Fanmao LIU ; Wenhao XIA ; Jun GUO ; Yan LI
Journal of Sun Yat-sen University(Medical Sciences) 2025;46(3):444-455
		                        		
		                        			
		                        			Abstract: ObjectiveThe study aims to explore the effects and regulatory roles of glucose transporter 1 (GLUT1) on the proliferation, migration, adhesion, and angiogenesis of human umbilical vein endothelial cells (HUVECs) under ischemia-hypoxic conditions. MethodsIn vitro experiments were conducted to subject HUVECs to an ischemia-hypoxic-mimicking environment (1% O2, 5% CO2, 94% N2). The biological characteristics of HUVECs under normoxic and ischemia-hypoxic conditions were compared by assessing cell viability, proliferation capacity, and examining the expression changes of GLUT1, HIF-1α, and VEGFA proteins under ischemia-hypoxia using Western blot technology. Further, GLUT1 was overexpressed using plasmid transfection and the proliferation, migration, adhesion, and angiogenic capabilities of HUVECs were evaluated through scratch assays, cell adhesion assays, and tube formation assays. Mitochondrial morphological changes were observed by transmission electron microscopy,and oxygen consumption rate (OCR) was detected by Seahorse metabolic analyzer to evaluate mitochondrial function. ResultsCompared with normoxic conditions, the ischemia-hypoxic environment significantly inhibited the proliferation, cell viability, migration, and adhesion capabilities of HUVECs and impaired their angiogenic potential. The expression levels of GLUT1, HIF-1α and VEGFA proteins were also markedly reduced. However, when GLUT1 expression was upregulated, the migration, adhesion, and angiogenic capabilities of HUVECs were significantly improved, and the protein expression levels of HIF-1α, VEGFA and VEGFR were increased. Transmission electron microscopy revealed that ischemic-hypoxia leads to mitochondrial swelling and matrix damage, while GLUT1 overexpression significantly alleviates mitochondrial morphology abnormalities. OCR results suggest that GLUT1 overexpression may enhance oxidative phosphorylation of endothelial cells in ischemic-hypoxic environments to improve energy metabolism. These results suggest that GLUT1 may influence the function and angiogenic potential of HUVECs by regulating glucose metabolism and energy supply. ConclusionsThis study reveals the significant regulatory role of GLUT1 in the function of HUVECs under ischemia-hypoxic conditions, potentially through modulating cellular energy metabolism and signal transduction pathways, thereby affecting cell proliferation, migration, adhesion, and angiogenesis. These findings provide a new perspective on the role of GLUT1 in cardiovascular diseases and may offer potential targets for the development of new therapeutic strategies. 
		                        		
		                        		
		                        		
		                        	
            

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