1.Total Flavonoids from Cuscutae Semen Inhibit Depression in CUMS Mice via UCP2/TXNIP/NLRP3 Signaling Pathway
Andong SONG ; Guohua LI ; Bo YUAN ; Menghui JIA ; Zhantao LI ; Xiaoli WANG ; Long WANG ; Huiling FU
Chinese Journal of Experimental Traditional Medical Formulae 2025;31(21):109-119
ObjectiveTo investigate the antidepressant effects and mechanisms of total flavonoids from Cuscutae Semen (TFCC) in the mouse model of chronic unpredictable mild stress (CUMS). MethodsFifty male 4-week-old ICR mice were randomized into five groups (n=10 per group): blank control, model, Cuscutae Semen decoction (10.2 g·kg-1·d-1), paroxetine (2.6 mg·kg-1·d-1), and TFCC (173.2 mg·kg-1·d-1). The other groups except the blank control group underwent chronic unpredictable mild stress (CUMS) for 4 weeks. Behavioral assessments were conducted post-modeling. Then, the model group received distilled water (10 mL·kg-1·d-1), while treatment groups were administrated with respective agents via oral gavage (10 mL·kg-1) for 4 weeks. Depression-like behaviors were evaluated by the sucrose preference test (SPT), forced swimming test (FST), and tail suspension test (TST). Hippocampal neuronal morphology was observed via hematoxylin-eosin staining, and apoptosis in the brain tissue was assessed via terminal- deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL). Enzyme-linked immunosorbent assay (ELISA) was employed to measure the hippocampal levels of inflammatory cytokines [interleukin (IL)-1β, IL-6, and TNF-α)] and neurotransmitters [5-hydroxytryptamine (5-HT), dopamine (DA), and brain-derived neurotrophic factor (BDNF)], while the reactive oxygen species (ROS) levels were quantified via the DCFH-DA probe. Real-time PCR was performed to measure the mRNA levels of NOD-like receptor protein 3 (NLRP3), apoptosis-associated Speck-like protein containing a CARD (ASC), cysteinyl aspartate-specific proteinase-1 (Caspase-1), IL-1β, and inducible nitric oxide synthase (iNOS). Western blot was employed to evaluate the protein levels of NLRP3, ASC, Caspase-1, uncoupling protein 2 (UCP2), and thioredoxin-interacting protein (TXNIP). ResultsCompared with the blank control group, the model group exhibited weight loss (P<0.01), reduced sucrose preference (P<0.01), prolonged immobility time in FST and TST (P<0.01), neuron disarrangement with nuclear pyknosis in hippocampal CA3 region, increased apoptosis in the brain tissue, elevated levels of IL-1β, IL-6, and TNF-α (P<0.01), declined levels of 5-HT, DA, and BDNF (P<0.01), increased ROS accumulation (P<0.01), upregulated mRNA levels of NLRP3, ASC, Caspase-1, IL-1β, and iNOS (P<0.01), down-regulated protein level of UCP2 (P<0.01), and up-regulated protein levels of NLRP3, ASC, Caspase-1, and TXNIP (P<0.01). Compared with the model group, the interventions restored sucrose preference (P<0.01), shortened immobility time (P<0.01), repaired hippocampal neuronal structure, reduced apoptosis, lowered the levels of inflammatory cytokines (P<0.01), restored the levels of neurotransmitters (P<0.01), alleviated ROS accumulation (P<0.01), downregulated the mRNA levels of NLRP3, ASC, Caspase-1, IL-1β, and iNOS (P<0.01), upregulated the protein level of UCP2 (P<0.01), and reduced the protein levels of NLRP3, ASC, Caspase-1, and TXNIP (P<0.01). Moreover, TFCC outperformed Cuscutae Semen decoction in ameliorating depressive behaviors. TFCC excelled in neuronal repair, neurotransmitter regulation, anti-inflammatory effects, and modulation of the UCP2/TXNIP/NLRP3 pathway (P<0.05). ConclusionTFCC modulates the hippocampal UCP2/TXNIP/NLRP3 pathway to inhibit inflammasome activation, reduce oxidative stress, restore neurotransmitters, thus suppressing neuronal apoptosis and promoting the rearrangement and morphology recovery of hippocampal cells. It outperforms Cuscutae Semen decoction in the antidepressant efficacy.
2.Total Flavonoids from Cuscutae Semen Inhibit Depression in CUMS Mice via UCP2/TXNIP/NLRP3 Signaling Pathway
Andong SONG ; Guohua LI ; Bo YUAN ; Menghui JIA ; Zhantao LI ; Xiaoli WANG ; Long WANG ; Huiling FU
Chinese Journal of Experimental Traditional Medical Formulae 2025;31(21):109-119
ObjectiveTo investigate the antidepressant effects and mechanisms of total flavonoids from Cuscutae Semen (TFCC) in the mouse model of chronic unpredictable mild stress (CUMS). MethodsFifty male 4-week-old ICR mice were randomized into five groups (n=10 per group): blank control, model, Cuscutae Semen decoction (10.2 g·kg-1·d-1), paroxetine (2.6 mg·kg-1·d-1), and TFCC (173.2 mg·kg-1·d-1). The other groups except the blank control group underwent chronic unpredictable mild stress (CUMS) for 4 weeks. Behavioral assessments were conducted post-modeling. Then, the model group received distilled water (10 mL·kg-1·d-1), while treatment groups were administrated with respective agents via oral gavage (10 mL·kg-1) for 4 weeks. Depression-like behaviors were evaluated by the sucrose preference test (SPT), forced swimming test (FST), and tail suspension test (TST). Hippocampal neuronal morphology was observed via hematoxylin-eosin staining, and apoptosis in the brain tissue was assessed via terminal- deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL). Enzyme-linked immunosorbent assay (ELISA) was employed to measure the hippocampal levels of inflammatory cytokines [interleukin (IL)-1β, IL-6, and TNF-α)] and neurotransmitters [5-hydroxytryptamine (5-HT), dopamine (DA), and brain-derived neurotrophic factor (BDNF)], while the reactive oxygen species (ROS) levels were quantified via the DCFH-DA probe. Real-time PCR was performed to measure the mRNA levels of NOD-like receptor protein 3 (NLRP3), apoptosis-associated Speck-like protein containing a CARD (ASC), cysteinyl aspartate-specific proteinase-1 (Caspase-1), IL-1β, and inducible nitric oxide synthase (iNOS). Western blot was employed to evaluate the protein levels of NLRP3, ASC, Caspase-1, uncoupling protein 2 (UCP2), and thioredoxin-interacting protein (TXNIP). ResultsCompared with the blank control group, the model group exhibited weight loss (P<0.01), reduced sucrose preference (P<0.01), prolonged immobility time in FST and TST (P<0.01), neuron disarrangement with nuclear pyknosis in hippocampal CA3 region, increased apoptosis in the brain tissue, elevated levels of IL-1β, IL-6, and TNF-α (P<0.01), declined levels of 5-HT, DA, and BDNF (P<0.01), increased ROS accumulation (P<0.01), upregulated mRNA levels of NLRP3, ASC, Caspase-1, IL-1β, and iNOS (P<0.01), down-regulated protein level of UCP2 (P<0.01), and up-regulated protein levels of NLRP3, ASC, Caspase-1, and TXNIP (P<0.01). Compared with the model group, the interventions restored sucrose preference (P<0.01), shortened immobility time (P<0.01), repaired hippocampal neuronal structure, reduced apoptosis, lowered the levels of inflammatory cytokines (P<0.01), restored the levels of neurotransmitters (P<0.01), alleviated ROS accumulation (P<0.01), downregulated the mRNA levels of NLRP3, ASC, Caspase-1, IL-1β, and iNOS (P<0.01), upregulated the protein level of UCP2 (P<0.01), and reduced the protein levels of NLRP3, ASC, Caspase-1, and TXNIP (P<0.01). Moreover, TFCC outperformed Cuscutae Semen decoction in ameliorating depressive behaviors. TFCC excelled in neuronal repair, neurotransmitter regulation, anti-inflammatory effects, and modulation of the UCP2/TXNIP/NLRP3 pathway (P<0.05). ConclusionTFCC modulates the hippocampal UCP2/TXNIP/NLRP3 pathway to inhibit inflammasome activation, reduce oxidative stress, restore neurotransmitters, thus suppressing neuronal apoptosis and promoting the rearrangement and morphology recovery of hippocampal cells. It outperforms Cuscutae Semen decoction in the antidepressant efficacy.
3.Effects of croton cream on JNK/p38 MAPK signaling pathway and neuronal apoptosis in cerebral ischemia-reperfusion injury rats
Yun YUE ; Peipei WANG ; Zhaohe YUAN ; Shengcun HE ; Xusheng JIA ; Qian LIU ; Zhantao LI ; Huiling FU ; Fei SONG ; Menghui JIA
Chinese Journal of Tissue Engineering Research 2024;28(8):1186-1192
BACKGROUND:Croton cream can activate ERK pathways and have anti-apoptotic effects on neuronal cells.It is not clear whether it synergistically exerts anti-apoptotic effects by inhibiting the activation of JNK and p38 pathways. OBJECTIVE:To explore the effects and mechanisms of croton cream on neuronal damage and apoptosis in the ischemic cortex of rats with cerebral ischemia-reperfusion injury. METHODS:(1)Ninety Sprague-Dawley rats were randomly divided into sham operation group,model group,croton cream low-dose group,croton cream medium-dose group,croton cream high-dose group and nimodipine group,with 15 rats in each group.Except for the sham operation group,animal models of middle cerebral artery occlusion were prepared in rats by the thread method.Rats in the three croton cream groups were given 20,40,and 60 mg/kg croton cream,respectively.Rats in the sham operation and model groups were given the same amount of normal saline,once a day,for 7 consecutive days.The optimal concentration of croton cream,namely the high dose of croton cream,was selected based on neurological deficit score,TTC staining,brain tissue water content,hematoxylin-eosin staining and Nissl staining.(2)Another 120 Sprague-Dawley rats were randomly divided into sham operation group,model group,croton cream group,JNK inhibitor group,croton cream+JNK inhibitor group,p38 MAPK inhibitor group,croton cream+p38 MAPK inhibitor group,and nimodipine group,with 15 rats in each group.Animal models of middle cerebral artery occlusion were prepared using the thread method in all the groups except in the sham operation group.Thirty minutes before modeling,10 μL of SP600125(JNK inhibitor)and 10 μL of SB203580(p38 MAPK inhibitor)were injected into the lateral ventricle of the rats,respectively.Rats in croton cream groups were intragastrically given 60 mg/kg croton cream.Seven days later,the JNK/p38 MAPK signaling pathway,apoptosis-related proteins and cell apoptosis were detected by western blot,TUNEL staining and flow cytometry,respectively. RESULTS AND CONCLUSION:(1)Compared with the sham operation group,neurological deficit score,cerebral water content,cerebral infarction volume and apoptosis rate were significantly increased in the model group(P<0.05),where nerve cells showed scattered distribution.Compared with the model group,neurological deficit score,water content of brain tissue and cerebral infarction volume were significantly decreased in the croton cream medium-dose group,high-dose group and nimodipine group(P<0.05),and the pathological morphology of nerve cells was significantly improved.(2)Compared with the JNK inhibitor group,p-JNK/JNK,p-p38/p38 and Bax expressions in rat brain tissue and the apoptotic rate were significantly decreased in the croton cream+inhibitor groups(P<0.05),while the expression of and Bcl-2 was significantly increased(P<0.05).To conclude,croton cream may inhibit the activation of JNK/p38 MAPK signaling pathway and reduce neuronal apoptosis to achieve neuroprotective effects in rats with cerebral ischemia-reperfusion injury.
4.Prevalence of hearing loss among community-dwelling older people in China in 2020
Shige QI ; Yuzhang HUANG ; Menghui DING ; Han ZHANG ; Lu CUI ; Zhihui WANG
Chinese Journal of Geriatrics 2023;42(4):446-452
Objective:To investigate the prevalence of hearing loss among community-dwelling older people aged 60 and over, and also to compare the discrepancies between self-reported hearing loss and hearing loss diagnosed via audiometry.Methods:Subjects were from the Prevention and Intervention on Neurodegenerative Disease for the Elderly in China(PINDEC)project.By using the stratified multi-stage cluster random sampling method, a total of 10 347 residents aged 60 years and over were selected from 12 counties and districts in Liaoning, Henan and Guangdong Provinces and hearing function assessment was performed in 2020 through otoscopy, pure-tone audiometry and questionnaires.Hearing loss(HL)was defined by the World Health Organization criteria.Self-reported hearing loss was assessed by asking participants whether they had difficulty in hearing.The χ2 and Cochran-Armitage trend tests were used to analyze the differences in HL between different groups.The multivariate Logistic regression model was applied to assess factors influencing HL. Results:In 2020, the prevalence of HL among the elderly aged 60 and older in Liaoning, Henan and Guangdong Provinces was 69.8%(95% CI: 68.9%-70.7%). The prevalence of HL in men was higher than that in women, and increased gradually with age.The prevalence of mild HL was 47.2%, and the prevalence of moderate, severe and profound HL were 18.0%, 3.6% and 0.9%, respectively.Multivariate Logistic regression analysis showed that factors positively correlated with HL were aging, male sex, living in rural areas and working in manual labor.Education level was negatively correlated with HL.Of the 7223 participants who were found to have HL, 5106(70.7%)self-reported having good hearing.Those of a younger age, with a higher educational achievement, having a spouse, or with mild HL were more likely to report having good hearing(all P<0.05). Conclusions:Hearing loss is quite prevalent among community-dwelling older people, and there is a large discrepancy in prevalence between self-reported HL and HL diagnosed via audiometry.Screening and comprehensive intervention for hearing loss for the elderly should be strengthened.
5.Effects of Burdock Leaf Extract NBY-4 on Oxidative Damage of Vascular Endothelial Cells
Kaixia WANG ; Jingjing YAN ; Panxia CAO ; Menghui HU ; Liping DAI ; Hong WU
World Science and Technology-Modernization of Traditional Chinese Medicine 2023;25(12):3899-3907
Objective To investigate the function of burdock leaf extract NBY-4 in protecting vascular endothelial cells from oxidative damage.Methods The oxidative damage model of vascular endothelial cells was established with hydrogen peroxide(H2O2).ROS,LDH,SOD,apoptosis rate and the expression of apoptosis were measured;Further test the nuclear transcription factor-κB(NF-κB).Results In the model group,H2O2 increased the apoptosis rate of endothelial cells,increased the ratio of Bax/Bcl-2 and the expression of Caspase-3,promoted the production of ROS and LDH in endothelial cells,and inhibited the level of SOD,resulting in oxidative damage to endothelial cells(P<0.05).NBY-4 could slow down the process of these effects;At the same time,NBY-4 can reduce NF-κB in endothelial cells.Conclusion NBY-4 can inhibit endothelial cell apoptosis and antioxidant damage by NF-κB signaling pathway.
6.Application value of 3D printed model in hemostasis training for laparoscopic sleeve gastrectomy
Jinlei MAO ; Zhihao ZHU ; Hao CHEN ; Menghui ZHOU ; Jianfu XIA ; Wei PENG ; Zhifei WANG
Chinese Journal of Digestive Surgery 2023;22(8):1009-1013
Objective:To investigate the application value of 3D printed model in hemostasis training for laparoscopic sleeve gastrectomy.Methods:The retrospective and descriptive study was conducted. Data were collected from six surgeons who participated in hemostasis training for laparoscopic sleeve gastrectomy using 3D printed model at Zhejiang Provincial People′s Hospital in July 2023. All participants were male, aged (33.5±9.9)years. A 3D printed model simulating bleeding during laparoscopic sleeve gastrectomy was created using hydrogel. Videos were recorded to document the surgeons′ hemostasis techniques and outcomes during laparoscopic sleeve gastrectomy. Two external expert reviewers blindly assessed the training videos using the objective structured assess-ment of technical skills (OSATS) scoring system to evaluate mesentery mobilization, vessel exposure, vessel clipping and bleeding after vessel clipping. Observation indicators: (1) face validity and content validity of the 3D printed model; (2) validity verification of the 3D printed model. Measurement data with normal distribution were represented as Mean± SD. Comparison between groups was conducted using the t test. Results:(1) Face validity and content validity of the 3D printed model. The surgeons′ scores for overall impression, fidelity, texture, appearance, workspace and tactile similarity of the 3D printed model were 4.5±0.6, 4.0±0.6, 3.7±0.5, 4.2±0.8, 3.8±0.8 and 4.2±0.4, respectively. The surgeons′ scores for similarity to real scenarios, operation convenience, learning curve shortening and operation skills improving, patient risk reduction, trainee′s interest enhancing, confidence increasing and recommendation for promotion were 4.0±0.6, 4.2±0.8, 4.3±0.8, 4.3±0.5, 4.3±0.5, 4.0±0.6 and 4.8±0.4, respectively. (2) Validity verification of the 3D printed model. The OSATS scores and operation time to treat bleeding during laparoscopic sleeve gastrectomy for expert surgeons were 18.7±0.6 and (125±12)seconds, respectively, versus 13.7±1.5 and (212±51)seconds for junior doctors, showing significant differences between the two groups ( t=5.30, -2.89, P<0.05). Conclusion:The 3D printed model effectively simulates bleeding scenarios during laparoscopic sleeve gastrectomy and distinguishes between different technical levels of expertise.
7.Research progress in measurement methods for210Po and 210Pb in environmental samples
Kaijun SU ; Xilong WANG ; Menghui HUO ; Wei DONG ; Hezheng ZHAI ; Ling JIAO
Chinese Journal of Radiological Health 2022;31(2):245-249
210Po and 210Pb exist widely in nature, and they have strong toxicity and strong ionization ability, which can cause continuous harm to human health. Therefore, it is of great significance to determine the activity concentrations of 210Po and 210Pb in environmental samples and to evaluate their harmful effects on human health. This article reviews the research progress in analytical methods and measurement techniques of 210Po and 210Pb in environmental samples.
8.Factors influencing changes in total radioactivity in differentiated thyroid cancer patients after 131I treatment
Liuyan GAO ; Wei HE ; Yunbo LI ; Haili TANG ; Menghui YUAN ; Junyan WANG ; Qianrong BAI ; Guangming WEI
Chinese Journal of Radiological Medicine and Protection 2022;42(12):973-979
Objective:To investigate the changes in total radioactivity in patient body with differentiated thyroid carcinoma (DTC) after 131I treatment and the factors influencing its metabolism. Methods:The clinical data from 218 patients after DTC treatment in the Department of Nuclear Medicine, the Second Affiliated Hospital of Air Force Medical University from September 2021 to April 2022 were retrospectively analyzed. Based on administrated 131I dose, 171 patients were divided into low-dose group (≤ 3.7 GBq) and 47 into high-dose group (>3.7 GBq) . A whole body dynamic radiation monitoring system was used to measure the in vivo residual activity of 131I 24, 48 and 72 h after 131I administration and to explore their influencing factors. Results:24, 48 and 72 h after adimination of 131I, the residual activity of 131I in the low-dose group patients was significantly lower than in the high-dose group patients ( t= -7.46, -3.31, -2.01, P<0.05) . The discharge compliance rate at 24 and 48 h in the low-dose group was significantly higher than that in the high-dose group (21.0% vs. 4.3%, 98.2% vs. 89.4%, χ2 = 7.23, 5.91, P<0.05) , and all patients could meet the discharge criteria at 72 h. Univariate analysis showed that the residual 131I activity at 24 and 48 h was dependent on age, body mass index (BMI) , basal metabolism rate (BMR) and thyroid stimulating hormone (TSH) . As have been shown by multiple linear regression analysis, in the low-dose group, the older age, the higher BMR and the higher TSH level at 24 h tended to the higher 131I residual activity in the body. At 48 h, the higher BMI and the higher TSH level lead to the higher 131I residual activity in patient body. Meanwhile, in the high-dose group, the higher age and BMR at 24 h, tended to the higher in vivo131I residual activity. The influencing factors were analyzed in terms that 131I residual activity reaching 400 MBq in patient body at 24 and 36 h. The result showed that at 24 h the lower TSH level leaded to the lower 131I residual activity in patient body. At 36 h, the younger age, the lower TSH level, and the smaller 131I treatment dose tended to the lower in vivo131I residual activity. Conclusions:Age, BMI, BMR and TSH levels are the influencing factors for the change in total activity in patient body after 131I treatment of DTC. Radiation dose assessment based on the above indicators can provide a reference for adjusting the length of hospitalization time.
9.Appraisal of Guidelines for the Management of Blood Pressure in Patients with Diabetes Mellitus: The Consensuses, Controversies and Gaps
Menghui LIU ; Shaozhao ZHANG ; Xiaohong CHEN ; Yue GUO ; Xiangbin ZHONG ; Zhenyu XIONG ; Yifen LIN ; Huimin ZHOU ; Yiquan HUANG ; Zhengzhipeng ZHANG ; Lichun WANG ; Xiaodong ZHUANG ; Xinxue LIAO
Diabetes & Metabolism Journal 2021;45(5):753-764
Background:
Currently available guidelines contain conflicting recommendations on the management of blood pressure (BP) in patients with diabetes mellitus (DM). Therefore, it is necessary to appraise the guidelines and summarize the agreements and differences among recommendations.
Methods:
Four databases and the websites of guideline organizations were searched for guidelines regarding BP targets and thresholds for pharmacologic therapy in DM patients, and the included guidelines were appraised with the Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument.
Results:
In 6,498 records identified, 20 guidelines met our inclusion criteria with 64.0% AGREE II scores (interquartile range, 48.5% to 72.0%). The scores of the European and American guidelines were superior to those of the Asian guidelines (both adjusted P<0.001). Most of the guidelines advocated systolic BP targets <130 mm Hg (12 guidelines, 60%) and diastolic BP targets <80 mm Hg (14 guidelines, 70%) in DM patients. Approximately half of the guidelines supported systolic BP thresholds >140 mm Hg (10 guidelines, 50%) and diastolic BP thresholds >90 mm Hg (nine guidelines, 45%). The tiny minority of the guidelines provided the relevant recommendations regarding the lower limit of official BP targets and the ambulatory BP monitoring (ABPM)/home BP monitoring (HBPM) targets and thresholds in DM patients.
Conclusion
The lower official BP targets (<130/80 mm Hg) in patients with DM are advocated by most of the guidelines, but they contain conflicting recommendations on the official BP thresholds. Moreover, the gaps regarding the lower limit of official BP targets and the ABPM/HBPM targets and thresholds need to be considered by future study.
10.Functional connectivity and metabolic effective connectivity patterns within default-mode network in healthy male adults revealed by hybrid PET/MR
Lei WANG ; Ming GAO ; Long JIN ; Yunbo LI ; Menghui YUAN ; Yarong WANG ; Jianlin YUAN ; Longxiao WEI
Chinese Journal of Nuclear Medicine and Molecular Imaging 2021;41(2):88-92
Objective:To study the functional connectivity (FC) and metabolic effective connectivity (MEC) patterns of the default mode network (DMN) in healthy male adults based on a novel hybrid PET/MR system.Methods:Fifteen healthy male adults with median age of 29 years were recruited locally in Xi′an from January to May 2019. All subjects went through PET/MR scan to get the whole brain 18F-fluorodeoxyglucose (FDG) PET, resting-state functional MRI (fMRI) and magnetization prepared rapid gradient echo (MPRAGE) T 1 weighted imaging data. CONN18b and statistical parametric mapping (SPM) 12 softwares were used to analyze data. The voxel-wise FC and FDG metabolic data were extracted within 4 sub-networks of DMN, which included medial prefrontal cortex (MPFC), posterior cingulate cortex (PCC) and bilateral lateral parietal (LP). The FC and MEC between 4 sub-networks were calculated based on merged resting-state fMRI and metabolic data, and analyzed by one-sample t test separately, with Bonferroni correction. Results:FC pathways were all significant within 4 sub-networks of DMN ( t values: 6.00-7.71, all P<0.008, Bonferroni corrected). Meanwhile, there were significant bi-directional MEC between MPFC and PCC(MPFC to PCC: t=10.03; PCC to MPFC: t=3.73, both P<0.004, Bonferroni corrected), as well as between bilateral LP (LP_L to LP_R: t=5.28; LP_R to LP_L: t=4.76, both P<0.004, Bonferroni corrected). There were significant uni-directional MEC from both MPFC and PCC to bilateral LP ( t values: 3.44-6.93, all P<0.004, Bonferroni corrected). Conclusions:Special FC and MEC patterns exist within DMN. The closely interrelated MPFC and PCC play more important roles in DMN, and they may mediate LP jointly. The novel integrated PET/MR system will bring new perspective on the organization of brain networks, which may deepen the comprehensive understanding of DMN.

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