1.Herbal Textual Research on Inulae Flos in Famous Classical Formulas
Caixia LIU ; Yue HAN ; Yanzhu MA ; Lei GAO ; Sheng WANG ; Yan YANG ; Wenchuan LUO ; Ling JIN ; Jing SHAO ; Zhijia CUI ; Zhilai ZHAN
Chinese Journal of Experimental Traditional Medical Formulae 2026;32(3):210-221
In this paper, by referring to ancient and modern literature, the textual research of Inulae Flos has been conducted to clarify the name, origin, production area, quality evaluation, harvesting, processing and others, so as to provide reference and basis for the development and utilization of famous classical formulas containing this herb. After textual research, it could be verified that the medicinal use of Inulae Flos was first recorded in Shennong Bencaojing of the Han dynasty. In successive dynasties, Xuanfuhua has been taken as the official name, and it also has other alternative names such as Jinfeicao, Daogeng and Jinqianhua. The period before the Song and Yuan dynasties, the main origin of Inulae Flos was the Asteraceae plant Inula japonica, and from the Ming and Qing dynasties to the present, I. japonica and I. britannica are the primary source. In addition to the dominant basal species, there are also regional species such as I. linariifolia, I. helianthus-aquatili, and I. hupehensis. The earliest recorded production areas in ancient times were Henan, Hubei and other places, and the literature records that it has been distributed throughout the country since modern times. The medicinal part is its flower, the harvesting and processing method recorded in the past dynasties is mainly harvested in the fifth and ninth lunar months, and dried in the sun, and the modern harvesting is mostly harvested in summer and autumn when the flowers bloom, in order to remove impurities, dry in the shade or dry in the sun. In addition, the roots, whole herbs and aerial parts are used as medicinal materials. In ancient times, there were no records about the quality of Inulae Flos, and in modern times, it is generally believed that the quality of complete flower structure, small receptacles, large blooms, yellow petals, long filaments, many fluffs, no fragments, and no branches is better. Ancient processing methods primarily involved cleaning, steaming, and sun-drying, supplemented by techniques such as boiling, roasting, burning, simmering, stir-frying, and honey-processing. Modern processing focuses mainly on cleaning the stems and leaves before use. Regarding the medicinal properties, ancient texts describe it as salty and sweet in taste, slightly warm in nature, and mildly toxic. Modern studies characterize it as bitter, pungent, and salty in taste, with a slightly warm nature. Its therapeutic effects remain consistent across eras, including descending Qi, resolving phlegm, promoting diuresis, and stopping vomiting. Based on the research results, it is recommended that when developing famous classical formulas containing Inulae Flos, either I. japonica or I. britannica should be used as the medicinal source. Processing methods should follow formula requirements, where no processing instructions are specified, the raw products may be used after cleaning.
2.Herbal Textual Research on Inulae Flos in Famous Classical Formulas
Caixia LIU ; Yue HAN ; Yanzhu MA ; Lei GAO ; Sheng WANG ; Yan YANG ; Wenchuan LUO ; Ling JIN ; Jing SHAO ; Zhijia CUI ; Zhilai ZHAN
Chinese Journal of Experimental Traditional Medical Formulae 2026;32(3):210-221
In this paper, by referring to ancient and modern literature, the textual research of Inulae Flos has been conducted to clarify the name, origin, production area, quality evaluation, harvesting, processing and others, so as to provide reference and basis for the development and utilization of famous classical formulas containing this herb. After textual research, it could be verified that the medicinal use of Inulae Flos was first recorded in Shennong Bencaojing of the Han dynasty. In successive dynasties, Xuanfuhua has been taken as the official name, and it also has other alternative names such as Jinfeicao, Daogeng and Jinqianhua. The period before the Song and Yuan dynasties, the main origin of Inulae Flos was the Asteraceae plant Inula japonica, and from the Ming and Qing dynasties to the present, I. japonica and I. britannica are the primary source. In addition to the dominant basal species, there are also regional species such as I. linariifolia, I. helianthus-aquatili, and I. hupehensis. The earliest recorded production areas in ancient times were Henan, Hubei and other places, and the literature records that it has been distributed throughout the country since modern times. The medicinal part is its flower, the harvesting and processing method recorded in the past dynasties is mainly harvested in the fifth and ninth lunar months, and dried in the sun, and the modern harvesting is mostly harvested in summer and autumn when the flowers bloom, in order to remove impurities, dry in the shade or dry in the sun. In addition, the roots, whole herbs and aerial parts are used as medicinal materials. In ancient times, there were no records about the quality of Inulae Flos, and in modern times, it is generally believed that the quality of complete flower structure, small receptacles, large blooms, yellow petals, long filaments, many fluffs, no fragments, and no branches is better. Ancient processing methods primarily involved cleaning, steaming, and sun-drying, supplemented by techniques such as boiling, roasting, burning, simmering, stir-frying, and honey-processing. Modern processing focuses mainly on cleaning the stems and leaves before use. Regarding the medicinal properties, ancient texts describe it as salty and sweet in taste, slightly warm in nature, and mildly toxic. Modern studies characterize it as bitter, pungent, and salty in taste, with a slightly warm nature. Its therapeutic effects remain consistent across eras, including descending Qi, resolving phlegm, promoting diuresis, and stopping vomiting. Based on the research results, it is recommended that when developing famous classical formulas containing Inulae Flos, either I. japonica or I. britannica should be used as the medicinal source. Processing methods should follow formula requirements, where no processing instructions are specified, the raw products may be used after cleaning.
3.Effect and mechanism of Prunus mume against hepatic fibrosis
Feng HAO ; Ji LI ; Jing DU ; Yuchen OUYANG ; Yichun CUI ; Shuang WEI
China Pharmacy 2025;36(2):172-178
OBJECTIVE To explore the effect and mechanism of Prunus mume against hepatic fibrosis (HF). METHODS Male SD rats were randomly divided into normal control group (n=10) and modeling group (n=50). The modeling group established HF model using carbon tetrachloride. The modeled rats were randomly divided into model group (normal saline), positive control group [colchicine, 0.09 mg/(kg·d)], and P. mume low-dose, medium-dose and high-dose groups [1.35, 2.70, 5.40 g/(kg·d)], with 9 rats in each group. They were given the corresponding drug/normal saline intragastrically, once a day, for 8 consecutive weeks. After the last medication, the liver index was calculated, while liver function indexes, liver fiber indexes, oxidative stress indicators and inflammatory factors of rats were measured. HE staining was used to observe the pathological changes in liver tissue of rats; Masson staining was used to observe the degree of HF in liver tissue of rats; transmission electron microscopy was used to observe the ultrastructure of liver tissue in rats; TUNEL staining was used to detect liver cell apoptosis in each group of rats. Western blot method was used to detect the protein expressions of transforming growth factor-β1 (TGF-β1) and platelet-derived growth factor (PDGF) in liver tissue of rats. RESULTS Compared with normal control group, the levels of alanine transaminase, alkaline phosphatase, aspartate transaminase, total bilirubin, malondialdehyde, procollagen type Ⅲ protein, Ⅳ-type pre collagenase, laminin, hyaluronic acid, interleukin-6, tumor necrosis factor-α, as well as the protein expressions of TGF-β1 and PDGF in model group were increased significantly, while the levels of superoxide dismutase and glutathione peroxidase were significantly reduced (P<0.01); the HE, Masson staining and transmission electron microscopy observation results showed obvious HF characteristics in rats of model group. Compared with model group, varying degrees of improvement in above indexes were observed in P. mume groups, and the above 2021BSZR011) indicators of rats in P. mume medium-dose and high-dose groups were reversed significantly (P<0.05 or P<0.01). CONCLUSIONS P. mume has an anti-HF effect, which may be achieved through mechanisms such as antioxidation, anti-inflammation, reduction of collagen production, inhibition of PDGF protein expression, and regulation of TGF- β1 signaling pathway.
4.Effect and mechanism of Prunus mume against hepatic fibrosis
Feng HAO ; Ji LI ; Jing DU ; Yuchen OUYANG ; Yichun CUI ; Shuang WEI
China Pharmacy 2025;36(2):172-178
OBJECTIVE To explore the effect and mechanism of Prunus mume against hepatic fibrosis (HF). METHODS Male SD rats were randomly divided into normal control group (n=10) and modeling group (n=50). The modeling group established HF model using carbon tetrachloride. The modeled rats were randomly divided into model group (normal saline), positive control group [colchicine, 0.09 mg/(kg·d)], and P. mume low-dose, medium-dose and high-dose groups [1.35, 2.70, 5.40 g/(kg·d)], with 9 rats in each group. They were given the corresponding drug/normal saline intragastrically, once a day, for 8 consecutive weeks. After the last medication, the liver index was calculated, while liver function indexes, liver fiber indexes, oxidative stress indicators and inflammatory factors of rats were measured. HE staining was used to observe the pathological changes in liver tissue of rats; Masson staining was used to observe the degree of HF in liver tissue of rats; transmission electron microscopy was used to observe the ultrastructure of liver tissue in rats; TUNEL staining was used to detect liver cell apoptosis in each group of rats. Western blot method was used to detect the protein expressions of transforming growth factor-β1 (TGF-β1) and platelet-derived growth factor (PDGF) in liver tissue of rats. RESULTS Compared with normal control group, the levels of alanine transaminase, alkaline phosphatase, aspartate transaminase, total bilirubin, malondialdehyde, procollagen type Ⅲ protein, Ⅳ-type pre collagenase, laminin, hyaluronic acid, interleukin-6, tumor necrosis factor-α, as well as the protein expressions of TGF-β1 and PDGF in model group were increased significantly, while the levels of superoxide dismutase and glutathione peroxidase were significantly reduced (P<0.01); the HE, Masson staining and transmission electron microscopy observation results showed obvious HF characteristics in rats of model group. Compared with model group, varying degrees of improvement in above indexes were observed in P. mume groups, and the above 2021BSZR011) indicators of rats in P. mume medium-dose and high-dose groups were reversed significantly (P<0.05 or P<0.01). CONCLUSIONS P. mume has an anti-HF effect, which may be achieved through mechanisms such as antioxidation, anti-inflammation, reduction of collagen production, inhibition of PDGF protein expression, and regulation of TGF- β1 signaling pathway.
5.Key questions of translational research on international standards of acupuncture-moxibustion techniques: an example from the WFAS Technical Benchmark of Acupuncture and Moxibustion: General Rules for Drafting.
Shuo CUI ; Jingjing WANG ; Zhongjie CHEN ; Jin HUO ; Jing HU ; Ziwei SONG ; Yaping LIU ; Wenqian MA ; Qi GAO ; Zhongchao WU
Chinese Acupuncture & Moxibustion 2025;45(8):1159-1165
OBJECTIVE:
To provide the experience and demonstration for the transformation of acupuncture-moxibustion techniques standards from Chinese national standards to international standards.
METHODS:
Questionnaire research, literature research, semi-structured interviews and expert consultation were used.
RESULTS:
The safety of acupuncture-moxibustion techniques was evaluated through literature research, and based on the results of the questionnaire survey, expert interviews, and expert consultation, 11 main bodies and structure of the former Chinese national standard, Technical Benchmark of Acupuncture and Moxibustion: General Rules for Drafting, were adjusted and optimized in accordance with the requirements of international standard (including the language, normative references, purpose, scope, applicable environment, target population, work team, terms and definitions, general principles and basic requirements, structural elements and text structure, and compilation process); and the first international standard, World Federation of Acupuncture-Moxibustion Societis (WFAS) Technical Benchmark of Acupuncture and Moxibustion: General Rules for Drafting was formulated to specify the general rules for drafting.
CONCLUSION
The 3 key questions, "international compatibility", "technical operability" and "safety" should be solved technically on the basis of explicit international requirements. It is the core technical issue during transforming the national standards of technical benchmark of acupuncture and moxibustion into international standards.
Moxibustion/methods*
;
Acupuncture Therapy/methods*
;
Humans
;
Translational Research, Biomedical/standards*
;
Surveys and Questionnaires
;
China
;
Benchmarking/standards*
6.The Mechanism of Exercise Regulating Intestinal Flora in The Prevention and Treatment of Depression
Lei-Zi MIN ; Jing-Tong WANG ; Qing-Yuan WANG ; Yi-Cong CUI ; Rui WANG ; Xin-Dong MA
Progress in Biochemistry and Biophysics 2025;52(6):1418-1434
Depression, a prevalent mental disorder with significant socioeconomic burdens, underscores the urgent need for safe and effective non-pharmacological interventions. Recent advances in microbiome research have revealed the pivotal role of gut microbiota dysbiosis in the pathogenesis of depression. Concurrently, exercise, as a cost-effective and accessible intervention, has demonstrated remarkable efficacy in alleviating depressive symptoms. This comprehensive review synthesizes current evidence on the interplay among exercise, gut microbiota modulation, and depression, elucidating the mechanistic pathways through which exercise ameliorates depressive symptoms via the microbiota-gut-brain (MGB) axis. Depression is characterized by gut microbiota alterations, including reduced alpha and beta diversity, depletion of beneficial taxa (e.g., Bifidobacterium, Lactobacillus, and Coprococcus), and overgrowth of pro-inflammatory and pathogenic bacteria (e.g., Morganella, Klebsiella, and Enterobacteriaceae). Metagenomic analyses reveal disrupted metabolic functions in depressive patients, such as diminished synthesis of short-chain fatty acids (SCFAs), impaired tryptophan metabolism, and dysregulated bile acid conversion. For instance, Bifidobacterium longum deficiency correlates with reduced synthesis of neuroactive metabolites like homovanillic acid, while decreased Coprococcus abundance limits butyrate production, exacerbating neuroinflammation. Furthermore, elevated levels of indole derivatives from Clostridium species inhibit serotonin (5-HT) synthesis, contributing to depressive phenotypes. These dysbiotic profiles disrupt the MGB axis, triggering systemic inflammation, neurotransmitter imbalances, and hypothalamic-pituitary-adrenal (HPA) axis hyperactivity. Exercise exerts profound effects on gut microbiota composition, diversity, and metabolic activity. Longitudinal studies demonstrate that sustained aerobic exercise increases alpha diversity, enriches SCFA-producing genera (e.g., Faecalibacterium prausnitzii, Roseburia, and Akkermansia), and suppresses pathobionts (e.g., Desulfovibrio and Streptococcus). For example, a meta-analysis of 25 trials involving 1 044 participants confirmed that exercise enhances microbial richness and restores the Firmicutes/Bacteroidetes ratio, a biomarker of metabolic health. Notably, endurance training promotes Veillonella proliferation, which converts lactate into propionate, enhancing energy metabolism and delaying fatigue. Exercise also strengthens intestinal barrier integrity by upregulating tight junction proteins (e.g., ZO-1, occludin), thereby reducing lipopolysaccharide (LPS) translocation and systemic inflammation. However, excessive exercise may paradoxically diminish microbial diversity and exacerbate intestinal permeability, highlighting the importance of moderate intensity and duration. Exercise ameliorates depressive symptoms through multifaceted interactions with the gut microbiota, primarily via 4 interconnected pathways. First, exercise mitigates neuroinflammation by elevating anti-inflammatory SCFAs such as butyrate, which suppresses NF-κB signaling to attenuate microglial activation and oxidative stress in the hippocampus. Animal studies demonstrate that voluntary wheel running reduces hippocampal TNF‑α and IL-17 levels in stress-induced depression models, while fecal microbiota transplantation (FMT) from exercised mice reverses depressive behaviors by modulating the TLR4/NF‑κB pathway. Second, exercise regulates neurotransmitter dynamics by enriching GABA-producing Lactobacillus and Bifidobacterium, thereby counteracting neuronal hyperexcitability. Aerobic exercise also enhances the abundance of Lactobacillus plantarum and Streptococcus thermophilus, which facilitate 5-HT and dopamine synthesis. Clinical trials reveal that 12 weeks of moderate exercise increases fecal Coprococcus and Blautia abundance, correlating with improved 5-HT bioavailability and reduced depression scores. Third, exercise normalizes HPA axis hyperactivity by reducing cortisol levels and restoring glucocorticoid receptor sensitivity. In rodent models, chronic stress-induced corticosterone elevation is reversed by probiotic supplementation (e.g., Lactobacillus), which enhances endocannabinoid signaling and hippocampal neurogenesis. Furthermore, exercise upregulates brain-derived neurotrophic factor (BDNF) via microbial metabolites like butyrate, promoting histone acetylation and synaptic plasticity. FMT experiments confirm that exercise-induced microbiota elevates prefrontal BDNF expression, reversing stress-induced neuronal atrophy. Fourth, exercise reshapes microbial metabolic crosstalk, diverting tryptophan metabolism toward 5-HT synthesis instead of neurotoxic kynurenine derivatives. Butyrate inhibits indoleamine 2,3-dioxygenase (IDO), a key enzyme in the kynurenine pathway linked to depression. Concurrently, exercise-induced Akkermansia enrichment enhances mucin production, fortifies the gut barrier, and reduces LPS-driven neuroinflammation. Collectively, these mechanisms underscore exercise as a potent modulator of the microbiota-gut-brain axis, offering a holistic approach to alleviating depression through microbial and neurophysiological synergy. Current evidence supports exercise as a potent adjunct therapy for depression, with personalized regimens (e.g., aerobic, resistance, or yoga) tailored to individual microbiota profiles. However, challenges remain in optimizing exercise prescriptions (intensity, duration, and type) and integrating them with probiotics, prebiotics, or FMT for synergistic effects. Future research should prioritize large-scale randomized controlled trials to validate causality, multi-omics approaches to decipher MGB axis dynamics, and mechanistic studies exploring microbial metabolites as therapeutic targets. The authors advocate for a paradigm shift toward microbiota-centric interventions, emphasizing the bidirectional relationship between physical activity and gut ecosystem resilience in mental health management. In conclusion, this review underscores exercise as a multifaceted modulator of the gut-brain axis, offering novel insights into non-pharmacological strategies for depression. By bridging microbial ecology, neuroimmunology, and exercise physiology, this work lays a foundation for precision medicine approaches targeting the gut microbiota to alleviate depressive disorders.
7.Effect of childhood maltreatment on depression in college students: a moderated mediation model
Xinghua LAI ; Huitong ZHAO ; Ruofan XIAO ; Can CUI ; Ameng ZHAO ; Wei FU ; Jing JIANG ; Tinghuizi SHANG ; Honglong LI ; Zengyan YU
Sichuan Mental Health 2025;38(3):247-253
BackgroundCurrently, the problem of depressed mood in college students is becoming more prominent. The experience of childhood maltreatment is a significant contributor to depression among college students. Although the association between the two has been confirmed, the specific psychosocial mechanisms underlying how childhood maltreatment affects college students' mental health remain insufficiently evidenced. ObjectiveTo explore the mediating role of emotion regulation difficulties in the relationship between childhood maltreatment and depression among college students, and to investigate the moderated effects of psychological resilience and family socioeconomic status, aiming to provide references for improving depressive symptoms in college students. MethodsOn 14 March 2024, a cluster sampling method was employed to recruit 751 college students from a university in Heilongjiang Province. Participants were assessed with Childhood Trauma Questionnaire (CTQ), Difficulties in Emotion Regulation Scale (DERS), Patients' Health Questionnaire Depression Scale-9 item (PHQ-9), 10-item Connor-Davidson Resilience Scale (CD-RISC-10) and Family Socioeconomic Status Questionnaire. Pearson correlation analysis was adopted to examine the correlation between the scores of scales. Model 4 and model 7 in Process 4.2 were used to test the mediating effects of emotional regulation difficulties and the moderated effects of psychological resilience and family socioeconomic status. Results① A total of 712 (94.81%) valid questionnaires were collected. ② College students' CTQ score was positively correlated with DERS score and PHQ-9 score (r=0.296, 0.507, P<0.01), and negatively correlated with CD-RISC-10 score and Family Socioeconomic Status Questionnaire score (r=-0.148, -0.229, P<0.01). ③ The indirect effect value of difficulties in emotion regulation on the relationship between childhood maltreatment and depression was 0.091 (95% CI: 0.018~0.046), accounting for 17.95% of the total effect. ④ The first half of the mediation model "childhood maltreatment → difficulties in emotion regulation → depression" (childhood maltreatment → difficulties in emotion regulation) was moderated by psychological resilience (β=-0.030, t=-6.147, 95% CI: -0.040~-0.020) and family socioeconomic status (β=-0.051, t=-3.929, 95% CI: -0.077~-0.026). ConclusionChildhood maltreatment exerts both a direct effect on college students' depression and an indirect effect through emotion regulation difficulties. The childhood maltreatment → emotion regulation difficulties pathway in this mediation model is moderated by psychological resilience and family socioeconomic status. [Funded by Qiqihar Medical University Graduate Student Innovation Fund Project (number, QYYCX2023-48); Special Research Fund Project for Young Doctors of Qiqihar Academy of Medical Sciences (number, QMSI2021B-08)]
8.Exploring Role of Energy Dyshomeostasis in Metabolic Dysfunction-associated Fatty Liver Disease Panvasculopathy from Theory of Liver Being Substantial Yin and Functional Yang
Jing CUI ; Qian XU ; Wenting WANG ; Mengmeng ZHU ; Yanfei LIU ; Yue LIU
Chinese Journal of Experimental Traditional Medical Formulae 2025;31(17):227-233
Liver being substantial Yin and functional Yang maintain normal function of Qi, blood and meridians. In clinical practice, it is often found that pan-vascular lesions with atherosclerosis as the predominant pathological change often co-occur with metabolic dysfunction-associated fatty liver disease(MAFLD). MAFLD leads to increased risk and worse prognosis for many pan-vascular diseases, including cardiovascular disease. Dysregulation of energy homeostasis disrupts the hepatic homeostasis of body use, and representative drugs to improve metabolism, such as metformin, sodium-glucose co-transporter 2 inhibitors, and glucagon-like peptide-1 agonists, not only have a clear cardiovascular benefit, potential improvement of MAFLD has also been demonstrated. The liver stores blood and the heart pumps blood, and liver diseases affect the heart, that's why the unsmoothness of vessels appears. So the treatment should from the standpoint of liver, restoring liver function, soothing the liver and nourishing heart, activating blood and dredging meridian. It is of great significance to explore in depth the pathogenesis and treatment of pan-vascular lesions caused by MAFLD, and to restore the energy homeostasis by adjusting the balance of liver Yin and Yang.
9.Exploring Role of Energy Dyshomeostasis in Metabolic Dysfunction-associated Fatty Liver Disease Panvasculopathy from Theory of Liver Being Substantial Yin and Functional Yang
Jing CUI ; Qian XU ; Wenting WANG ; Mengmeng ZHU ; Yanfei LIU ; Yue LIU
Chinese Journal of Experimental Traditional Medical Formulae 2025;31(17):227-233
Liver being substantial Yin and functional Yang maintain normal function of Qi, blood and meridians. In clinical practice, it is often found that pan-vascular lesions with atherosclerosis as the predominant pathological change often co-occur with metabolic dysfunction-associated fatty liver disease(MAFLD). MAFLD leads to increased risk and worse prognosis for many pan-vascular diseases, including cardiovascular disease. Dysregulation of energy homeostasis disrupts the hepatic homeostasis of body use, and representative drugs to improve metabolism, such as metformin, sodium-glucose co-transporter 2 inhibitors, and glucagon-like peptide-1 agonists, not only have a clear cardiovascular benefit, potential improvement of MAFLD has also been demonstrated. The liver stores blood and the heart pumps blood, and liver diseases affect the heart, that's why the unsmoothness of vessels appears. So the treatment should from the standpoint of liver, restoring liver function, soothing the liver and nourishing heart, activating blood and dredging meridian. It is of great significance to explore in depth the pathogenesis and treatment of pan-vascular lesions caused by MAFLD, and to restore the energy homeostasis by adjusting the balance of liver Yin and Yang.
10.A case of postoperative candida bloodstream infection in patients with digestive tract perforation
Guangwei FENG ; Jing ZHANG ; Yangxi LIU ; Min CUI
Journal of Pharmaceutical Practice and Service 2025;43(9):463-465
Objective To explore the drug selection, usage, dosage and effect of clinical pharmacists in the treatment of secondary Candida bloodstream infection in patients with digestive tract perforation, and provide reference for rational clinical use of such anti-infection therapy. Methods During the treatment of Candida infection, anti-infection specialist clinical pharmacists suggested replacing fluconazole for anti-infection treatment, and adjusted the usage and dosage of caspofungin to ensure the application of full treatment course. Results The patient’s Candida bloodstream infection was effectively controlled. Conclusion Echininocandins such as caspofungin are the first choice for Candida infection. The maintenance dose should be reduced to 35 mg qd in patient with moderate liver function injury, and the anti-infection treatment should be done at least 14 days after the blood culture being negative. Clinical pharmacists participate in clinical pharmaceutical care practices such as clinical ward rounds, and actively assist doctors to develop individualized anti-infection programs, which could improve the level of clinical drug use and the clinical outcome of diseases.

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