1.Effect of repetitive transcranial magnetic stimulation and transcranial direct current stimulation on motor function and gait in children with cerebral palsy:a network meta-analysis
Xinyan CAO ; Zifu YU ; Xiaoxuan LENG ; Shiai GAO ; Jinhui CHEN ; Xihua LIU
Chinese Journal of Tissue Engineering Research 2026;30(6):1539-1548
OBJECTIVE:Repetitive transcranial magnetic stimulation and transcranial direct current stimulation have shown positive effects in improving gross motor function in children with cerebral palsy.A network meta-analysis was performed to analyze the clinical efficacy of repetitive transcranial magnetic stimulation and transcranial direct current stimulation on the improvement of lower limb motor function and gait in children with cerebral palsy.METHODS:Randomized controlled trials(RCT)about repetitive transcranial magnetic stimulation and transcranial direct current stimulation on lower limb motor function and gait in children with cerebral palsy were collected from CNKI,WanFang,VIP,SinoMed,PubMed,Web of Science,Medline.The search time limit was from the inception to October 5,2024.After screening literature,extracting data and evaluating the risk of bias of included studies,Stata 15.0 software was used for network meta-analysis,AND GRADE profiler was used for quality evaluation.RESULTS:A total of 19 studies were included,involving 4 treatment measures:conventional therapy,high-frequency repetitive transcranial magnetic stimulation,low-frequency repetitive transcranial magnetic stimulation and anodic transcranial direct current stimulation.The results of network meta-analysis showed that in terms of improving gross motor function,low-frequency repetitive transcranial magnetic stimulation[mean difference(MD)=9.48,95%confidence interval(CI)(6.61,12.34),P<0.05]was the most effective.In terms of alleviating spasticity,high-frequency repetitive transcranial magnetic stimulation[MD=-0.63,95%CI(-1.72,0.45),P<0.05]had the best efficacy.In terms of improving ankle joint range of motion and step speed,transcranial direct current stimulation[MD=2.27,95%CI(1.37,3.17),P<0.05;MD=0.11,95%CI(0.05,0.17),P<0.05]was the most effective.CONCLUSION:Existing clinical evidence suggests that low-frequency repetitive transcranial magnetic stimulation has the best therapeutic effect compared with other intervention measures in terms of improving lower limb gross motor function.In terms of reducing spasticity,high-frequency repetitive transcranial magnetic stimulation has a more significant effect.In terms of improving gait,transcranial direct current stimulation has more advantages.
2.Effect of repetitive transcranial magnetic stimulation and transcranial direct current stimulation on motor function and gait in children with cerebral palsy:a network meta-analysis
Xinyan CAO ; Zifu YU ; Xiaoxuan LENG ; Shiai GAO ; Jinhui CHEN ; Xihua LIU
Chinese Journal of Tissue Engineering Research 2026;30(6):1539-1548
OBJECTIVE:Repetitive transcranial magnetic stimulation and transcranial direct current stimulation have shown positive effects in improving gross motor function in children with cerebral palsy.A network meta-analysis was performed to analyze the clinical efficacy of repetitive transcranial magnetic stimulation and transcranial direct current stimulation on the improvement of lower limb motor function and gait in children with cerebral palsy.METHODS:Randomized controlled trials(RCT)about repetitive transcranial magnetic stimulation and transcranial direct current stimulation on lower limb motor function and gait in children with cerebral palsy were collected from CNKI,WanFang,VIP,SinoMed,PubMed,Web of Science,Medline.The search time limit was from the inception to October 5,2024.After screening literature,extracting data and evaluating the risk of bias of included studies,Stata 15.0 software was used for network meta-analysis,AND GRADE profiler was used for quality evaluation.RESULTS:A total of 19 studies were included,involving 4 treatment measures:conventional therapy,high-frequency repetitive transcranial magnetic stimulation,low-frequency repetitive transcranial magnetic stimulation and anodic transcranial direct current stimulation.The results of network meta-analysis showed that in terms of improving gross motor function,low-frequency repetitive transcranial magnetic stimulation[mean difference(MD)=9.48,95%confidence interval(CI)(6.61,12.34),P<0.05]was the most effective.In terms of alleviating spasticity,high-frequency repetitive transcranial magnetic stimulation[MD=-0.63,95%CI(-1.72,0.45),P<0.05]had the best efficacy.In terms of improving ankle joint range of motion and step speed,transcranial direct current stimulation[MD=2.27,95%CI(1.37,3.17),P<0.05;MD=0.11,95%CI(0.05,0.17),P<0.05]was the most effective.CONCLUSION:Existing clinical evidence suggests that low-frequency repetitive transcranial magnetic stimulation has the best therapeutic effect compared with other intervention measures in terms of improving lower limb gross motor function.In terms of reducing spasticity,high-frequency repetitive transcranial magnetic stimulation has a more significant effect.In terms of improving gait,transcranial direct current stimulation has more advantages.
3.Effects of different neuromodulatory stimulation modalities on non-motor symptoms in Parkinson's patients:a network meta-analysis
Xiaoxuan LENG ; Yuxin ZHAO ; Xihua LIU
Chinese Journal of Tissue Engineering Research 2026;30(5):1282-1293
OBJECTIVE:It has been confirmed that neuromodulation technology can improve the clinical symptoms of patients with Parkinson's disease,and there are differences in the efficacy of different neuromodulation stimulation methods.Herein,a network meta-analysis was used to evaluate the efficacy of different neuromodulation stimulation modalities in improving non-motor symptoms such as sleep disorders and depression and anxiety in patients with Parkinson's disease,thereby exploring the optimal neuromodulation stimulation regimen.METHODS:The Chinese Biomedical Literature Database,WanFang Database,VIP Database,CNKI Database,Web of Science,PubMed,The Cochrane Library,and EMbase databases were searched for randomized controlled trials on neuromodulation techniques to improve sleep disorders,depression and anxiety in patients with Parkinson's disease.The control group was treated with conventional treatments(drugs,conventional rehabilitation therapy,etc.)or sham stimulation,and the experimental group was supplemented with neuromodulation technology on the basis of the control group.The quality of the included studies was evaluated using the PEDro scale and the deviation risk assessment tool recommended by the Cochrane Collaboration.RevMan 5.4 and Stata 17.0 were used for network meta-analysis of the four outcomes(sleep disorders,anxiety symptoms,depressive symptoms,and quality of life).RESULTS:(1)Twenty-nine randomized controlled trials involving six neuromodulation stimulation modalities were included.These modalities were transcranial direct current stimulation,high-frequency repetitive transcranial magnetic stimulation,low-frequency repetitive transcranial magnetic stimulation,deep brain stimulation of the subthalamic nucleus,deep brain stimulation of the globus pallidus,multi-target deep brain stimulation.(2)The results of network meta-analysis showed that compared with conventional treatment,transcranial direct current stimulation[standardized mean difference(SMD)=-2.57,95%confidence interval(CI)=-4.52 to-0.63,P<0.05)had the best effect in improving sleep disorders in patients with Parkinson's disease.In terms of improving depressive symptoms,deep brain stimulation of the globus pallidus(SMD=-1.00,95%CI=-1.87 to-0.14,P<0.05)had the best effect,followed by low-frequency repetitive transcranial magnetic stimulation(SMD=-0.91,95%CI=-1.60 to-0.23,P<0.05),deep brain stimulation of the subthalamic nucleus(SMD=-0.82,95%CI=-1.56 to-0.08,P<0.05),and high-frequency repetitive transcranial magnetic stimulation(SMD=-0.75,95%CI=-0.97 to-0.53,P<0.05).In terms of improving anxiety symptoms,high-frequency repetitive transcranial magnetic stimulation(SMD=-0.86,95%CI=-1.54 to-0.18,P<0.05)had the best effect.In terms of improving the quality of life,deep brain stimulation of the globus pallidus(SMD=-0.79,95%CI=-1.55 to-0.04,P<0.05)had the best efficacy,followed by high-frequency repetitive transcranial magnetic stimulation(SMD=-0.63,95%CI=-0.90 to-0.36,P<0.05)and transcranial direct current stimulation(SMD=-0.50,95%CI=-0.80 to-0.19,P<0.05).CONCLUSION:Neuromodulation technology has significant efficacy in improving non-motor symptoms in patients with Parkinson's disease.Transcranial direct current stimulation has the best efficacy in improving sleep disorders,deep electrical stimulation of the medial cerebral part of the globus pallidus has the best efficacy in improving depressive symptoms,high-frequency repetitive transcranial magnetic stimulation has the best efficacy in improving anxiety symptoms,and deep electrical stimulation of the globus pallidus has the best efficacy in improving quality of life.
4.Effects of different neuromodulatory stimulation modalities on non-motor symptoms in Parkinson's patients:a network meta-analysis
Xiaoxuan LENG ; Yuxin ZHAO ; Xihua LIU
Chinese Journal of Tissue Engineering Research 2026;30(5):1282-1293
OBJECTIVE:It has been confirmed that neuromodulation technology can improve the clinical symptoms of patients with Parkinson's disease,and there are differences in the efficacy of different neuromodulation stimulation methods.Herein,a network meta-analysis was used to evaluate the efficacy of different neuromodulation stimulation modalities in improving non-motor symptoms such as sleep disorders and depression and anxiety in patients with Parkinson's disease,thereby exploring the optimal neuromodulation stimulation regimen.METHODS:The Chinese Biomedical Literature Database,WanFang Database,VIP Database,CNKI Database,Web of Science,PubMed,The Cochrane Library,and EMbase databases were searched for randomized controlled trials on neuromodulation techniques to improve sleep disorders,depression and anxiety in patients with Parkinson's disease.The control group was treated with conventional treatments(drugs,conventional rehabilitation therapy,etc.)or sham stimulation,and the experimental group was supplemented with neuromodulation technology on the basis of the control group.The quality of the included studies was evaluated using the PEDro scale and the deviation risk assessment tool recommended by the Cochrane Collaboration.RevMan 5.4 and Stata 17.0 were used for network meta-analysis of the four outcomes(sleep disorders,anxiety symptoms,depressive symptoms,and quality of life).RESULTS:(1)Twenty-nine randomized controlled trials involving six neuromodulation stimulation modalities were included.These modalities were transcranial direct current stimulation,high-frequency repetitive transcranial magnetic stimulation,low-frequency repetitive transcranial magnetic stimulation,deep brain stimulation of the subthalamic nucleus,deep brain stimulation of the globus pallidus,multi-target deep brain stimulation.(2)The results of network meta-analysis showed that compared with conventional treatment,transcranial direct current stimulation[standardized mean difference(SMD)=-2.57,95%confidence interval(CI)=-4.52 to-0.63,P<0.05)had the best effect in improving sleep disorders in patients with Parkinson's disease.In terms of improving depressive symptoms,deep brain stimulation of the globus pallidus(SMD=-1.00,95%CI=-1.87 to-0.14,P<0.05)had the best effect,followed by low-frequency repetitive transcranial magnetic stimulation(SMD=-0.91,95%CI=-1.60 to-0.23,P<0.05),deep brain stimulation of the subthalamic nucleus(SMD=-0.82,95%CI=-1.56 to-0.08,P<0.05),and high-frequency repetitive transcranial magnetic stimulation(SMD=-0.75,95%CI=-0.97 to-0.53,P<0.05).In terms of improving anxiety symptoms,high-frequency repetitive transcranial magnetic stimulation(SMD=-0.86,95%CI=-1.54 to-0.18,P<0.05)had the best effect.In terms of improving the quality of life,deep brain stimulation of the globus pallidus(SMD=-0.79,95%CI=-1.55 to-0.04,P<0.05)had the best efficacy,followed by high-frequency repetitive transcranial magnetic stimulation(SMD=-0.63,95%CI=-0.90 to-0.36,P<0.05)and transcranial direct current stimulation(SMD=-0.50,95%CI=-0.80 to-0.19,P<0.05).CONCLUSION:Neuromodulation technology has significant efficacy in improving non-motor symptoms in patients with Parkinson's disease.Transcranial direct current stimulation has the best efficacy in improving sleep disorders,deep electrical stimulation of the medial cerebral part of the globus pallidus has the best efficacy in improving depressive symptoms,high-frequency repetitive transcranial magnetic stimulation has the best efficacy in improving anxiety symptoms,and deep electrical stimulation of the globus pallidus has the best efficacy in improving quality of life.
5.Research progress on the therapeutic roles and mechanisms of hydrogen-rich water in periodontitis
LIU Fushuang ; WEI Xiaoxuan ; ZHOU Jianpeng ; WANG Jun
Journal of Prevention and Treatment for Stomatological Diseases 2025;33(1):68-74
Hydrogen-rich water (HRW) shows excellent antibacterial, anti-inflammatory, antioxidant, and wound-healing properties and plays a positive role in the treatment of various diseases, such as brain injury, kidney injury, and periodontitis. Current studies found that HRW can inhibit periodontopathogenic biofilm formation, inhibit oral connective tissue and bone tissue destruction, and show anti-inflammatory and antioxidant properties in periodontitis. Additionally, HRW can alleviate periodontal tissue damage by inhibiting oxidative stress and up-regulating the expression of antioxidant enzymes, such as glutathione peroxidase and superoxide dismutase. HRW exerts anti-inflammatory effects by regulating the nuclear factor erythroid 2-related factor 2 and mitogen-activated protein kinase pathways, which are closely associated with inflammation. Additionally, HRW inhibits the expression of inflammatory cytokines, such as interleukins, inhibits the growth and proliferation of bacterial plaque biofilms, and down-regulates glycosyltransferases and glucan-binding proteins to prevent bacterial adhesion and subsequent development of periodontitis. Furthermore, HRW has a positive effect on the expression of various cell growth factors, α-smooth muscle actin, and type I collagen, which promotes wound healing. Current clinical studies have demonstrated the biological safety of HRW (to a certain extent) and reported no adverse reactions. However, most studies on HRW in oral diseases are preclinical in vivo and in vitro studies. Therefore, further clinical studies are required to validate the therapeutic significance and optimal therapeutic regimen of HRW in human periodontitis. This article aims to review the therapeutic role and the underlying mechanisms of HRW in periodontitis.
6.Treating Blood-Bi-Syndrome from the Perspective of Theories of Classical Prescriptions Yindan and Yangdan Formulas
Guiwei SU ; Shiya HUANG ; Tianlin WANG ; Chang LIU ; Jiadong XU ; Xiaoxuan ZHANG
Journal of Guangzhou University of Traditional Chinese Medicine 2025;42(11):2883-2887
Blood-bi-syndrome is primarily characterized by localized numbness and mild pain in the limbs.Records about the diagnosis and treatment of blood-bi-syndrome are scattered throughout classical medical literature.According to the theory of Yindan and Yangdan formulas in the classical prescription system,when the body's ascending function of qi movement is insufficiency,Yangdan formulas which contain Astragali Radix can be used for warming and uplifting yang qi.Conversely,when the descending function of qi movement is insufficiency,Yindan formulas which contain containing Bupleuri Radix can be used for astringing,descending,clearing and purging.This article,based on the principles of Yindan and Yangdan formulas,analyzed the fundamental pathogenesis of blood-bi-syndrome developing from the transmission of superficial syndromes,as well as its clinical manifestations during the transmission and change between taiyin disease and yangming disease.And the therapeutic strategies for blood-bi-syndrome were also summarized.It is proposed that taiyin blood-bi-syndrome arises in individuals with constitutionally deficient cold after the attack of pathogenic factors,resulting from fluid depletion,blood insufficiency,and stomach deficiency,which should be treated by Yangdan Formulas with pungent-sweet-warm properties for warming and uplifting yang qi.For the treatment of patients with taiyin blood-bi-syndrome characterized by exterior syndrome,Astragali Radix-containing classical prescriptions like Astragali Radix and Cinnamomi Ramulus Five-Component Decoction(Huangqi Guizhi Wuwu Decoction)can be chosen;for the treatment of patients with taiyin blood-bi-syndrome characterized by interior syndrome,Zingiberis Rhizoma Recens-containing classical prescriptions like Citri Reticulatae Pericarpium and Bambusae Caulis in Taenia Decoction(Jupi Zhuru Decoction)is adopted.Conversely,yangming blood-bi-syndrome occurs in individuals with constitutionally excessive heat after the attack of pathogenic factors,resulting from the internal accumulation of blood stasis and heat and the impairment of the fluid and blood,which should be treated by Yindan Formulas with pungent-sweet-cold or sour-cold properties for astringing,descending,clearing and purging.For the treatment of patients with yangming blood-bi-syndrome characterized by exterior syndrome,Puerariae Lobatae Radix-containing classical prescriptions like Phyllostachydis Henonis Folium and Puerariae Lobatae Radix Decoction(Zhuye Gegen Decoction)can be used;for the treatment of patients with yangming blood-bi-syndrome characterized by interior syndrome,Paeoniae Radix Alba-containing classical prescriptions like Rhei Radix et Rhizoma and Eupolyphaga seu Steleophaga Decoction(Dahuang Zhechong Wan)is recommended.
7.Exploration of Rat Fetal Lung Tissue Fixation Methods
Liyu LIU ; Bo JI ; Xiaoxuan LIU ; Yang FANG ; Ling ZHANG ; Tingting GUO ; Ye QUAN ; Hewen LI ; Yitian LIU
Laboratory Animal and Comparative Medicine 2025;45(4):432-438
ObjectiveThis study explores the methods of lung tissue extraction and fixation required for pathological studies of fetal rats, based on the unique physiological structure of fetal rat lung tissue and existing lung tissue fixation techniques for adult rats. MethodsSix pregnant adult SD rats at 20.5 days of gestation were subjected to cesarean section to obtain fetal rats. Four healthy fetal rats with similar body weight, vital signs, and respiratory status were selected from each pregnant rat, and they were randomly divided into the following groups using a random number table: direct lung infiltration group, lung infiltration group after intratracheal infusion, whole-body infiltration group of fetal rats, and whole-body infiltration group after intratracheal infusion of fetal rats. To systematically compare and analyze the anatomical morphology under different fixation methods, lung tissues from four groups of fetal rats were harvested, perfused, and fixed, and the gross morphology of lung tissues in each group was observed. Paraffin sections were prepared and stained with Hematoxylin-Eosin (H&E). The histological morphology of the whole lung, alveoli, and bronchi was further examined under optical microscopy. ResultsIn the direct lung infiltration group, the hilar structures were unclear, lung lobation was indistinct, the shape was irregular, lung cavities were small, and alveoli and bronchi were shrunken. In the lung infiltration group after intratracheal infusion, the hilar structures were clear, lobation was pronounced, the shape was regular, lung cavities were large, and alveoli and bronchi were full. Both the whole-body infiltration group and whole-body infiltration group after intratracheal infusion of fetal rats exhibited visible lungs, hearts, skins, and other organs. The lung tissues of both groups showed obvious lobulation, irregular shape, and damage at the margins of lung lobes. In the whole-body infiltration group, the thoracic cavities of the fetus were flattened, lung cavities were small, and alveoli and bronchi were shrunken. In the whole-body infiltration group after intratracheal infusion of fetal rats, the fetal thoracic cavities were full, lung cavities were large, and alveoli and bronchi were relatively full. ConclusionThe lung infiltration after intratracheal infusion method for fetal rat lung tissue fixation outperforms direct lung infiltration, whole-body infiltration of fetal rats, and whole-body infiltration after intratracheal infusion of fetal rats in terms of preservation of the lung tissue's original morphology, paraffin sectioning, staining, and pathological observation and analysis. The embedding, sectioning, and staining processes are also simple and save consumables. Therefore, intratracheal infusion followed by lung infiltration method is recommended for fixation in histopathological observation of fetal rat lung tissue.
8.Cinnamaldehyde inhibits growth, metastasis and induces apoptosis of human endometriotic cells through RPS7
Xiaoxuan Zhan ; Chengyi Liu ; Jiahua Peng ; Shuzhen Liu ; Xin Li ; Yunying Ren ; Danni Chen ; Peishuang Li ; Ruining Liang
Acta Universitatis Medicinalis Anhui 2025;60(3):405-413
Objective :
To investigate the effects of cinnamaldehyde(CA) on the growth, metastasis and apoptosis of human endometriosis(EMs) cells and to explore whether the mechanism is related to ribosomal protein S7(RPS7) expression.
Methods :
Endometriosis cells were divided into control group, CA group, sh-NC group, CA+sh-RPS7 group. Effects of CA on cell growth in human endometriotic cells were determined using Cell Counting Kit-8(CCK-8) and colony formation assay. Effects of CA on cell metastasis were performed by motility assay and Transwell assay. Effects of CA on cell apoptosis were evaluated by Hoechst 33258 staining and flow cytometry. Meanwhile, the levels of PCNA, E-cadherin, Vimentin, Bax and Bcl-2 were evaluated using Western blot in human endometriotic cells with treatment CA. The expression of RPS7 was detected by qRT-PCR and Western blot assay. The RPS7 overexpression of human endometriotic cells was established by cell transfection. CA-mediated effects on cell proliferation and apoptosis were determined by CCK-8 assay and flow cytometry in human endometriotic cells with RPS7 overexpression.
Results :
CA repressed cell growth as well as down-regulated PCNA. The half inhibitory concentration(IC50) value was 53.60 μmol/L after 24 h treatment, and colony formation rate was 25.32%. Additionally, CA inhibited metastasis which was associated with downregulated Vimentin and upregulated E-cadherin. The relative migration rates were 35% and 29% as well as invasion rate was 40%. Further, CA induced apoptosis by cell cycle G2/M phase arrest and cell apoptosis rate was 25.1%, which related to the up-regulation of of Bax and the down-regulation of Bcl-2. CA inhibited the expression of RPS7 and overexpression of RPS7 promoted cell proliferation and suppressed apoptosis in CA-mediated cells.
Conclusion
CA inhibits cell growth, metastasis, and induces cell apoptosis by downregulating the expression of RPS7.
9.Professor TONG Xiaolin's Experience in Treating Prediabetes with Overweight and Obesity Using the Method of Relieving Depression and Reducing Turbidity
Sicheng WANG ; Yangyang LIU ; Yan YAN ; Zishan JIN ; Boxun ZHANG ; Qingwei LI ; Xiaoxuan XU ; Linhua ZHAO ;
Journal of Traditional Chinese Medicine 2025;66(14):1424-1427
To summarise the clinical experience of Professor TONG Xiaolin in treating prediabetes combined with overweight or obesity using the method of relieving depression and reducing turbidity. It is believed that prediabetes belongs to the category of "spleen-heat syndrome" in traditional Chinese medicine, and its core pathogenesis is center fullness with internal heat, while obesity is the initiating factor for exacerbating center fullness and internal heat, therefore, it is of great significance to reduce the risk of diabetes by interrupting the transformation between overweight, obesity and glucose metabolism abnormality. It is proposed that the main pathogenesis of prediabetes combined with overweight or obesity is qi depression and turbidity obstruction in middle jiao, with qi depression as the root and turbidity obstruction as the cause, forming a treatment idea with the method of relieving depression and reducing turbidity as the core. In clinic, Dahuang Huanglian Xiexin Decoction (大黄黄连泻心汤) is used as the basic prescription, with a primary focus on directing the turbid downward, supplemented by regulating qi, which embodies the concept of "promoting movement through descent, then figuring out the root of spleen-heat syndrome. Furthermore, the treatment is flexibly modified based on the patient's deficiency-excess syndrome to ensure individualized therapy.
10.Different exercise modalities promote functional recovery after peripheral nerve injury
Xiaoxuan ZHAO ; Shuaiyi LIU ; Qi LI ; Zheng XING ; Qingwen LI ; Xiaolei CHU
Chinese Journal of Tissue Engineering Research 2025;29(6):1248-1256
BACKGROUND:Exercise as a form of active rehabilitation can improve the dysfunction caused by peripheral nerve injury,and different exercise modalities target different lesion sites and recovery mechanisms. OBJECTIVE:To comprehensively analyze the application and mechanisms of different exercise modalities in functional recovery from peripheral nerve injury. METHODS:A computerized search was conducted in PubMed and CNKI databases for relevant literature published before January 2024.The search terms used were"peripheral nerve injury,spinal cord,exercise,cerebral cortex,muscle atrophy,mirror therapy,blood flow restriction training"in both English and Chinese.Finally,77 articles were included for review. RESULTS AND CONCLUSION:Peripheral nerve injury can cause systemic pathological changes such as skeletal muscle atrophy,corresponding spinal cord segmental lesions,and sensorimotor cortex remodeling.Aerobic exercise can improve dysfunction by enhancing the immune response,promoting glial cell polarization,and promoting the release of nerve growth factor.Blood flow restriction exercise can regulate the secretion of muscle growth factor,promote muscle growth and enhance muscle strength.Mirror movement has a good effect in activating the cerebral cortex and reducing cortical remodeling.Different exercise modalities have potential benefits in functional recovery after peripheral nerve injury;however,there are still some problems and challenges,such as the choice of exercise modalities,the control of exercise intensity and frequency,and the detailed analysis of mechanisms.


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