Neurotherapeutics最新文献

{"title":"Intranasal administration of mesenchymal stem cells overexpressing FGF21 demonstrates therapeutic potential in experimental Parkinson's disease.","authors":"You-Yen Lin, De-Maw Chuang, Cheng-Yu Chi, Shih-Ya Hung","doi":"10.1016/j.neurot.2024.e00501","DOIUrl":"https://doi.org/10.1016/j.neurot.2024.e00501","url":null,"abstract":"<p><p>Parkinson's disease (PD) is a prevalent movement disorder characterized by mitochondrial dysfunction and dopaminergic neuronal loss in the substantia nigra of the midbrain. Currently, there are no effective treatments to cure or slow the progression of PD, highlighting an urgent need for new therapeutic strategies. Emerging evidence suggests that mesenchymal stem cells (MSCs) and fibroblast growth factor 21 (FGF21) are potential candidates for PD treatment. This study investigates a therapeutic strategy involving FGF21 delivered via mouse MSCs in the PD model of mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and dopaminergic SH-SY5Y cells exposed to 1-methyl-4-phenylpyridinium (MPP⁺). FGF21-overexpressing MSCs were administered intranasally, either before or after MPTP treatment in mice. Intranasally delivered FGF21-overexpressing MSCs efficiently migrated to the injured substantia nigra, ameliorated MPTP-induced PD-like motor deficits, reinstated dopaminergic neurons in the substantia nigra and nerve terminals in the striatum, as well as normalized brain-derived neurotrophic factor (BDNF) and FGF21 levels. In contrast, MSCs not overexpressing FGF21 showed limited or no impact on these parameters. In a PD cellular model of MPP⁺-treated SH-SY5Y cells, FGF21-overexpressing MSCs showed enhanced PD cell viability. Treatment with conditioned medium from FGF21-overexpressing MSCs or exogenous FGF21 prevented cell death, reduced mitochondrial reactive oxygen species (ROS), and restored neuroprotective proteins, including phospho-Akt, BDNF, and Bcl-2. These findings indicate that intranasal delivery of FGF21-overexpressing MSCs holds promise as a potential PD therapy, likely through activating the Akt-BDNF-Bcl-2 pathway, normalizing mitochondrial dysfunction, and mitigating dopaminergic neurodegeneration. Further clinical investigations are essential to validate these promising findings.</p>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":" ","pages":"e00501"},"PeriodicalIF":5.6,"publicationDate":"2024-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142751396","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dehydroervatamine as a promising novel TREM2 agonist, attenuates neuroinflammation.","authors":"Lin Li, Nan Xu, Yulin He, Mingsui Tang, Binrui Yang, Jun Du, Liang Chen, Xiaowen Mao, Bing Song, Zhou Hua, Benqin Tang, Simon Ming-Yuen Lee","doi":"10.1016/j.neurot.2024.e00479","DOIUrl":"https://doi.org/10.1016/j.neurot.2024.e00479","url":null,"abstract":"<p><p>Microglia play a dual role in neuroinflammatory disorders that affect millions of people worldwide. These specialized cells are responsible for the critical clearance of debris and toxic proteins through endocytosis. However, activated microglia can secrete pro-inflammatory mediators, potentially exacerbating neuroinflammation and harming adjacent neurons. TREM2, a cell surface receptor expressed by microglia, is implicated in the modulation of neuroinflammatory responses. In this study, we investigated if and how Dehydroervatamine (DHE), a natural alkaloid, reduced the inflammatory phenotype of microglia and suppressed neuroinflammation. Our findings revealed that DHE was directly bound to and activated TREM2. Moreover, DHE effectively suppressed the production of pro-inflammatory cytokines, restored mitochondrial function, and inhibited NLRP3 inflammasome activation via activating the TREM2/DAP12 signaling pathway in LPS-stimulated BV2 microglial cells. Notably, silencing TREM2 abolished the suppression effect of DHE on the neuroinflammatory response, mitochondrial dysfunction, and NF-κB/NLRP3 pathways in vitro. Additionally, DHE pretreatment exhibited remarkable neuroprotective effects, as evidenced by increased neuronal viability and reduced apoptotic cell numbers in SH-SY5Y neuroblastoma cells co-cultured with LPS-stimulated BV2 microglia. Furthermore, in our zebrafish model, DHE pretreatment effectively alleviated behavioral impairments, reduced neutrophil aggregation, and suppressed neuroinflammation in the brain by regulating TREM2/NF-κB/NLRP3 pathways after intraventricular LPS injection. These findings provide novel insights into the potent protective effects of DHE as a promising novel TREM2 agonist against LPS-induced neuroinflammation, revealing its potential therapeutic role in the treatment of central nervous system diseases associated with neuroinflammation.</p>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":" ","pages":"e00479"},"PeriodicalIF":5.6,"publicationDate":"2024-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142751395","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Small molecule modulation of p75^NTR engages the autophagy-lysosomal pathway and reduces huntingtin aggregates in cellular and mouse models of Huntington's disease.","authors":"Danielle A Simmons, Namitha Alexander, Gloria Cao, Ido Rippin, Yarine Lugassy, Hagit Eldar-Finkelman, Frank M Longo","doi":"10.1016/j.neurot.2024.e00495","DOIUrl":"https://doi.org/10.1016/j.neurot.2024.e00495","url":null,"abstract":"<p><p>Huntington's disease (HD) is a neurodegenerative disorder caused by a CAG repeat expansion in the HTT gene encoding a mutant huntingtin (mHtt) protein. mHtt aggregates within neurons causing degeneration primarily in the striatum. There is currently a need for disease-modifying treatments for HD. Many therapeutic studies have focused on lowering mHtt levels by reducing its production or enhancing its clearance. One way to clear mHtt aggregates is to promote autophagy, which is disrupted in HD. Our previous studies showed that the small molecule p75 neurotrophin receptor (p75^NTR) ligand, LM11A-31, prevented HD-related neuropathologies and behavioral deficits in multiple HD mouse models. This study investigated whether modulating p75^NTR with LM11A-31, would reduce mHtt aggregates via autophagic/lysosomal mechanisms in HD models. LM11A-31 decreased mHtt aggregates in human neuroblastoma SH-SY5Y cells expressing mHtt (exon 1 with 74 CAG repeats) and in the striatum of R6/2 and zQ175dn mouse models of HD. The LM11A-31 associated decrease in mHtt aggregates in vitro was accompanied by increased autophagic/lysosomal activity as indicated by altered levels of relevant markers including p62/SQSTM1 and the lysosomal protease, mature cathepsin D, and increased autophagy flux. In R6/2 and/or zQ175dn striatum, LM11A-31 increased AMPK activation, normalized p62/SQSTM1 and LC3II levels, and enhanced LAMP1 and decreased LC3B association with mHtt. Thus, LM11A-31 reduces mHtt aggregates and may do so via engaging autophagy/lysosomal systems. LM11A-31 has successfully completed a Phase 2a clinical trial for mild-to-moderate Alzheimer's disease and our results here strengthen its potential as a candidate for HD clinical testing.</p>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":" ","pages":"e00495"},"PeriodicalIF":5.6,"publicationDate":"2024-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142731119","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abdominal ultrasound stimulation alleviates DSS-induced colitis and behavioral disorders in mice by mediating the microbiota-gut-brain axis balance.","authors":"Cong-Yong Gao, Yi-Ju Pan, Wei-Shen Su, Chun-Yi Wu, Ting-Yu Chang, Feng-Yi Yang","doi":"10.1016/j.neurot.2024.e00494","DOIUrl":"https://doi.org/10.1016/j.neurot.2024.e00494","url":null,"abstract":"<p><p>Inflammatory bowel disease (IBD) has the potential to induce neuroinflammation, which may increase the risk of developing neurodegenerative disorders. Ultrasound stimulation to the abdomen is a potential treatment for dextran sulfate sodium (DSS)-induced acute colitis. The present study aimed to investigate whether abdominal low-intensity pulsed ultrasound (LIPUS) can alleviate DSS-induced neuroinflammation through the microbiota-gut-brain axis. Male mice were fed DSS to induce ulcerative colitis. LIPUS stimulation was then applied to the abdomen at intensities of 0.5 and 1.0 ​W/cm². Mouse biological samples were analyzed, and behavior was evaluated. [¹⁸F]FEPPA PET/CT imaging was employed to track and quantify inflammation in the abdomen and brain. Changes in the gut microbiota composition were analyzed using 16S rRNA sequencing. Abdominal LIPUS significantly inhibited the DSS-induced inflammatory response, repaired destroyed crypts, and partially preserved the epithelial barrier. [¹⁸F]FEPPA accumulation in the colitis-induced neuroinflammation in the abdomen and specific brain regions significantly decreased after LIPUS treatment. LIPUS maintained intestinal integrity by increasing zonula occludens and occludin levels, reduced lipopolysaccharide-binding protein and lipopolysaccharide levels in the serum, and improved behavioral dysfunctions. Moreover, LIPUS, at an intensity of 0.5 ​W/cm², reshaped the gut microbiota in colitis-induced mice by increasing the relative abundance of the Firmicutes and decreasing the relative abundance of the Bacteroidota. Our findings demonstrated that abdominal LIPUS stimulation has the potential to be a novel therapeutic strategy to improve colitis-induced behavioral disorders through microbiota-gut-brain axis signaling.</p>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":" ","pages":"e00494"},"PeriodicalIF":5.6,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142695080","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Intrathecal administration of Anti-Nogo-A antibody in macaque monkeys: Pharmacokinetics, tissue penetration and target interaction.","authors":"Pascal B Kunz, Michael A Maurer, Jannik Vollmer, Matthias Machacek, Oliver Weinmann, Jelena Klisic, Martin E Schwab","doi":"10.1016/j.neurot.2024.e00484","DOIUrl":"https://doi.org/10.1016/j.neurot.2024.e00484","url":null,"abstract":"<p><p>Intrathecal drug administration represents a promising method to deliver biologics effectively to the central nervous system (CNS). However, little is known about the tolerability and pharmacokinetics of intrathecally applied antibodies. Hence, the focus of this study was to evaluate the toxicity, pharmacokinetic, and pharmacodynamic properties of an intrathecally administered human monoclonal antibody against the growth inhibitory CNS membrane protein Nogo-A in the non-human primate (NHP). The antibody was repeatedly injected into the lumbar cerebrospinal fluid (CSF) sack of NHPs, Macaca fascicularis (N ​= ​18), at three dose levels (placebo, 75 and 150 ​mg antibody/injection, n ​= ​6/group). CSF and serum samples were collected for pharmacokinetic analysis. The health status was constantly monitored to detect any treatment-related abnormalities. After sacrifice, the CNS tissues were evaluated by immunohistochemistry and biochemistry to study the antibody distribution and target interaction in the spinal cord and brain. No treatment-related side effects were observed, and the treatment was well tolerated by NHPs. After administration, the antibody was rapidly cleared from the CSF with a half-life of 6.4 ​h and accumulated in the serum where it showed a half-life of 13.7 days. The antibody distributed over the spinal cord and brain, penetrated into the CNS parenchyma where it bound to Nogo-A expressing neurons and oligodendrocytes, and induced significant (P ​< ​0.05) downregulation of the target antigen Nogo-A. Collectively, these results support the direct administration of therapeutic antibodies into the CSF and are of relevance for the antibody-based therapeutics currently in development for different CNS diseases.</p>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":" ","pages":"e00484"},"PeriodicalIF":5.6,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142686750","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"From defense to disease: IFITM3 in immunity and Alzheimer's disease.","authors":"Zoe Kehs, Abigail C Cross, Yue-Ming Li","doi":"10.1016/j.neurot.2024.e00482","DOIUrl":"https://doi.org/10.1016/j.neurot.2024.e00482","url":null,"abstract":"<p><p>Innate immunity protein interferon induced transmembrane protein 3 (IFITM3) is a transmembrane protein that has a wide array of functions, including in viral infections, Alzheimer's Disease (AD), and cancer. As an interferon stimulated gene (ISG), IFITM3's expression is upregulated by type-I, II, and III interferons. Moreover, the antiviral activity of IFITM3 is modulated by post-translational modifications. IFITM3 functions in innate immunity to disrupt viral fusion and entry to the plasma membrane as well as prevent viral escape from endosomes. As a γ-secretase modulatory protein, IFITM3 distinctly modulates the processing of amyloid precursor protein (APP) to generate amyloid beta peptides (Aβ) and Notch1 cleavages. Increased IFITM3 expression, which can result from aging, cytokine activation, inflammation, and infection, can lead to an upregulation of γ-secretase for Aβ production that causes a risk of AD. Therefore, the prevention of IFITM3 upregulation has potential in the development of novel therapies for the treatment of AD.</p>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":" ","pages":"e00482"},"PeriodicalIF":5.6,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142624489","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Differential analgesic effects of high-frequency or accelerated intermittent theta burst stimulation of M1 on experimental tonic pain: Correlations with cortical activity changes assessed by TMS-EEG","authors":"Bolin Tan ,&nbsp;Jielin Chen ,&nbsp;Ying Liu ,&nbsp;Qiuye Lin ,&nbsp;Ying Wang ,&nbsp;Shuyan Shi ,&nbsp;Yang Ye ,&nbsp;Xianwei Che","doi":"10.1016/j.neurot.2024.e00451","DOIUrl":"10.1016/j.neurot.2024.e00451","url":null,"abstract":"<div><div>Accelerated intermittent theta burst stimulation (AiTBS) has attracted much attention in the past few years as a new form of brain stimulation paradigm. However, it is unclear the relative efficacy of AiTBS on cortical excitability compared to conventional high-frequency rTMS. Using concurrent TMS and electroencephalogram (TMS-EEG), this study systematically compared the efficacy on cortical excitability and a typical clinical application (i.e. pain), between AiTBS with different intersession interval (ISIs) and 10-Hz rTMS. Participants received 10-Hz rTMS, AiTBS-15 (3 iTBS sessions with a 15-min ISI), AiTBS-50 (3 iTBS sessions with a 50-min ISI), or Sham stimulation over the primary motor cortex on four separate days. All four protocols included a total of 1800 pulses but with different session durations (10-Hz rTMS ​= ​18, AiTBS-15 ​= ​40, and AiTBS-50 ​= ​110 ​min). AiTBS-50 and 10-Hz rTMS were more effective in pain reduction compared to AiTBS-15. Using single-pulse TMS-induced oscillation, our data revealed low gamma oscillation as a shared cortical excitability change across all three active rTMS protocols but demonstrated completely opposite directions. Changes in low gamma oscillation were further associated with changes in pain perception across the three active conditions. In contrast, a distinct pattern of TMS-evoked potentials (TEPs) was revealed, with 10-Hz rTMS decreasing inhibitory N100 amplitude and AiTBS-15 reducing excitatory P60 amplitude. These changes in TEPs were also covarying with low gamma power changes. Sham stimulation indicated no significant effect on either cortical excitability or pain perception. These results are relevant only for provoked experimental pain, without being predictive for chronic pain, and revealed a change in low gamma oscillation, particularly around the very particular frequency of 40 ​Hz, shared between AiTBS and high-frequency rTMS. Conversely, cortical excitability (balance between excitation and inhibition) assessed by TEP recording was modulated differently by AiTBS and high-frequency rTMS paradigms.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"21 6","pages":"Article e00451"},"PeriodicalIF":5.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142292175","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Retraction notice to: “LncRNA PVT1 facilitates tumorigenesis and progression of Glioma via regulation of MiR-128-3p/GREM1 Axis and BMP signaling pathway” Neurotherapeutics 15 (4) 2018 1139–1157","authors":"Chao Fu ,&nbsp;Dongyuan Li ,&nbsp;Xiaonan Zhang ,&nbsp;Naijie Liu ,&nbsp;Guonan Chi ,&nbsp;Xingyi Jin","doi":"10.1016/j.neurot.2024.e00449","DOIUrl":"10.1016/j.neurot.2024.e00449","url":null,"abstract":"","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"21 6","pages":"Article e00449"},"PeriodicalIF":5.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142350821","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Microbiome-based therapeutics for Parkinson's disease","authors":"Adam M. Hamilton ,&nbsp;Ian N. Krout ,&nbsp;Alexandria C. White ,&nbsp;Timothy R. Sampson","doi":"10.1016/j.neurot.2024.e00462","DOIUrl":"10.1016/j.neurot.2024.e00462","url":null,"abstract":"<div><div>Recent experimental and clinical data demonstrate a significant dysregulation of the gut microbiome in individuals with Parkinson's disease (PD). With an immense influence on all aspects of physiology, this dysregulation has potential to directly or indirectly contribute to disease pathology. Experimental models have bridged these associations toward defined contributions, identifying various microbiome-dependent impacts to PD pathology. These studies have laid the foundation for human translation, examining whether certain members of the microbiome and/or whole restoration of the gut microbiome community can provide therapeutic benefit for people living with PD. Here, we review recent and ongoing clinically-focused studies that use microbiome-targeted therapies to limit the severity and progression of PD. Fecal microbiome transplants, prebiotic interventions, and probiotic supplementation are each emerging as viable methodologies to augment the gut microbiome and potentially limit PD symptoms. While still early, the data in the field to date support continued cross-talk between experimental systems and human studies to identify key microbial factors that contribute to PD pathologies.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"21 6","pages":"Article e00462"},"PeriodicalIF":5.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142406645","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gut microbiota immune cross-talk in amyotrophic lateral sclerosis","authors":"Megha Kaul,&nbsp;Debanjan Mukherjee,&nbsp;Howard L. Weiner,&nbsp;Laura M. Cox","doi":"10.1016/j.neurot.2024.e00469","DOIUrl":"10.1016/j.neurot.2024.e00469","url":null,"abstract":"<div><div>Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by the loss of motor neurons. While there has been significant progress in defining the genetic contributions to ALS, greater than 90 ​% of cases are sporadic, which suggests an environmental component. The gut microbiota is altered in ALS and is an ecological factor that contributes to disease by modulating immunologic, metabolic, and neuronal signaling. Depleting the microbiome worsens disease in the SOD1 ALS animal model, while it ameliorates disease in the C9orf72 model of ALS, indicating critical subtype-specific interactions. Furthermore, administering beneficial microbiota or microbial metabolites can slow disease progression in animal models. This review discusses the current state of microbiome research in ALS, including interactions with different ALS subtypes, evidence in animal models and human studies, key immunologic and metabolomic mediators, and a path toward microbiome-based therapies for ALS.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"21 6","pages":"Article e00469"},"PeriodicalIF":5.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142605716","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}