Translational Neurodegeneration最新文献

{"title":"Cellular senescence in Alzheimer's disease: from physiology to pathology.","authors":"Jing Zhu, Chongyun Wu, Luodan Yang","doi":"10.1186/s40035-024-00447-4","DOIUrl":"https://doi.org/10.1186/s40035-024-00447-4","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is one of the most common neurodegenerative disorders, characterized by the accumulation of Aβ and abnormal tau hyperphosphorylation. Despite substantial efforts in development of drugs targeting Aβ and tau pathologies, effective therapeutic strategies for AD remain elusive. Recent attention has been paid to the significant role of cellular senescence in AD progression. Mounting evidence suggests that interventions targeting cellular senescence hold promise in improving cognitive function and ameliorating hallmark pathologies in AD. This narrative review provides a comprehensive summary and discussion of the physiological roles, characteristics, biomarkers, and commonly employed in vivo and in vitro models of cellular senescence, with a particular focus on various cell types in the brain, including astrocytes, microglia, oligodendrocyte precursor cells, neurons, and endothelial cells. The review further delves into factors influencing cellular senescence in AD and emphasizes the significance of targeting cellular senescence as a promising approach for AD treatment, which includes the utilization of senolytics and senomorphics.</p>","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"13 1","pages":"55"},"PeriodicalIF":10.8,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142682762","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Critical role of ROCK1 in AD pathogenesis via controlling lysosomal biogenesis and acidification.","authors":"Chenghuan Song, Wanying Huang, Pingao Zhang, Jiyun Shi, Ting Yu, Jing Wang, Yongbo Hu, Lanxue Zhao, Rui Zhang, Gang Wang, Yongfang Zhang, Hongzhuan Chen, Hao Wang","doi":"10.1186/s40035-024-00442-9","DOIUrl":"10.1186/s40035-024-00442-9","url":null,"abstract":"<p><strong>Background: </strong>Lysosomal homeostasis and functions are essential for the survival of neural cells. Impaired lysosomal biogenesis and acidification in Alzheimer's disease (AD) pathogenesis leads to proteolytic dysfunction and neurodegeneration. However, the key regulatory factors and mechanisms of lysosomal homeostasis in AD remain poorly understood.</p><p><strong>Methods: </strong>ROCK1 expression and its co-localization with LAMP1 and SQSTM1/p62 were detected in post-mortem brains of healthy controls and AD patients. Lysosome-related fluorescence probe staining, transmission electron microscopy and immunoblotting were performed to evaluate the role of ROCK1 in lysosomal biogenesis and acidification in various neural cell types. The interaction between ROCK1 and TFEB was confirmed by surface plasmon resonance and in situ proximity ligation assay (PLA). Moreover, we performed AAV-mediated ROCK1 downregulation followed by immunofluorescence, enzyme-linked immunosorbent assay (ELISA) and behavioral tests to unveil the effects of the ROCK1-TFEB axis on lysosomes in APP/PS1 transgenic mice.</p><p><strong>Results: </strong>ROCK1 level was significantly increased in the brains of AD individuals, and was positively correlated with lysosomal markers and Aβ. Lysosomal proteolysis was largely impaired by the high abundance of ROCK1, while ROCK1 knockdown mitigated the lysosomal dysfunction in neurons and microglia. Moreover, we verified ROCK1 as a previously unknown upstream kinase of TFEB independent of m-TOR or GSK-3β. ROCK1 elevation resulted in abundant extracellular Aβ deposition which in turn bound to Aβ receptors and activated RhoA/ROCK1, thus forming a vicious circle of AD pathogenesis. Genetically downregulating ROCK1 lowered its interference with TFEB, promoted TFEB nuclear distribution, lysosomal biogenesis and lysosome-mediated Aβ clearance, and eventually prevented pathological traits and cognitive deficits in APP/PS1 mice.</p><p><strong>Conclusion: </strong>In summary, our results provide a mechanistic insight into the critical role of ROCK1 in lysosomal regulation and Aβ clearance in AD by acting as a novel upstream serine kinase of TFEB.</p>","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"13 1","pages":"54"},"PeriodicalIF":10.8,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11533276/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142576622","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TRPV1 alleviates APOE4-dependent microglial antigen presentation and T cell infiltration in Alzheimer's disease.","authors":"Jia Lu, Kexin Wu, Xudong Sha, Jiayuan Lin, Hongzhuan Chen, Zhihua Yu","doi":"10.1186/s40035-024-00445-6","DOIUrl":"10.1186/s40035-024-00445-6","url":null,"abstract":"<p><strong>Background: </strong>Persistent innate and adaptive immune responses in the brain contribute to the progression of Alzheimer's disease (AD). APOE4, the most important genetic risk factor for sporadic AD, encodes apolipoprotein E4, which by itself is a potent modulator of immune response. However, little is known about the immune hub that governs the crosstalk between the nervous and the adaptive immune systems. Transient receptor potential vanilloid type 1 (TRPV1) channel is a ligand-gated, nonselective cation channel with Ca²⁺ permeability, which has been proposed as a neuroprotective target in AD.</p><p><strong>Methods: </strong>Using Ca²⁺-sensitive dyes, dynamic changes of Ca²⁺ in microglia were measured, including exogenous Ca²⁺ uptake and endoplasmic reticulum Ca²⁺ release. The mRFP-GFP-tagged LC3 plasmid was expressed in microglia to characterize the role of TRPV1 in the autophagic flux. Transcriptomic analyses and flow cytometry were performed to investigate the effects of APOE4 on brain microglia and T cells from APOE-targeted replacement mice with microglia-specific TRPV1 gene deficiency.</p><p><strong>Results: </strong>Both APOE4 microglia derived from induced pluripotent stem cells of AD patients and APOE4-related tauopathy mouse model showed significantly increased cholesterol biosynthesis and accumulation compared to their APOE3 counterparts. Further, cholesterol dysregulation was associated with persistent activation of microglia and elevation of major histocompatibility complex II-dependent antigen presentation in microglia, subsequently accompanied by T cell infiltration. In addition, TRPV1-mediated transient Ca²⁺ influx mitigated cholesterol biosynthesis in microglia by suppressing the transcriptional activation of sterol regulatory element-binding protein 2, promoted autophagic activity and reduced lysosomal cholesterol accumulation, which were sufficient to resolve excessive immune response and neurodegeneration in APOE4-related tauopathy mouse model. Moreover, microglia-specific deficiency of TRPV1 gene accelerated glial inflammation, T cell response and associated neurodegeneration in an APOE4-related tauopathy mouse model.</p><p><strong>Conclusions: </strong>The findings provide new perspectives for the treatment of APOE4-dependent neurodegeneration including AD.</p>","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"13 1","pages":"52"},"PeriodicalIF":10.8,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11520887/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142523207","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A tumorigenicity evaluation platform for cell therapies based on brain organoids.","authors":"Jun Xue, Youjun Chu, Yanwang Huang, Ming Chen, Meng Sun, Zhiqin Fan, Yonghe Wu, Liang Chen","doi":"10.1186/s40035-024-00446-5","DOIUrl":"10.1186/s40035-024-00446-5","url":null,"abstract":"<p><strong>Background: </strong>Tumorigenicity represents a critical challenge in stem cell-based therapies requiring rigorous monitoring. Conventional approaches for tumorigenicity evaluation are based on animal models and have numerous limitations. Brain organoids, which recapitulate the structural and functional complexity of the human brain, have been widely used in neuroscience research. However, the capacity of brain organoids for tumorigenicity evaluation needs to be further elucidated.</p><p><strong>Methods: </strong>A cerebral organoid model produced from human pluripotent stem cells (hPSCs) was employed. Meanwhile, to enhance the detection sensitivity for potential tumorigenic cells, we created a glioblastoma-like organoid (GBM organoid) model from TP53^-/-/PTEN^-/- hPSCs to provide a tumor microenvironment for injected cells. Midbrain dopamine (mDA) cells from human embryonic stem cells were utilized as a cell therapy product. mDA cells, hPSCs, mDA cells spiked with hPSCs, and immature mDA cells were then injected into the brain organoids and NOD SCID mice. The injected cells within the brain organoids were characterized, and compared with those injected in vivo to evaluate the capability of the brain organoids for tumorigenicity evaluation. Single-cell RNA sequencing was performed to identify the differential gene expression between the cerebral organoids and the GBM organoids.</p><p><strong>Results: </strong>Both cerebral organoids and GBM organoids supported maturation of the injected mDA cells. The hPSCs and immature mDA cells injected in the GBM organoids showed a significantly higher proliferative capacity than those injected in the cerebral organoids and in NOD SCID mice. Furthermore, the spiked hPSCs were detectable in both the cerebral organoids and the GBM organoids. Notably, the GBM organoids demonstrated a superior capacity to enhance proliferation and pluripotency of spiked hPSCs compared to the cerebral organoids and the mouse model. Kyoto Encyclopedia of Genes and Genomes analysis revealed upregulation of tumor-related metabolic pathways and cytokines in the GBM organoids, suggesting that these factors underlie the high detection sensitivity for tumorigenicity evaluation.</p><p><strong>Conclusions: </strong>Our findings suggest that brain organoids could represent a novel and effective platform for evaluating the tumorigenic risk in stem cell-based therapies. Notably, the GBM organoids offer a superior platform that could complement or potentially replace traditional animal-based models for tumorigenicity evaluation.</p>","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"13 1","pages":"53"},"PeriodicalIF":10.8,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11520457/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142547661","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Elevated plasma and CSF neurofilament light chain concentrations are stabilized in response to mutant huntingtin lowering in the brains of Huntington's disease mice.","authors":"Nicholas S Caron, Lauren M Byrne, Fanny L Lemarié, Jeffrey N Bone, Amirah E-E Aly, Seunghyun Ko, Christine Anderson, Lorenzo L Casal, Austin M Hill, David J Hawellek, Peter McColgan, Edward J Wild, Blair R Leavitt, Michael R Hayden","doi":"10.1186/s40035-024-00443-8","DOIUrl":"https://doi.org/10.1186/s40035-024-00443-8","url":null,"abstract":"<p><strong>Background: </strong>Therapeutic approaches aimed at lowering toxic mutant huntingtin (mHTT) levels in the brain can reverse disease phenotypes in animal models of Huntington's disease (HD) and are currently being evaluated in clinical trials. Sensitive and dynamic response biomarkers are needed to assess the efficacy of such candidate therapies. Neurofilament light chain (NfL) is a biomarker of neurodegeneration that increases in cerebrospinal fluid (CSF) and blood with progression of HD. However, it remains unknown whether NfL in biofluids could serve as a response biomarker for assessing the efficacy of disease-modifying therapies for HD.</p><p><strong>Methods: </strong>Longitudinal plasma and cross-sectional CSF samples were collected from the YAC128 transgenic mouse model of HD and wild-type (WT) littermate control mice throughout the natural history of disease. Additionally, biofluids were collected from YAC128 mice following intracerebroventricular administration of an antisense oligonucleotide (ASO) targeting the mutant HTT transgene (HTT ASO), at ages both before and after the onset of disease phenotypes. NfL concentrations in plasma and CSF were quantified using ultrasensitive single-molecule array technology.</p><p><strong>Results: </strong>Plasma and CSF NfL concentrations were significantly elevated in YAC128 compared to WT littermate control mice from 9 months of age. Treatment of YAC128 mice with either 15 or 50 µg HTT ASO resulted in a dose-dependent, allele-selective reduction of mHTT throughout the brain at a 3-month interval, which was sustained with high-dose HTT ASO treatment for up to 6 months. Lowering of brain mHTT prior to the onset of regional brain atrophy and HD-like motor deficits in this model had minimal effect on plasma NfL at either dose, but led to a dose-dependent reduction of CSF NfL. In contrast, initiating mHTT lowering in the brain after the onset of neuropathological and behavioural phenotypes in YAC128 mice resulted in a dose-dependent stabilization of NfL increases in both plasma and CSF.</p><p><strong>Conclusions: </strong>Our data provide evidence that the response of NfL in biofluids is influenced by the magnitude of mHTT lowering in the brain and the timing of intervention, suggesting that NfL may serve as a promising exploratory response biomarker for HD.</p>","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"13 1","pages":"50"},"PeriodicalIF":10.8,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11460072/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142393566","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ultrasensitive detection of TDP-43 and amyloid-β protein aggregates using micelle-assisted seed amplification assay.","authors":"Sora Sakamoto, Yuichi Riku, Teiko Komori Nomura, Akio Kimura, Naoki Yamahara, Kazuki Ohuchi, Mari Yoshida, Yasushi Iwasaki, Takayoshi Shimohata, Masatoshi Inden, Ryo Honda","doi":"10.1186/s40035-024-00444-7","DOIUrl":"https://doi.org/10.1186/s40035-024-00444-7","url":null,"abstract":"","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"13 1","pages":"51"},"PeriodicalIF":10.8,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11460235/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142393567","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"GCN2 inhibition reduces mutant SOD1 clustering and toxicity and delays disease progression in an amyotrophic lateral sclerosis mouse model.","authors":"Didio Alberto Ortiz, Nuria Peregrín, Miguel Valencia, Rodrigo Vinueza-Gavilanes, Elisa Marín-Ordovas, Roberto Ferrero, María Jesús Nicolás, Gloria González-Aseguinolaza, Montserrat Arrasate, Tomás Aragón","doi":"10.1186/s40035-024-00441-w","DOIUrl":"https://doi.org/10.1186/s40035-024-00441-w","url":null,"abstract":"","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"13 1","pages":"49"},"PeriodicalIF":10.8,"publicationDate":"2024-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11414287/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142296296","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical, mechanistic, biomarker, and therapeutic advances in GBA1-associated Parkinson’s disease","authors":"Xuxiang Zhang, Heng Wu, Beisha Tang, Jifeng Guo","doi":"10.1186/s40035-024-00437-6","DOIUrl":"https://doi.org/10.1186/s40035-024-00437-6","url":null,"abstract":"Parkinson’s disease (PD) is the second most common neurodegenerative disease. The development of PD is closely linked to genetic and environmental factors, with GBA1 variants being the most common genetic risk. Mutations in the GBA1 gene lead to reduced activity of the coded enzyme, glucocerebrosidase, which mediates the development of PD by affecting lipid metabolism (especially sphingolipids), lysosomal autophagy, endoplasmic reticulum, as well as mitochondrial and other cellular functions. Clinically, PD with GBA1 mutations (GBA1-PD) is characterized by particular features regarding the progression of symptom severity. On the therapeutic side, the discovery of the relationship between GBA1 variants and PD offers an opportunity for targeted therapeutic interventions. In this review, we explore the genotypic and phenotypic correlations, etiologic mechanisms, biomarkers, and therapeutic approaches of GBA1-PD and summarize the current state of research and its challenges.","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"56 1","pages":""},"PeriodicalIF":12.6,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142217397","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The microglial P2Y₆ receptor as a therapeutic target for neurodegenerative diseases.","authors":"Jacob M Dundee, Guy C Brown","doi":"10.1186/s40035-024-00438-5","DOIUrl":"10.1186/s40035-024-00438-5","url":null,"abstract":"<p><p>Neurodegenerative diseases are associated with chronic neuroinflammation in the brain, which can result in microglial phagocytosis of live synapses and neurons that may contribute to cognitive deficits and neuronal loss. The microglial P2Y₆ receptor (P2Y₆R) is a G-protein coupled receptor, which stimulates microglial phagocytosis when activated by extracellular uridine diphosphate, released by stressed neurons. Knockout or inhibition of P2Y₆R can prevent neuronal loss in mouse models of Alzheimer's disease (AD), Parkinson's disease, epilepsy, neuroinflammation and aging, and prevent cognitive deficits in models of AD, epilepsy and aging. This review summarises the known roles of P2Y₆R in the physiology and pathology of the brain, and its potential as a therapeutic target to prevent neurodegeneration and other brain pathologies.</p>","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"13 1","pages":"47"},"PeriodicalIF":10.8,"publicationDate":"2024-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11380353/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142146317","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neurodegenerative disorders, metabolic icebergs, and mitohormesis.","authors":"Matthew C L Phillips, Martin Picard","doi":"10.1186/s40035-024-00435-8","DOIUrl":"10.1186/s40035-024-00435-8","url":null,"abstract":"<p><p>Neurodegenerative disorders are typically \"split\" based on their hallmark clinical, anatomical, and pathological features, but they can also be \"lumped\" by a shared feature of impaired mitochondrial biology. This leads us to present a scientific framework that conceptualizes Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD) as \"metabolic icebergs\" comprised of a tip, a bulk, and a base. The visible tip conveys the hallmark neurological symptoms, neurodegenerative regions, and neuronal protein aggregates for each disorder. The hidden bulk depicts impaired mitochondrial biology throughout the body, which is multifaceted and may be subdivided into impaired cellular metabolism, cell-specific mitotypes, and mitochondrial behaviours, functions, activities, and features. The underlying base encompasses environmental factors, especially modern industrial toxins, dietary lifestyles, and cognitive, physical, and psychosocial behaviours, but also accommodates genetic factors specific to familial forms of AD, PD, and ALS, as well as HD. Over years or decades, chronic exposure to a particular suite of environmental and genetic factors at the base elicits a trajectory of impaired mitochondrial biology that maximally impacts particular subsets of mitotypes in the bulk, which eventually surfaces as the hallmark features of a particular neurodegenerative disorder at the tip. We propose that impaired mitochondrial biology can be repaired and recalibrated by activating \"mitohormesis\", which is optimally achieved using strategies that facilitate a balanced oscillation between mitochondrial stressor and recovery phases. Sustainably harnessing mitohormesis may constitute a potent preventative and therapeutic measure for people at risk of, or suffering with, neurodegenerative disorders.</p>","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"13 1","pages":"46"},"PeriodicalIF":10.8,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11378521/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142146305","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}