NeuroImmune pharmacology and therapeutics最新文献

{"title":"Cannabis use, oral dysbiosis, and neurological disorders","authors":"Amber A. Hazzard, Marice K McCrorey, Tabinda Salman, Douglas E. Johnson, Zhenwu Luo, Xiaoyu Fu, Andrew P. Keegan, Andreana Benitez, Sylvia Fitting, Wei Jiang","doi":"10.1515/nipt-2024-0012","DOIUrl":"https://doi.org/10.1515/nipt-2024-0012","url":null,"abstract":"\u0000 Cannabis (marijuana) is a leafy plant that has medical, recreational, and other uses. Cannabis is socially accepted and widely used throughout the United States. Though cannabis use is increasingly gaining popularity, studies detail the deleterious effects of chronic cannabis smoking on mental health, as well as the immunosuppressive properties of cannabinoids. Additionally, oral dysbiosis induced by cannabis smoking serves as a novel catalyst for neurological abnormalities, potentially possible through microbial translocation via the oral-brain axis. This review summarizes the effects and link of smoking cannabis on neurological abnormalities, immunity, and oral microbiome.","PeriodicalId":74278,"journal":{"name":"NeuroImmune pharmacology and therapeutics","volume":"54 48","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141923594","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Biodegradable cannabidiol: a potential nanotherapeutic for neuropathic pain","authors":"Sana Qayum, Rebecca R. Schmitt, Janvhi S. Machhar, Sonali Garg, Caroline Bass, V. Muthaiah, Tracey A. Ignatowski, Supriya D. Mahajan","doi":"10.1515/nipt-2024-0008","DOIUrl":"https://doi.org/10.1515/nipt-2024-0008","url":null,"abstract":"\u0000 Cannabidiol (CBD) is a promising pharmaceutical agent to treat pain, inflammation, and seizures without the psychoactive effects of delta-9-tetrahydrocannabinol (THC). While CBD is highly lipophilic and can cross the blood-brain barrier (BBB), its bioavailability is limited and clearance is quick, limiting its effectiveness in the brain. To improve its effectiveness, we developed a unique nanoformulation consisting of CBD encapsulated within the biodegradable and biocompatible polymer, methoxy polyethylene glycol-poly(lactic-co-glycolic acid) (mPEG-PLGA). mPEG-PLGA-CBD nanoparticles exhibited negligible cytotoxicity over a range of concentrations in CCK-8 assays performed in human astrocytes and brain microvascular endothelial cells. Furthermore, in an in-vitro BBB model, they exhibited rapid BBB permeability without harming BBB integrity. An in vivo Chronic Constriction Injury animal pain model was employed to study the efficacy of mPEG-PLGA-CBD in doses 1, 3 and 10 mg/kg, and it was found that 45–55 nm CBD nanoparticles with an encapsulation efficiency of 65 % can cross the BBB. Additionally, 3 and 10 mg/kg mPEG-PLGA-CBD nanoformulation provided prolonged analgesia in rats on day 2 and -4 post-injection, which we propose is attributed to the sustained and controlled release of CBD. Future studies are required to understand the pharmacokinetics of this nanoformulation.","PeriodicalId":74278,"journal":{"name":"NeuroImmune pharmacology and therapeutics","volume":"6 9","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141807643","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Something to talk about; crosstalk disruption at the neurovascular unit during HIV infection of the CNS","authors":"Kalpani N U Galpayage Dona, Mohammed M. Benmassaoud, Cassandra D. Gipson, Jay P. McLaughlin, Servio H. Ramirez, Allison M. Andrews","doi":"10.1515/nipt-2024-0003","DOIUrl":"https://doi.org/10.1515/nipt-2024-0003","url":null,"abstract":"\u0000 Although treatable with antiretroviral therapy, HIV infection persists in people living with HIV (PLWH). It is well known that the HIV virus finds refuge in places for which antiretroviral medications do not reach therapeutic levels, mainly the CNS. It is clear that as PLWH age, the likelihood of developing HIV-associated neurological deficits increases. At the biochemical level neurological dysfunction is the manifestation of altered cellular function and ineffective intercellular communication. In this review, we examine how intercellular signaling in the brain is disrupted in the context of HIV. Specifically, the concept of how the blood-brain barrier can be a convergence point for crosstalk, is explored. Crosstalk between the cells of the neurovascular unit (NVU) (endothelium, pericytes, astrocytes, microglia and neurons) is critical for maintaining proper brain function. In fact, the NVU allows for rapid matching of neuronal metabolic needs, regulation of blood-brain barrier (BBB) dynamics for nutrient transport and changes to the level of immunosurveillance. This review invites the reader to conceptually consider the BBB as a router or convergence point for NVU crosstalk, to facilitate a better understanding of the intricate signaling events that underpin the function of the NVU during HIV associated neuropathology.","PeriodicalId":74278,"journal":{"name":"NeuroImmune pharmacology and therapeutics","volume":"53 18","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141809856","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sedation with midazolam in the NICU: implications on neurodevelopment","authors":"Nghi M Nguyen, Gurudutt Pendyala","doi":"10.1515/nipt-2024-0009","DOIUrl":"https://doi.org/10.1515/nipt-2024-0009","url":null,"abstract":"\u0000 The developing brain, particularly in premature infants, is highly susceptible to environmental and pharmacological influences. Premature neonates often require prolonged stays in the NICU, where midazolam (MDZ), a benzodiazepine, is commonly used as a sedative, despite concerns raised by the FDA in 2016 regarding its potential neurological complications in infants. Understanding the long-term effects of MDZ on these vulnerable patients is hindered by ethical considerations and limited research. This review emphasizes the vulnerability of premature infants to sedation and anesthesia and outlines how early exposure to MDZ can impact brain development at both molecular and behavioral levels, drawing from clinical and preclinical data. Additionally, we highlighted existing knowledge gaps and suggested avenues for further research to better comprehend the enduring consequences of MDZ exposure on neurodevelopment in this population.","PeriodicalId":74278,"journal":{"name":"NeuroImmune pharmacology and therapeutics","volume":"51 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141806911","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"X-chromosome linked genes associated with myeloid cell CNS trafficking contributes to female–male differences in the disease outcome for neuroinflammatory diseases","authors":"Sopiko Darchiashvili, Ratuja Kulkarni, Ritesh Tandon, Peter Deak, Kayla L. Nguyen, Pooja Jain","doi":"10.1515/nipt-2024-0007","DOIUrl":"https://doi.org/10.1515/nipt-2024-0007","url":null,"abstract":"\u0000 Certain diseases such as Multiple Sclerosis (MS), a chronic demyelinating disease, affect more women than men, despite males appearing to be predisposed to infections and malignancies. X-linked genes contribute to increased MS susceptibility. Currently, an immense body of research exists that explores the complexity surrounding underlying risk factors for MS development including X-chromosome-linked inflammatory processes. Female–male disparities in disease susceptibility have been found at both the gene and chromosomal level. Genes such as CXORF21 and DDX3X can escape X-chromosome inactivation (XCI) and contribute to various disease pathogenesis. Additionally, blocking immune cell entry to the central nervous system (CNS) can have a major impact on MS. Prior research on MS has shown that immune cells such as T cells and dendritic cells (DCs) infiltrate the CNS. Due to persistent tissue stress, these cells may induce local inflammation and autoimmunity, subsequent neurodegeneration, and both the onset and progression of MS. Chemokines are signaling proteins which regulate leukocyte trafficking to the site of injury, contributing to cell recruitment, CNS inflammation, and disease severity. Some chemokine receptors (CXCR3) are X-linked and may escape XCI. This review provides an account of the contribution of x-linked genes in MS in relation to the chemotaxis of myeloid cells into CNS and subsequent neuroinflammation. The impact of the X-chromosome on autoimmunity, including XCI and the expression of X-linked genes is evaluated. Collectively, the analyses from this review seek to advance both our understanding of MS and advocate for more patient-specific therapies.","PeriodicalId":74278,"journal":{"name":"NeuroImmune pharmacology and therapeutics","volume":"43 5","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141654052","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Viral-mediated inflammation by Poly I:C induces the chemokine CCL5 in NK cells and its receptors CCR1 and CCR5 in microglia in the neonatal rat cerebellum","authors":"Miguel Perez-Pouchoulen, Amanda S. Holley, E. Reinl, J. VanRyzin, Amir Mehrabani, Christie Dionisos, Muhammed Mirza, Margaret M. McCarthy","doi":"10.1515/nipt-2024-0002","DOIUrl":"https://doi.org/10.1515/nipt-2024-0002","url":null,"abstract":"\u0000 \u0000 \u0000 To study the effect of viral inflammation induced by Polyinosinic:polycytidylic acid (PIC) on the cerebellum during a critical period of development in rats.\u0000 \u0000 \u0000 \u0000 Neonatal rat pups were treated with PIC on postnatal days (PN) 8 and 10 after which we quantified RNA using Nanostring, qRT-PCR and RNAscope and analyzed immune cells through flow cytometry and immunohistochemistry on PN11. Using the same paradigm, we also analyzed play juvenile behavior, anxiety-like behavior, motor balance using the balance beam and the rotarod assays as well as fine motor behavior using the sunflower seed opening test.\u0000 \u0000 \u0000 \u0000 We determined that male and female pups treated with PIC reacted with a significant increase in CCL5, a chemotactic cytokine that attracts T-cells, eosinophils and basophils to the site of inflammation, at PN11. PIC treatment also increased the expression of two receptors for CCL5, CCR1 and CCR5 in the cerebellar vermis in both males and females at PN11. In-situ hybridization (RNAscope®) for specific transcripts revealed that microglia express both CCL5 receptors under inflammatory and non-inflammatory conditions in both males and females. PIC treatment also increased the total number of CCL5+ cells in the developing cerebellum which were determined to be both natural killer cells and T-cells. There were modest but significant impacts of PIC treatment on large and fine motor skills and juvenile play behavior.\u0000 \u0000 \u0000 \u0000 Our findings suggest an important role for CCL5 and other immune cells in mediating inflammation in the developing cerebellum that potentially impact the maturation of cerebellar neurons during a critical period of development.\u0000","PeriodicalId":74278,"journal":{"name":"NeuroImmune pharmacology and therapeutics","volume":"58 8","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140666895","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sera from people with HIV and depression induce commensurate metabolic alterations in astrocytes: toward precision diagnoses and therapies","authors":"A. Laird, Alexandra Anh Le, J. Kulbe, A. Umlauf, Melody Sagarian, Matthew Spencer, Anish Sathe, D. Grelotti, J. Iudicello, Brook Henry, Ronald J. Ellis, J. Fields","doi":"10.1515/nipt-2024-0001","DOIUrl":"https://doi.org/10.1515/nipt-2024-0001","url":null,"abstract":"\u0000 \u0000 \u0000 People with HIV (PWH) have high rates of depression and neurocognitive impairment (NCI) despite viral suppression on antiretroviral therapy (ART). Mounting evidence suggests that immunometabolic disruptions may contribute to these conditions in some PWH. We hypothesized that metabolic dysfunction in astrocytes is associated with depressive symptoms and cognitive function in PWH.\u0000 \u0000 \u0000 \u0000 Human astrocytes were exposed to sera from PWH (n=40) with varying degrees of depressive symptomatology and cognitive function. MitoTrackerTM Deep Red FM (MT) was used to visualize mitochondrial activity and glial fibrillary acidic protein (GFAP) as an indicator of astrocyte reactivity using the high-throughput fluorescent microscopy and image analyses platform, CellInsight CX5 (CX5). The Seahorse platform was used to assess glycolytic and mitochondrial metabolism. \u0000 \u0000 \u0000 \u0000 More severe depression, as indexed by higher Beck's Depression Inventory (BDI-II) scores, was associated with lower MT signal measures. Better cognitive function, as assessed by neuropsychiatric testing t-scores, was associated with increased MT signal measures. GFAP intensity negatively correlated with several cognitive t-scores. Age positively correlated with (higher) MT signal measures and GFAP intensity. Worse depressive symptoms (higher BDI-II scores) were associated with decreased oxygen consumption rate and spare respiratory capacity, concomitant with increased extracellular acidification rate in astrocytes.\u0000 \u0000 \u0000 \u0000 These findings show that factors in the sera of PWH alter mitochondrial activity in cultured human astrocytes, suggesting that mechanisms that alter mitochondrial and astrocyte homeostasis can be detected peripherally. Thus, in vitro cultures may provide a model to identify neuropathogenic mechanisms of depression or neurocognitive impairment in PWH and test personalized therapeutics for neurologic and psychiatric disorders.\u0000","PeriodicalId":74278,"journal":{"name":"NeuroImmune pharmacology and therapeutics","volume":"62 26","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140376610","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cinnamic acid, a natural plant compound, exhibits neuroprotection in a mouse model of Sandhoff disease via PPARα","authors":"S. Raha, Ramesh K Paidi, Debashis Dutta, K. Pahan","doi":"10.1515/nipt-2023-0027","DOIUrl":"https://doi.org/10.1515/nipt-2023-0027","url":null,"abstract":"\u0000 Tay-Sachs disease (TSD) and its severe form Sandhoff disease (SD) are autosomal recessive lysosomal storage metabolic disorders, which often result into excessive GM2 ganglioside accumulation predominantly in lysosomes of nerve cells. Although patients with these diseases appear normal at birth, the progressive accumulation of undegraded GM2 gangliosides in neurons leads to early death accompanied by manifestation of motor difficulties and gradual loss of behavioral skills. Unfortunately, there is still no effective treatment available for TSD/SD. The present study highlights the importance of cinnamic acid (CA), a naturally occurring aromatic fatty acid present in a number of plants, in inhibiting the disease process in a transgenic mouse model of SD. Oral administration of CA significantly attenuated glial activation and inflammation and reduced the accumulation of GM2 gangliosides/glycoconjugates in the cerebral cortex of Sandhoff mice. Besides, oral CA also improved behavioral performance and increased the survival of Sandhoff mice. While assessing the mechanism, we found that oral administration of CA increased the level of peroxisome proliferator-activated receptor α (PPARα) in the brain of Sandhoff mice and that oral CA remained unable to reduce glycoconjugates, improve behavior and increase survival in Sandhoff mice lacking PPARα. Our results indicate a beneficial function of CA that utilizes a PPARα-dependent mechanism to halt the progression of SD and thereby increase the longevity of Sandhoff mice.","PeriodicalId":74278,"journal":{"name":"NeuroImmune pharmacology and therapeutics","volume":"14 30","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140240491","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neuroprotective mushrooms","authors":"M. M. Abdelmoaty, Rana Kadry, R. Mosley, H. Gendelman","doi":"10.1515/nipt-2024-0004","DOIUrl":"https://doi.org/10.1515/nipt-2024-0004","url":null,"abstract":"\u0000 \u0000 \u0000 Alternative medicines commonly supplement or, at times, replace standard medical treatment. One area of increasing attention is disease-modifying medicines for neurodegenerative diseases. However, few such alternatives have been investigated thoroughly with an eye towards understanding mechanisms of action for clinical use. Medicinal mushrooms have important health benefits and pharmacological activities with anti-inflammatory, antioxidant, antibacterial, antiviral, immunomodulatory, digestive, cytoprotective, homeostatic, and neuroprotective activities. Edible mushrooms are known to play roles in preventing age-related diseases. Several studies have revealed that polysaccharides, terpenes, and phenolic compounds are chemical components derived from mushrooms with pharmacological activities. Due to limited effective protocols for mushroom protein extraction for proteomic studies, information about these medicinally related proteins and their biological functions remains enigmatic.\u0000 \u0000 \u0000 \u0000 Herein, we have performed proteomic studies of two mushroom species Laricifomes officinalis (agarikon) and Grifola frondosa (maitake).\u0000 \u0000 \u0000 \u0000 These studies serve to uncover a foundation for putative proteome-associated neuroprotective processes. The recovered proteins from both species show multiple cell-specific signaling pathways including unfolded protein response, and mitochondrial protein import as well as those linked to BAG2, ubiquitination, apoptosis, microautophagy, glycolysis, SNARE, and immunogenic cell signaling pathways.\u0000 \u0000 \u0000 \u0000 This study uncovered mushroom proteome-associated proteins which serve to better understand the structural and functional properties of mushrooms used as alternative medicines for broad potential health benefits.\u0000","PeriodicalId":74278,"journal":{"name":"NeuroImmune pharmacology and therapeutics","volume":"27 10","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140261737","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HIV-1 and methamphetamine co-treatment in primary human astrocytes: TAARgeting ER/UPR dysfunction","authors":"J. Proulx, In-Woo Park, K. Borgmann","doi":"10.1515/nipt-2023-0020","DOIUrl":"https://doi.org/10.1515/nipt-2023-0020","url":null,"abstract":"\u0000 \u0000 \u0000 Human immunodeficiency virus 1 (HIV-1) can invade the central nervous system (CNS) early during infection and persist in the CNS for life despite effective antiretroviral treatment. Infection and activation of residential glial cells lead to low viral replication and chronic inflammation, which damage neurons contributing to a spectrum of HIV-associated neurocognitive disorders (HAND). Substance use, including methamphetamine (METH), can increase one’s risk and severity of HAND. Here, we investigate HIV-1/METH co-treatment in a key neurosupportive glial cell, astrocytes. Specifically, mitochondria-associated endoplasmic reticulum (ER) membrane (MAM) signaling pathways, such as calcium and the unfolded protein response (UPR), are key mechanisms underlying HAND pathology and arise as potential targets to combat astrocyte dysfunction.\u0000 \u0000 \u0000 \u0000 Primary human astrocytes were transduced with a pseudotyped HIV-1 model and exposed to low-dose METH for seven days. We assessed changes in astrocyte HIV-1 infection, inflammation, mitochondrial antioxidant and dynamic protein expression, respiratory acitivity, mitochondrial calcium flux, and UPR/MAM mediator expression. We then tested a selective antagonist for METH-binding receptor, trace amine-associated receptor 1 (TAAR1) as a potetnial upstream regulator of METH-induced calcium flux and UPR/MAM mediator expression.\u0000 \u0000 \u0000 \u0000 Chronic METH exposure increased astrocyte HIV-1 infection. Moreover, HIV-1/METH co-treatment suppressed astrocyte antioxidant and metabolic capacity while increasing mitochondrial calcium load and protein expression of UPR messengers and MAM mediators. Notably, HIV-1 increases astrocyte TAAR1 expression, thus, could be a critical regulator of HIV-1/METH co-treatment in astrocytes. Indeed, selective antagonism of TAAR1 significantly inhibited cytosolic calcium flux and induction of UPR/MAM protein expression.\u0000 \u0000 \u0000 \u0000 Altogether, our findings demonstrate HIV-1/METH-induced ER-mitochondrial dysfunction in astrocytes, whereas TAAR1 may be an upstream regulator for HIV-1/METH-mediated astrocyte dysfunction.\u0000","PeriodicalId":74278,"journal":{"name":"NeuroImmune pharmacology and therapeutics","volume":"11 9","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139958777","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}