bioRxiv - Neuroscience最新文献

{"title":"Neural basis of collective social behavior during environmental challenge","authors":"Tara Raam, Qin Li, Linfan Gu, Gabrielle Elagio, Kayla Y Lim, Xingjian Zhang, Stephanie M Correa, Weizhe Hong","doi":"10.1101/2024.09.17.613378","DOIUrl":"https://doi.org/10.1101/2024.09.17.613378","url":null,"abstract":"Humans and animals have a remarkable capacity to collectively coordinate their behavior to respond to environmental challenges. However, the underlying neurobiology remains poorly understood. Here, we found that groups of mice self-organize into huddles at cold ambient temperature during the thermal challenge assay. We found that mice make active (self-initiated) and passive (partner-initiated) decisions to enter or exit a huddle. Using microendoscopic calcium imaging, we found that active and passive decisions are encoded distinctly within the dorsomedial prefrontal cortex (dmPFC). Silencing dmPFC activity in some mice reduced their active decision-making, but also induced a compensatory increase in active decisions by non-manipulated partners, conserving the group's overall huddle time. These findings reveal how collective behavior is implemented in neurobiological mechanisms to meet homeostatic needs during environmental challenges.","PeriodicalId":501581,"journal":{"name":"bioRxiv - Neuroscience","volume":"19 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142250156","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":"Ocular hypertension impairs axonal transport in the optic nerve head leading to neurodegeneration in a novel Cre-inducible mouse model of myocilin glaucoma.","authors":"Balasankara Reddy Kaipa, Ramesh Kasetti, Linya Li, Cameron Millar, William Cho, Dorota Skowronska-Krawczyk, Prabhavathi Maddineni, Yogapriya Sundaresan, gulab zode","doi":"10.1101/2024.09.18.613712","DOIUrl":"https://doi.org/10.1101/2024.09.18.613712","url":null,"abstract":"Background: Degeneration of optic nerve (ON) axons and loss of retinal ganglion cells (RGCs) are the pathological hallmarks of Primary Open Angle Glaucoma (POAG). Elevation of intraocular pressure (IOP) due to dysfunction of trabecular meshwork (TM) is known to induce neurodegeneration. However, the early pathological events of glaucomatous neurodegeneration are poorly understood due to lack of robust and faithful mouse model that replicates all features of human POAG. Here, we report the generation and characterization of a novel Cre-inducible transgenic mouse model of myocilin (MYOC), the leading known genetic cause of POAG. Using this model, we further explore early pathological events of glaucomatous neurodegeneration due to chronic IOP elevation.\u0000Methods: We generated a Cre-inducible transgenic mouse model expressing DsRed-tagged Y437H mutant of human myocilin (Tg.CreMYOCY437H). A single intravitreal injection of helper adenovirus (HAd) 5 expressing empty cassette or Cre was performed in adult Tg.CreMYOCY437H mice, and glaucoma phenotypes including IOP, outflow facility, structural and functional loss of RGCs, ON degeneration, gliosis, and axonal transport deficits were examined at various stages of IOP elevation. Results: An intravitreal injection of HAd5-Cre led to selective MYOC expression in the TM at the level similar to endogenous Myoc. Expression of mutant MYOC induced biochemical and ultrastructural changes in TM leading to reduced outflow facility and significant IOP elevation. Notably, sustained IOP elevation led to significant functional and structural loss of RGCs and progressive ON degeneration. Glaucomatous neurodegeneration was associated with activation of astrocytes and neurodegenerative changes in the optic nerve head (ONH) region. Remarkably, chronic IOP elevation blocked anterograde axonal transport at the ONH prior to axonal degeneration and RGC loss. Interestingly, impaired axonal transport was associated with loss of cytoskeleton proteins including microtubules and neurofilaments resulting into accumulation of mitochondria in the ONH and neuronal dysfunction.\u0000Conclusions: Our studies indicate that Cre-inducible Tg.CreMYOCY437H mice recapitulates all glaucoma phenotypes observed in POAG patients. Importantly, sustained IOP elevation impairs axonal transport at ONH leading to glaucomatous neurodegeneration.","PeriodicalId":501581,"journal":{"name":"bioRxiv - Neuroscience","volume":"21 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142268637","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":"Role of copper during microglial inflammation","authors":"Laura Craciun, Sandra E. Muroy, Kaoru Saijo","doi":"10.1101/2024.09.18.613750","DOIUrl":"https://doi.org/10.1101/2024.09.18.613750","url":null,"abstract":"Copper plays crucial roles in various physiological functions of the nervous and immune systems. Dysregulation of copper homeostasis is linked to several diseases, including neurodegenerative diseases. Since dysfunctional microglial immunity can contribute to such diseases, we investigated the role of copper in microglial immunity. We found that both increased and decreased copper levels induced by chemical treatments suppresses lipopolysaccharide (LPS)-mediated inflammation in microglial cells, as determined by RT-qPCR analysis. RNA sequencing (RNA-seq) analysis confirmed that increased copper level reduces the inflammatory response to LPS; however, it also showed that decreased copper level affects genes involved in cell proliferation, transcription, and autophagosome regulation. These findings suggest that copper is vital for maintaining normal immune function in microglia, and both copper excess and deficiency can disrupt microglial immunity.","PeriodicalId":501581,"journal":{"name":"bioRxiv - Neuroscience","volume":"21 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142268635","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":"Development and evaluation of a non-invasive brain-spine interface using transcutaneous spinal cord stimulation","authors":"Carolyn J Atkinson, Lorenzo Lombardi, Meredith Lang, Rodolfo Edwin Keesey, Rachel Hawthorn, Zachary Seitz, Eric C. Leuthardt, Peter Brunner, Ismael Seáñez","doi":"10.1101/2024.09.16.612897","DOIUrl":"https://doi.org/10.1101/2024.09.16.612897","url":null,"abstract":"Motor rehabilitation is a therapeutic process to facilitate functional recovery in people with spinal cord injury (SCI). However, its efficacy is limited to areas with remaining sensorimotor function. Spinal cord stimulation (SCS) creates a temporary prosthetic effect that may allow further rehabilitation-induced recovery in individuals without remaining sensorimotor function, thereby extending the therapeutic reach of motor rehabilitation to individuals with more severe injuries. In this work, we report our first steps in developing a non-invasive brain-spine interface (BSI) based on electroencephalography (EEG) and transcutaneous spinal cord stimulation (tSCS). The objective of this study was to identify EEG-based neural correlates of lower limb movement in the sensorimotor cortex of unimpaired individuals and to quantify the performance of a linear discriminant analysis (LDA) decoder in detecting movement onset from these neural correlates. Our results show that initiation of knee extension was associated with event-related desynchronization in the central-medial cortical regions at frequency bands between 4-44 Hz. Our neural decoder using μ (8-12 Hz), low β (16-20 Hz), and high β (24-28 Hz) frequency bands achieved an average area under the curve (AUC) of 0.83 ± 0.06 s.d. (n = 7) during a cued movement task offline. Generalization to imagery and uncued movement tasks served as positive controls to verify robustness against movement artifacts and cue-related confounds, respectively. With the addition of real-time decoder-modulated tSCS, the neural decoder performed with an average AUC of 0.81 ± 0.05 s.d. (n = 9) on cued movement and 0.68 ± 0.12 s.d. (n = 9) on uncued movement. Our results suggest that the decrease in decoder performance in uncued movement may be due to differences in underlying cortical strategies between conditions. Furthermore, we explore alternative applications of the BSI system by testing neural decoders trained on uncued movement and imagery tasks. By developing a non-invasive BSI, tSCS can be timed to be delivered only during voluntary effort, which may have implications for improving rehabilitation.","PeriodicalId":501581,"journal":{"name":"bioRxiv - Neuroscience","volume":"11 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142250195","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":"Histamine interferes with the early visual processing in mice","authors":"Matteo Tripodi, Hiroki Asari","doi":"10.1101/2024.09.02.610848","DOIUrl":"https://doi.org/10.1101/2024.09.02.610848","url":null,"abstract":"Sensory processing is dynamically modulated by an animal's behavior and internal states. Growing evidence suggests that such modulation starts from early stages, even at the retina, but the underlying mechanisms remain elusive. Combining pharmacological and chemogenetic tools with single-unit extracellular recordings in awake head-fixed mice, here we identified that the visual responses of retinal ganglion cells and the lateral geniculate nucleus were both made weaker and slower by histaminergic projections from the tuberomammillary nucleus of the posterior hypothalamus. The observed changes in the visual responses were, however, not directly linked with histaminergic modulation of pupil dynamics or locomotion behavior. Our computational modelling analysis instead suggests neuronal circuit effects, such as gain modulation via the histamine H1 receptors in the retina. As nocturnal animals, facilitation of visual processing at low histamine level is ethologically beneficial for mice to respond faster to visual threats when animals are less active during daytime.","PeriodicalId":501581,"journal":{"name":"bioRxiv - Neuroscience","volume":"24 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142250159","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":"Human Neural Organoid Microphysiological Systems Show the Building Blocks Necessary for Basic Learning and Memory","authors":"Dowlette-Mary Alam El Din, Leah Moenkemoeller, Alon Loeffler, Forough Habibollahi, Jack Schenkman, Amitav Mitra, Tjitse van der Molen, Lixuan Ding, Jason Laird, Maren Schenke, Erik Johnson, Brett Kagan, Thomas Hartung, Lena Smirnova","doi":"10.1101/2024.09.17.613333","DOIUrl":"https://doi.org/10.1101/2024.09.17.613333","url":null,"abstract":"Brain Microphysiological Systems including neural organoids derived from human induced pluripotent stem cells offer a unique lens to study the intricate workings of the human brain. This paper investigates the foundational elements of learning and memory in neural organoids, also known as Organoid Intelligence by quantifying immediate early gene expression, synaptic plasticity, neuronal network dynamics, and criticality to demonstrate the utility of these organoids in basic science research. Neural organoids showed synapse formation, glutamatergic and GABAergic receptor expression, immediate early gene expression basally and evoked, functional connectivity, criticality, and synaptic plasticity in response to theta-burst stimulation. In addition, pharmacological interventions on GABAergic and glutamatergic receptors, and input specific theta-burst stimulation further shed light on the capacity of neural organoids to mirror synaptic modulation and short-term potentiation, demonstrating their potential as tools for studying neurophysiological and neurological processes and informing therapeutic strategies for diseases.","PeriodicalId":501581,"journal":{"name":"bioRxiv - Neuroscience","volume":"32 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142268636","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":"Feature-specific divisive normalization improves natural image encoding for depth perception","authors":"Long Ni, Johannes Burge","doi":"10.1101/2024.09.05.611536","DOIUrl":"https://doi.org/10.1101/2024.09.05.611536","url":null,"abstract":"Vision science and visual neuroscience seek to understand how stimulus and sensor properties limit the precision with which behaviorally-relevant latent variables are encoded and decoded. In the primate visual system, binocular disparity-the canonical cue for stereo-depth perception-is initially encoded by a set of binocular receptive fields with a range of spatial frequency preferences. Here, with a stereo-image database having ground-truth disparity information at each pixel, we examine how response normalization and receptive field properties determine the fidelity with which binocular disparity is encoded in natural scenes. We quantify encoding fidelity by computing the Fisher information carried by the normalized receptive field responses. Several findings emerge from an analysis of the response statistics. First, broadband (or feature- unspecific) normalization yields Laplace-distributed receptive field responses, and narrowband (or feature-specific) normalization yields Gaussian-distributed receptive field responses. Second, the Fisher information in narrowband-normalized responses is larger than in broadband-normalized responses by a scale factor that grows with population size. Third, the most useful spatial frequency decreases with stimulus size and the range of spatial frequencies that is useful for encoding a given disparity decreases with disparity magnitude, consistent with neurophysiological findings. Fourth, the predicted patterns of psychophysical performance, and absolute detection threshold, match human performance with natural and artificial stimuli. The current computational efforts establish a new functional role for response normalization, and bring us closer to understanding the principles that should govern the design of neural systems that support perception in natural scenes.","PeriodicalId":501581,"journal":{"name":"bioRxiv - Neuroscience","volume":"50 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142250208","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":"Cortico-hippocampal interactions underlie schema-supported memory encoding in older adults","authors":"Shenyang Huang, Paul C. Bogdan, Cortney M. Howard, Kirsten Gillette, Lifu Deng, Erin Welch, Margaret L. McAllister, Kelly S. Giovanello, Simon W. Davis, Roberto Cabeza","doi":"10.1101/2024.09.18.613755","DOIUrl":"https://doi.org/10.1101/2024.09.18.613755","url":null,"abstract":"Although episodic memory is typically impaired in older adults (OAs) compared to young adults (YAs), this deficit is attenuated when OAs can leverage their rich semantic knowledge, such as their knowledge of schemas. Memory is better for items consistent with pre-existing schemas and this effect is larger in OAs. Neuroimaging studies have associated schema use with the ventromedial prefrontal cortex (vmPFC) and hippocampus (HPC), but most of this research has been limited to YAs. This fMRI study investigated the neural mechanisms underlying how schemas boost episodic memory in OAs. Participants encoded scene-object pairs with varying congruency, and memory for the objects was tested the following day. Congruency with schemas enhanced object memory for YAs and, more substantially, for OAs. FMRI analyses examined how cortical modulation of HPC predicted subsequent memory. Congruency-related vmPFC modulation of left HPC enhanced subsequent memory in both age groups, while congruency-related modulation from angular gyrus (AG) boosted subsequent memory only in OAs. Individual differences in cortico-hippocampal modulations indicated that OAs preferentially used their semantic knowledge to facilitate encoding via an AG-HPC interaction, suggesting a compensatory mechanism. Collectively, our findings illustrate age-related differences in how schemas influence episodic memory encoding via distinct routes of cortico-hippocampal interactions.","PeriodicalId":501581,"journal":{"name":"bioRxiv - Neuroscience","volume":"95 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142250199","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":"Intra-hypothalamic circuit orchestrates β-endorphin release following coital ejaculation in male mice","authors":"Xi Zha, Zhuolei Jiao, Shuai-Shuai Li, Xiao-Yao Liu, Xing-Yu Li, Yi-Zhuo Sun, Xiao-Jing Ding, Meng-Tong Gao, Shu-Chen Gao, Ai-Xiao Chen, Jun-Kai Lin, Wen Zhang, Xuan-Zi Cao, Yan-Li Zhang, Rong-Rong Yang, Chun Xu, Xiao-Hong Xu","doi":"10.1101/2024.09.18.613624","DOIUrl":"https://doi.org/10.1101/2024.09.18.613624","url":null,"abstract":"Survey-based evidence suggests that men experience a distinct post-ejaculation affective state1,2, marked by intense pleasure sometimes compared to the euphoric rush from intravenous injection of opioid drugs such as heroin3. However, the intrinsic neural circuit mechanisms underlying the ejaculation-triggered affective state remain unclear. Here, we discovered that Calbindin1-expressing (Calb1+) neurons in the preoptic area (POA) of the hypothalamus, an evolutionarily conserved regulatory region for male mating behavior4, are specifically activated during ejaculation in male mice. Inhibiting POA Calb1+ neurons prolongs mating and delays ejaculation. Importantly, POA Calb1+ neurons transmit the ejaculation signal and activate proopiomelanocortin-expressing (Pomc+) neurons in the arcuate nucleus of the hypothalamus, which show robust and sustained activity lasting for tens of seconds, specifically upon ejaculation. This activity is accompanied by elevated levels of β-endorphins5, opioid peptides secreted by Pomc+ neurons, post-ejaculation in male mice. Optogenetic activation of Pomc+ neurons increases β-endorphins levels and conditioned placed preference, similar to ejaculation. Conversely, intracerebroventricular (i.c.v.) infusion of drugs blocking Pomc neuropeptides signaling eliminates ejaculation-conditioned place preference. Collectively, these results elucidate an intra-hypothalamic circuit from POA Calb1+ neurons to arcuate Pomc+ neurons that coordinate β-endorphin release with ejaculation, shedding light on the neurobiological basis of the post-ejaculation affective state.","PeriodicalId":501581,"journal":{"name":"bioRxiv - Neuroscience","volume":"14 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142250164","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":"Basal activation of astrocytic Nrf2 in neuronal culture media: challenges and implications for neuron-astrocyte modelling","authors":"Mohamed M O Elsharkasi, Beatrice Villani, Geoffrey Wells, Fiona Kerr","doi":"10.1101/2024.09.18.613665","DOIUrl":"https://doi.org/10.1101/2024.09.18.613665","url":null,"abstract":"As a gate-keeper of anti-oxidant, anti-inflammatory and xenobiotic cell protection mechanisms, the transcription factor Nrf2 has been implicated as a promising therapeutic target for several neurodegenerative diseases, leading to the development of Nrf2 activators targeting Keap1-dependent and independent regulatory mechanisms. This study aimed to evaluate the efficacy of a Keap1-Nrf2 protein-protein interaction disruptor, 18e, in comparison with classical electrophilic Nrf2 activators, CDDO-Me and Dimethylfumarate (DMF), with a view to measuring their effects on neuronal protection using LUHMES neuron-astrocyte co-cultures. Astrocytes play a crucial role in regulating neuronal physiology in health and disease, including Nrf2 neuroprotective responses. As neurons require specific conditions for their differentiation and maintenance, most 2D and 3D co-culture systems use medias containing high glucose and a variety of growth factors, allowing astrocytes to survive without the media negatively impacting neuronal function. Few studies, however, assess the molecular adaptations of astrocytes in response to changes from astrocyte maintenance medias alone, and the potential consequences for neuronal function, which may represent technical rather than physiological changes. Our findings show that while Nrf2 can be effectively activated by 18e, DMF and CDDO-Me in human primary cortical astrocyte monocultures, their efficacy is lost in the LUHMES-astrocyte co-culture, as measured by NQO1 enzymatic activity. Further investigation revealed that the Advanced DMEM/F12-based LUHMES differentiation media maximally induced basal Nrf2 activity in astrocytes alone, in comparison to complete astrocyte maintenance media. Analysis of media components revealed that this was not due tetracycline or high glucose, and was unlikely to be due to REDOX-inducing phenol-red, the concentration of which is comparable across all medias used in our study. Although Neurobasal slightly activated basal Nrf2 compared to astrocyte media, trends toward further activation were observed in the presence of 18e and DMF, suggesting that this media impacts astrocytic Nrf2 responses less than Advanced DMEM/F12. Numerous studies model oxidative stress and neuroinflammation, key features of neurological diseases, using neuronal systems. As Nrf2 is a key regulator of cellular damage, the effects of these stressors could be confounded by cellular environments that maximally activate basal Nrf2, as observed in our experiments. Hence, this study highlights the need for caution in media selection for neuron-astrocyte co-culture modelling, not only for researchers investigating Nrf2 therapeutics, but also for other mechanisms by which astrocytes influence neuronal function in health and disease.","PeriodicalId":501581,"journal":{"name":"bioRxiv - Neuroscience","volume":"15 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142250203","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}