Brain Organoid and Systems Neuroscience Journal最新文献

{"title":"Structural and functional covariance architecture of major depressive disorder: A meta-analytic structural equation modeling approach to primary neuroimaging analysis","authors":"Jodie P. Gray ,&nbsp;Larry R. Price ,&nbsp;Crystal Franklin ,&nbsp;Cassandra D. Leonardo ,&nbsp;Florence L. Chiang ,&nbsp;Ki Sueng Choi ,&nbsp;John Blangero ,&nbsp;David C. Glahn ,&nbsp;Helen S. Mayberg ,&nbsp;Peter T. Fox","doi":"10.1016/j.bosn.2025.04.008","DOIUrl":"10.1016/j.bosn.2025.04.008","url":null,"abstract":"<div><div>Neuroimaging studies of major depressive disorder (MDD) report widespread disease-attributed abnormalities of brain structure and function. However, reports from mass univariate-driven studies are inconsistent. The objective of this study was to determine if a neuroimaging-based biomarker of MDD, which can reliably distinguish patients from healthy controls, can be generated using multivariate measures. Multivariate modeling of MDD was achieved through generation of a meta-analytic node-and-edge network model of MDD in which disease impacted brain regions (nodes) and their covariances (edges) were quantified with structural equation modeling (SEM). SEM assessment and voxel-based morphometry (VBM) analysis in primary datasets served to test our hypothesis that multivariate analyses of MDD provide improved signal over mass univariate methods. Brain areas reliably impacted by MDD (nodes) and their covariances (edges) were informed by previously published coordinate-based meta-analysis activation/anatomical likelihood estimation (CBMA-ALE) by our group. Meta-analytic model was then fit in primary structural (T1) magnetic resonance imaging (MRI) data and resting-state functional MRI (rs-fMRI) data. Primary datasets were derived from two previously recruited cohorts. Outcome measures (testing for differences between MDD and controls) from standardized SEM included: a) model goodness of fit assessment, and b) individual edge strength. SEM measures were assessed in heterogeneous MDD patient groups, and subsequently re-tested in 7 clinical subgroups of MDD patients. Meta-analytically generated MDD network model yielded 9 nodes with 6 edges among the regions. Model goodness of fit in meta-analytic datasets were good to exceptional. Model goodness of fit in regionally sampled gray matter density in primary T1 data was exceptional in clinical subgroups of MDD, poor in clinically heterogeneous subgroups of MDD, and poor in healthy control subjects. VBM analysis of the same T1 datasets yielded sparse results. Model goodness did not distinguish MDD from controls in regionally sampled primary rs-fMRI. These findings support our hypothesis of improved multivariate signal in MDD compared to findings derived from mass univariate analyses, however this effect was only detectable in T1 data (groupwise). Improved SEM goodness of fit in clinical subgroups of MDD patients supports our hypothesis of detectable neuroimaging effects of clinical heterogeneity in MDD.</div></div>","PeriodicalId":100198,"journal":{"name":"Brain Organoid and Systems Neuroscience Journal","volume":"3 ","pages":"Pages 96-106"},"PeriodicalIF":0.0,"publicationDate":"2025-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143891784","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":"Integration of omics to explore novel disease pathways in Down Syndrome neurodegeneration – Focusing on integrated stress response","authors":"Beatriz Barros-Santos ,&nbsp;Carlos Campos-Marques ,&nbsp;Andreia Filipa Salvador ,&nbsp;Joana Margarida Silva","doi":"10.1016/j.bosn.2025.04.006","DOIUrl":"10.1016/j.bosn.2025.04.006","url":null,"abstract":"<div><div>Down Syndrome is characterized by the trisomy of chromosome 21, leading to widespread molecular and neurological alterations, including early-onset Alzheimer's disease. Emerging evidence highlights the role of RNA metabolism, RNA-binding proteins, and stress granules in these processes. The integrated stress response, a key regulator of translation and protein homeostasis, may be particularly disrupted in DS due to the overexpression of genes involved in the balance between protein degradation and RNA transcription. However, its impact on neurodegeneration in DS remains poorly understood. This project aims to integrate transcriptomic and proteomic data from human and animal models with Down Syndrome to dissect the interplay between integrated stress response, RNA-binding proteins, and stress granule dynamics. By identifying key molecular disruptions in RNA homeostasis and protein synthesis, we aim to investigate novel disease-driving mechanisms that can be conserved among species. These insights will likely help to establish ISR as a potential therapeutic target, advancing our understanding of DS-related neurodegenerative pathways that could be behind the age-related neurodegeneration observed in DS.</div></div>","PeriodicalId":100198,"journal":{"name":"Brain Organoid and Systems Neuroscience Journal","volume":"3 ","pages":"Pages 89-95"},"PeriodicalIF":0.0,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143891785","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":"Inter subject variability analysis in normal ageing and prodromal AD","authors":"Surya Das ,&nbsp;Subha D. Puthankattil","doi":"10.1016/j.bosn.2025.04.007","DOIUrl":"10.1016/j.bosn.2025.04.007","url":null,"abstract":"<div><div>Inter subject variability examines the individual similarity/difference in neural dynamics within a population, both during rest and cognitive tasks. The current study investigates inter subject similarity using Inter Subject Correlation (<span><math><msub><mrow><mi>ISC</mi></mrow><mrow><mi>corr</mi></mrow></msub></math></span>), Inter Subject Coherence (<span><math><msub><mrow><mi>ISC</mi></mrow><mrow><mi>coh</mi></mrow></msub></math></span>) and Inter Subject Functional Connectivity (ISFC) in prodromal AD and healthy controls. Electroencephalogram (EEG) signals were recorded from 13 prodromal AD and 20 healthy subjects belonging to an ageing population. Inter subject correlation and inter subject coherence were estimated for all the EEG channels for each subject pair. Weighted phase lag index (WPLI) based functional connectivity is used for estimating ISFC. Reduction in values of <span><math><mrow><msub><mrow><mi>ISC</mi></mrow><mrow><mi>corr</mi></mrow></msub><mspace></mspace><mrow><mi>and</mi></mrow><mspace></mspace><msub><mrow><mi>ISC</mi></mrow><mrow><mi>coh</mi></mrow></msub></mrow></math></span> was observed in all the recording conditions for the patient group with respect to the healthy controls, with statistically significant difference being observed only in the resting state. ISFC analysis showed a reduction in inter subject similarity in the prodromal AD patient group in comparison to the healthy controls in both resting and cognitive tasks. Results from the study infers the reduction <span><math><mrow><mi>of</mi><mspace></mspace><msub><mrow><mi>ISC</mi></mrow><mrow><mi>corr</mi></mrow></msub><mspace></mspace><mrow><mi>and</mi></mrow><mspace></mspace><msub><mrow><mi>ISC</mi></mrow><mrow><mi>coh</mi></mrow></msub></mrow></math></span> and ISFC in the patient group indicating a reduction in intersubject similarity. The reduction in intersubject similarity observed in prodromal AD group may result from the heterogeneity of brain dynamics within the population during the progression of AD. The study further highlights that the reduction in intersubject similarity is more pronounced during resting states compared to cognitive tasks. Future studies shall benefit from examining intersubject similarity within the patient group which could aid in the development of biomarkers for early detection of the disease.</div></div>","PeriodicalId":100198,"journal":{"name":"Brain Organoid and Systems Neuroscience Journal","volume":"3 ","pages":"Pages 107-114"},"PeriodicalIF":0.0,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143905887","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":"Trehalose, but not other sugars, protects HT22 cells against amyloid-beta toxicity","authors":"Yue Xu ,&nbsp;Kartar Singh ,&nbsp;Michael A. Beazely ,&nbsp;Zoya Leonenko","doi":"10.1016/j.bosn.2025.04.005","DOIUrl":"10.1016/j.bosn.2025.04.005","url":null,"abstract":"<div><div>Trehalose sugar is being explored as a health supplement in Alzheimer’s Disease due to its neuroprotective potential, which is hypothesized to be mainly due to its regulation of pathological amyloid-beta (Aβ) production and aggregation via metabolic pathways. However, the impact of trehalose on neuronal systems against amyloid toxicity is unclear. This work presents a study of the impact of trehalose at different concentrations on HT22 cell viability and explores whether trehalose can directly reduce cell death caused by exogenous Aβ1–42 oligomers. We used an MTT cell viability assay to evaluate the viability of HT22 cells exposure to exogenous Aβ1–42 oligomers alone or in combination with trehalose and several other sugars. Our results reveal that trehalose has a protective effect on the cell viability against Aβ1–42 oligomers, while other sugars, lactulose, sucrose, and fructose, provided no protection against amyloid toxicity.</div></div>","PeriodicalId":100198,"journal":{"name":"Brain Organoid and Systems Neuroscience Journal","volume":"3 ","pages":"Pages 69-72"},"PeriodicalIF":0.0,"publicationDate":"2025-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143851521","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":"Aversive memory engrams in the hippocampus","authors":"Julia Leschik","doi":"10.1016/j.bosn.2025.04.003","DOIUrl":"10.1016/j.bosn.2025.04.003","url":null,"abstract":"<div><div>Negative episodic memories exert important control of behavioral responses during a real or anticipated threatening situation. Under pathological states, however, this control can extend to non-threatening scenarios. For example, pathological states of aversive memory involve fear-overgeneralization in post-traumatic stress disorder (PTSD) or other anxiety disorders. Furthermore, negative bias in cognitive processing and memory formation is seen in depressed individuals displaying enhanced encoding and recall, less forgetting or repetition of negative memory (rumination) as well as impaired recall of positive memory. Beyond pathological conditions, researchers have long aimed to understand the basic biological entity of memory. This unit termed “engram” is the cellular and molecular component of enduring physiological changes in the brain, enabling learning and memory retrieval. Herein, the hippocampus is central in the formation of context-dependent episodic memories and therefore most often studied in animal experiments to elucidate complex memory traces. In addition, the hippocampus is critically involved in fear-circuits and stress-related dysfunction. This review summarizes current knowledge about memory engrams in hippocampal (sub)regions and their functional relevance regarding neuronal correlates and rodent behavior. A special focus is placed on the negative valence of a memory and the formation of engrams for aversive memories, specifically induced by fear or stress. Finally, limitations of current engram research and possible future directions to improve our understanding of negatively valued memory and its implications in neuropathological conditions will be discussed.</div></div>","PeriodicalId":100198,"journal":{"name":"Brain Organoid and Systems Neuroscience Journal","volume":"3 ","pages":"Pages 79-88"},"PeriodicalIF":0.0,"publicationDate":"2025-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143874437","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":"On the implementation of single-cell omics and CRISPR screens for iPSC-models of Parkinson’s disease","authors":"Victoria Lievens ,&nbsp;Hugo J.R. Fernandes","doi":"10.1016/j.bosn.2025.04.001","DOIUrl":"10.1016/j.bosn.2025.04.001","url":null,"abstract":"<div><div>Parkinson’s disease (PD) is currently the fastest growing neurological condition, with an urgent need for effective treatments to slow or stop disease progression. The advent of induced pluripotent stem cells (iPSC) models has significantly enhanced our understanding of PD by providing unprecedented access to disease-relevant cell types. These PD <em>in vitro</em> models have provided novels insights into mitochondrial dysfunction, lysosomal and autophagic dysregulation, protein aggregation, stress response, inflammation and metabolic perturbations. However, cellular heterogeneity and variability across iPSC lines are inherent limitations of these models which are often overlooked. Here we discuss ongoing efforts and opportunities to improve PD models by incorporating recent advancements in single-cell multi-omics analyses. We also highlight the lack of genetic CRISPR screens using iPSC-models of PD and discuss current limitations and prospects. We argue that implementing and combining these tools has the potential to unlock novel insights into the pathological mechanisms of PD that could lead to new therapeutic targets for this devastating disorder.</div></div>","PeriodicalId":100198,"journal":{"name":"Brain Organoid and Systems Neuroscience Journal","volume":"3 ","pages":"Pages 73-78"},"PeriodicalIF":0.0,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143868528","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":"Studying the neural correlates of upper aerodigestive tract functions under natural conditions: A protocol using functional near-infrared spectroscopy, cervical acoustics, and accelerometry","authors":"Yohan Gallois ,&nbsp;Jeanne Souche ,&nbsp;Yann Lemaire ,&nbsp;Lila Gravellier ,&nbsp;Pascal Barone ,&nbsp;Linda Nicolini ,&nbsp;Jérome Farinas ,&nbsp;Pascal Gaillard ,&nbsp;Virginie Woisard","doi":"10.1016/j.bosn.2025.04.002","DOIUrl":"10.1016/j.bosn.2025.04.002","url":null,"abstract":"<div><h3>Background</h3><div>The upper aerodigestive tract (UADT) is a complex structure with multiple synchronized vital functions, including swallowing and breathing, that rely on central neurological controls and cervical effectors. Reference UADT assessments have questionable limitations in natural conditions. Here, we describe our new protocol addressing these limitations. Our protocol combines three non-invasive technologies to evaluate UADT functions in natural conditions. We aim to correlate the cortical and cervical activities of UADT functions in a real-world context.</div></div><div><h3>New method</h3><div>Healthy subjects perform speech, coughing, throat clearing, and swallowing tasks in a natural sitting position. Cervical evaluation uses acoustic and accelerometric measures that reflect the laryngeal movements and bolus progression. We manually segment the events of each task. Functional near-infrared spectroscopy measures the concurrent cortical activity from the bilateral inferior pericentral regions, including the laryngeal sensorimotor cortices. We statistically compare event signal duration and bolus types under volitional and spontaneous conditions across the three technologies.</div></div><div><h3>Comparison with existing methods</h3><div>Reference UADT evaluations show limitations: cervical assessment references are irradiating (videofluoroscopy) or invasive (flexible nasal laryngoscopy); neurological assessment with functional magnetic resonance imaging (fMRI) does not allow swallowing in sitting position.</div></div><div><h3>Expected results and perspectives</h3><div>We aim to validate this protocol in natural settings and correlate cervical activity with cortical responses. This protocol opens perspectives to investigations on UADT functions in subjects currently with reduced access to gold standards, including children and dysphagic subjects with neurological dystonia.</div></div><div><h3>Conclusion</h3><div>We propose an innovative protocol for UADT evaluation in non-invasive natural conditions.</div></div>","PeriodicalId":100198,"journal":{"name":"Brain Organoid and Systems Neuroscience Journal","volume":"3 ","pages":"Pages 56-68"},"PeriodicalIF":0.0,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143816880","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":"Comprehensive review of in vitro gut-brain axis models in Parkinson’s disease research","authors":"John Nicholas Cauba,&nbsp;Jihoo Woo,&nbsp;Russell W. Wiggins,&nbsp;Shizue Mito","doi":"10.1016/j.bosn.2025.03.002","DOIUrl":"10.1016/j.bosn.2025.03.002","url":null,"abstract":"<div><div>This systematic review critically evaluates <em>in vitro</em> gut-brain axis models based on their effectiveness in advancing treatment strategies for Parkinson’s disease (PD). Models such as microfluidic devices, combined organ-on-a-chips (OOCs), and gut-brain organoids are analyzed for their ability to replicate key PD mechanisms, including intestinal barrier dysfunction, microbial dysbiosis, and α-synuclein aggregation. While these models are prospective tools in isolating facets of PD pathology such as microbiota modulation, neurotoxin transport, and neuroinflammation mitigation, challenges remain in their physiological relevance, scalability, and translational potential. This review discusses the designs and limitations of the latest <em>in vitro</em> models and identifies areas that may enhance their utility in developing effective treatments for PD.</div></div>","PeriodicalId":100198,"journal":{"name":"Brain Organoid and Systems Neuroscience Journal","volume":"3 ","pages":"Pages 44-55"},"PeriodicalIF":0.0,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143808376","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":"Disrupted functional connectivity in carotid artery stenosis patients: Insights from fNIRS during a vasoreactivity test","authors":"Víctor Sánchez ,&nbsp;Luis Felipe Bortoletto ,&nbsp;Caroline G. Mazala ,&nbsp;Andrés Quiroga ,&nbsp;Sergio Novi ,&nbsp;Rickson C. Mesquita","doi":"10.1016/j.bosn.2025.03.001","DOIUrl":"10.1016/j.bosn.2025.03.001","url":null,"abstract":"<div><div>Carotid artery stenosis (CAS) reduces cerebral perfusion, which can contribute to neurodegeneration and cognitive decline. While fMRI studies have identified CAS-related disruptions in functional connectivity (FC) associated with neurodegeneration, translating these methods to functional near-infrared spectroscopy (fNIRS) offers a portable, clinically practical alternative. In this study, we assessed FC using fNIRS in 44 CAS patients and 20 controls during breath-holding, a clinical vasoreactivity task. Our results demonstrate clear differences between FC during breath-holding and the resting state, highlighting the task's impact on network connectivity. Patients with unilateral mild stenosis (50–69 % occlusion) exhibited FC patterns comparable to those of controls, whereas patients with bilateral severe stenosis showed a 26 % reduced connectivity and a 14 % lower clustering. When accounting for time delays of 0.9–1.3 seconds, network synchrony was restored across all CAS groups, suggesting that the proposed fNIRS-based method can be used to investigate compensatory hemodynamic delays in CAS. Although sample size limits broader clinical generalizations, this work demonstrates the feasibility of using fNIRS for FC analysis in CAS during a vasodilatory task and provides evidence that fNIRS-based FC metrics are sensitive to CAS severity.</div></div>","PeriodicalId":100198,"journal":{"name":"Brain Organoid and Systems Neuroscience Journal","volume":"3 ","pages":"Pages 36-43"},"PeriodicalIF":0.0,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143679706","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A simulated memristor architecture of neural networks of human memory","authors":"Tihomir Taskov,&nbsp;Juliana Dushanova","doi":"10.1016/j.bosn.2025.02.001","DOIUrl":"10.1016/j.bosn.2025.02.001","url":null,"abstract":"<div><div>The project presents a hybrid approach between artificial intelligence and neuroscience as a more common framework to investigate the function-structure relationship, emphasizing the computational properties of neural networks. The human connectome will be reconstructed using electrophysiological studies, implemented as an artificial reservoir, and trained to perform memory tasks. By comparing connectome-informed reservoirs with arbitrary architectures, the computational properties of the human connectome will be optimized at a unique macroscale network topology and its mesoscale modular organization under critical network dynamics, assumed to perform optimal information processing. The hypothesis is that regardless of global network dynamics, the human connectome maximizes memory capacity by minimizing metabolic and material costs. The idea that the interplay of network dynamics and structure sustains and modulates the computational capacity of connectome-informed reservoirs may explain the spectrum of computational abilities of the anatomical macroscale brain network. By combining connectomics and reservoir computing, it will be possible to implement biologically derived network architectures and connectomes as artificial neural networks in memory tasks. Opportunities to investigate novel facets of the function-structure relationship in brain neuronal networks will arise from the adaptable approach concerning task paradigm, network dynamics, and architecture. Another question is how variations in the connectome architecture give rise to different developmental cognitive abilities in information and computational processing of neural networks. Artificial reservoirs such as memristors have been proposed to explore information processing aspects of the brain by combining modern electrophysiological computing tools and those from artificial intelligence, such as spiking artificial neural (memristor) networks.</div></div>","PeriodicalId":100198,"journal":{"name":"Brain Organoid and Systems Neuroscience Journal","volume":"3 ","pages":"Pages 25-35"},"PeriodicalIF":0.0,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143551467","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}