{"title":"Remifentanil-induced inflammation in microglial cells: Activation of the PAK4-mediated NF-κB/NLRP3 pathway and onset of hyperalgesia","authors":"Chang Cui , Xiaochu Wu , Shuhua Dong , Benzhen Chen , Tianyao Zhang","doi":"10.1016/j.bbi.2024.09.018","DOIUrl":"10.1016/j.bbi.2024.09.018","url":null,"abstract":"<div><h3>Background</h3><div>The perioperative use of remifentanil is associated with postoperative hyperalgesia, which can impair recovery and extend hospitalization. Recent studies have revealed that microglia-mediated activation of the NLRP3 inflammasome plays a critical role in opioid-induced hyperalgesia, with NF-κB acting as a pivotal activation point for NLRP3. Despite these findings, the specific molecular mechanisms underlying remifentanil-induced postoperative hyperalgesia remain unclear. This study aims to develop a model of remifentanil-induced hyperalgesia and investigate the molecular mechanisms, focusing on the NF-κB/NLRP3 pathway, using both in vitro and in vivo approaches.</div></div><div><h3>Method</h3><div>We established a remifentanil-induced hyperalgesia model and performed proteomic analysis to identify differential protein expression in the spinal cord tissue of rats. NLRP3 or PAK4 antagonists were administered intrathecally in vivo, and mechanical pain thresholds in the hind paws were measured using Von Frey testing. In vitro, we applied NLRP3 or PAK4 inhibitors or used lentivirus infection to silence PAK4, NF-κB, and NLRP3 genes. Protein expression was assessed through immunohistochemistry, immunofluorescence, and Western blotting. Additionally, ELISA was performed to measure IL-1β and IL-18 levels, and RT-qPCR was conducted to evaluate the transcription of target genes.</div></div><div><h3>Results</h3><div>Proteomic analysis revealed that remifentanil upregulates PAK4 protein in spinal cord tissue two hours after the surgery. In addition, remifentanil induces morphological changes in the spinal cord dorsal horn, characterized by increased expression of PAK4, p-p65, NLRP3 and Iba-1 proteins, which in turn leads to elevated IL-1β and IL-18 levels and an inflammatory response. Intrathecal injection of NLRP3 or PAK4 inhibitors mitigates remifentanil-induced hyperalgesia and associated changes. In vitro, downregulation of PAK4 inhibits the increase in PAK4, p-p65, NLRP3 and Caspase-1 induced by LPS. Conversely, the downregulation of NLRP3 does not impact the levels of PAK4 and p-p65 proteins, aligning with the in vivo results and suggesting that PAK4 acts as an upstream signaling molecule of NLRP3.</div></div><div><h3>Conclusion</h3><div>Remifentanil can increase PAK4 expression in spinal cord dorsal horn cells by activating the NF-κB/NLRP3 pathway and mediating microglial activation, thereby contributing to postoperative hyperalgesia.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"123 ","pages":"Pages 334-352"},"PeriodicalIF":8.8,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142326488","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Adrien Dufour , Ariane Heydari Olya , Sophie Foulon , Clémence Réda , Amazigh Mokhtari , Valérie Faivre , Jennifer Hua , Cindy Bokobza , Andrew D. Griffiths , Philippe Nghe , Pierre Gressens , Andrée Delahaye-Duriez , Juliette Van Steenwinckel
{"title":"Neonatal inflammation impairs developmentally-associated microglia and promotes a highly reactive microglial subset","authors":"Adrien Dufour , Ariane Heydari Olya , Sophie Foulon , Clémence Réda , Amazigh Mokhtari , Valérie Faivre , Jennifer Hua , Cindy Bokobza , Andrew D. Griffiths , Philippe Nghe , Pierre Gressens , Andrée Delahaye-Duriez , Juliette Van Steenwinckel","doi":"10.1016/j.bbi.2024.09.019","DOIUrl":"10.1016/j.bbi.2024.09.019","url":null,"abstract":"<div><div>Microglia and border-associated macrophages play critical roles in both immunity and neurodevelopment. The disruption of microglial development trajectories by neonatal inflammation is an important issue in research on neurodevelopmental disorders (NDDs), as models have suggested a strong association between inflammation and cognitive deficits. Here, we explored by single-cell RNA sequencing and flow cytometry the impact of neonatal inflammation in a mouse NDD model on brain myeloid cell subsets. A specific subset of microglia expressing the complement receptor C5ar1 has been identified, in which inflammatory pathways are most strongly activated. Based on transcriptional similarity, this subset appears to originate from the most mature and “homeostatic“ microglia at this stage of development and demonstrated hypersensitivity to inflammation. Besides that, Spp1-microglia supporting oligodendrocyte differentiation, primitive and proliferative microglia were reduced by inflammation. These findings suggest major changes in microglial subsets developmental trajectories and reactivity contributing to NDDs induced by neonatal inflammation.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"123 ","pages":"Pages 466-482"},"PeriodicalIF":8.8,"publicationDate":"2024-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142341885","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"The role of Kupffer cells in microbiota-brain communication: Sleep and fever signaling in response to lipopolysaccharide","authors":"Éva Szentirmai , Katelin Buckley , Levente Kapás","doi":"10.1016/j.bbi.2024.09.028","DOIUrl":"10.1016/j.bbi.2024.09.028","url":null,"abstract":"<div><div>Microbial molecules translocated from the intestinal lumen into the host’s internal environment play a role in various physiological functions. Previously, we identified that butyrate, a short-chain fatty acid produced by intestinal bacteria, lipoteichoic acid, a cell wall component of gram-positive bacteria, and lipopolysaccharide (LPS), a cell wall component of gram-negative bacteria, induce sleep when their naturally occurring translocation is mimicked by direct delivery into the portal vein. Our findings suggested that these microbial molecules exert their sleep-promoting effects within the hepatoportal region. In the present experiments, we tested the hypothesis that resident liver macrophages, known as Kupffer cells, play a crucial role in the LPS-responsive, sleep-promoting mechanisms within the hepatoportal region. Intraportal administration of LPS induced increased sleep and fever in control rats. Remarkably, in Kupffer cell-depleted animals, both of these responses were significantly suppressed. These findings highlight the potential role of Kupffer cells in mediating the non-rapid-eye movement sleep-promoting and febrile effects of LPS translocated from the intestinal microbiota into the portal circulation. The strategic location of Kupffer cells within the hepatoportal region, coupled with their ability to rapidly take up LPS and other microbial molecules, together with their high secretory activity of multiple signaling molecules, underlie their key role in the communication between the intestinal microbiota and the brain.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"123 ","pages":"Pages 306-314"},"PeriodicalIF":8.8,"publicationDate":"2024-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142322977","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Kate Ormiston , Zihan Melink , Rebecca Andridge , Maryam Lustberg , A. Courtney DeVries , Kelly Murphy , Katie Emmers , Ouliana Ziouzenkova , Martha A. Belury , Tonya S. Orchard
{"title":"Dietary EPA and DHA enrichment of a high fat diet during doxorubicin-based chemotherapy attenuated neuroinflammatory gene expression in the brain of C57bl/6 ovariectomized mice","authors":"Kate Ormiston , Zihan Melink , Rebecca Andridge , Maryam Lustberg , A. Courtney DeVries , Kelly Murphy , Katie Emmers , Ouliana Ziouzenkova , Martha A. Belury , Tonya S. Orchard","doi":"10.1016/j.bbi.2024.09.021","DOIUrl":"10.1016/j.bbi.2024.09.021","url":null,"abstract":"<div><div>Chemotherapy agents in breast cancer are associated with chemotherapy-related cognitive impairments (CRCI). Mechanisms are not fully clear, but alterations of glucose and lipid metabolism, neuroinflammation and neurodegeneration may contribute to CRCI. The aim of this study was to investigate the combined effects of a high fat (HF) diet combined with doxorubicin-based chemotherapy on glucose and lipid metabolism, neuroinflammation, and neurodegeneration in mice. Additionally, we examined the therapeutic potential of dietary eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) to attenuate these effects. Female C57Bl/6 mice (n = 42) were fed HF, HFn-3 (2 % kcals as EPA + DHA) or Low Fat (LF) diets for seven weeks, with and without chemotherapy. In this study, two chemotherapy injections led to weight and body fat loss associated with a decrease in insulin resistance measured by HOMA-IR. HOMA-IR was significantly greater in HF versus LF groups; but HOMA-IR in HFn-3 group did not significantly differ from either HF or LF groups. Chemotherapy resulted in higher brain concentrations of the inflammatory chemokine KC/GRO. Compared to LF diet plus chemotherapy, HF diet plus chemotherapy upregulated multiple genes involved in neuroinflammation and neurodegeneration pathways. HFn-3 diet plus chemotherapy attenuated gene expression by downregulating multiple genes involved in neuroinflammation and blood brain barrier regulation, including <em>Mapkapk2</em>, <em>Aqp4,</em> and <em>s100b</em>, and upregulating <em>Kcnb1</em> and <em>Atxn3</em>, genes involved in reduction of oxidative stress and anxiety, respectively. Overall, a HF diet combined with chemotherapy is associated with neuroinflammatory and neurodegenerative gene expression changes in this mouse model; dietary enrichment of EPA and DHA attenuated these effects. Further studies are needed to understand how diet impacts behavioral outcomes of CRCI.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"123 ","pages":"Pages 370-382"},"PeriodicalIF":8.8,"publicationDate":"2024-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142307052","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Response Letter to “Cumulative infection burden, cognitive impairment and dementia”","authors":"Yanxia Lu","doi":"10.1016/j.bbi.2024.09.024","DOIUrl":"10.1016/j.bbi.2024.09.024","url":null,"abstract":"","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"123 ","pages":"Page 606"},"PeriodicalIF":8.8,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142280418","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jonas Hagenberg , BeCOME study group , OPTIMA study group , Tanja M. Brückl , Mira Erhart , Johannes Kopf-Beck , Maik Ködel , Ghalia Rehawi , Simone Röh-Karamihalev , Susann Sauer , Natan Yusupov , Monika Rex-Haffner , Victor I. Spoormaker , Philipp Sämann , Elisabeth Binder , Janine Knauer-Arloth
{"title":"Dissecting depression symptoms: Multi-omics clustering uncovers immune-related subgroups and cell-type specific dysregulation","authors":"Jonas Hagenberg , BeCOME study group , OPTIMA study group , Tanja M. Brückl , Mira Erhart , Johannes Kopf-Beck , Maik Ködel , Ghalia Rehawi , Simone Röh-Karamihalev , Susann Sauer , Natan Yusupov , Monika Rex-Haffner , Victor I. Spoormaker , Philipp Sämann , Elisabeth Binder , Janine Knauer-Arloth","doi":"10.1016/j.bbi.2024.09.013","DOIUrl":"10.1016/j.bbi.2024.09.013","url":null,"abstract":"<div><div>In a subset of patients with mental disorders, such as depression, low-grade inflammation and altered immune marker concentrations are observed. However, these immune alterations are often assessed by only one data type and small marker panels. Here, we used a transdiagnostic approach and combined data from two cohorts to define subgroups of depression symptoms across the diagnostic spectrum through a large-scale multi-omics clustering approach in 237 individuals. The method incorporated age, body mass index (BMI), 43 plasma immune markers and RNA-seq data from peripheral mononuclear blood cells (PBMCs). Our initial clustering revealed four clusters, including two immune-related depression symptom clusters characterized by elevated BMI, higher depression severity and elevated levels of immune markers such as interleukin-1 receptor antagonist (IL-1RA), C-reactive protein (CRP) and C-C motif chemokine 2 (CCL2 or MCP-1). In contrast, the RNA-seq data mostly differentiated a cluster with low depression severity, enriched in brain related gene sets. This cluster was also distinguished by electrocardiography data, while structural imaging data revealed differences in ventricle volumes across the clusters. Incorporating predicted cell type proportions into the clustering resulted in three clusters, with one showing elevated immune marker concentrations. The cell type proportion and genes related to cell types were most pronounced in an intermediate depression symptoms cluster, suggesting that RNA-seq and immune markers measure different aspects of immune dysregulation. Lastly, we found a dysregulation of the <em>SERPINF1</em>/VEGF-A pathway that was specific to dendritic cells by integrating immune marker and RNA-seq data. This shows the advantages of combining different data modalities and highlights possible markers for further stratification research of depression symptoms.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"123 ","pages":"Pages 353-369"},"PeriodicalIF":8.8,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142280416","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Xiaoxian Xie , Wenwen Li , Ze Xiong , Junyu Xu , Tailin Liao , Lei Sun , Haoshen Xu , Mengya Zhang , Jiafeng Zhou , Wenzheng Xiong , Zhengwei Fu , Zezhi Li , Qi Han , Donghong Cui , Daniel C. Anthony
{"title":"Metformin reprograms tryptophan metabolism via gut microbiome-derived bile acid metabolites to ameliorate depression-Like behaviors in mice","authors":"Xiaoxian Xie , Wenwen Li , Ze Xiong , Junyu Xu , Tailin Liao , Lei Sun , Haoshen Xu , Mengya Zhang , Jiafeng Zhou , Wenzheng Xiong , Zhengwei Fu , Zezhi Li , Qi Han , Donghong Cui , Daniel C. Anthony","doi":"10.1016/j.bbi.2024.09.014","DOIUrl":"10.1016/j.bbi.2024.09.014","url":null,"abstract":"<div><div>As an adjunct therapy, metformin enhances the efficacy of conventional antidepressant medications. However, its mode of action remains unclear. Here, metformin was found to ameliorate depression-like behaviors in mice exposed to chronic restraint stress (CRS) by normalizing the dysbiotic gut microbiome. Fecal transplants from metformin-treated mice ameliorated depressive behaviors in stressed mice. Microbiome profiling revealed tha<em>t Akkermansia muciniphila (A. muciniphila</em>), in particular, was markedly increased in the gut by metformin and that oral administration of this species alone was sufficient to reverse CRS-induced depressive behaviors and normalize aberrant stress-induced 5-hydroxytryptamine (5-HT) metabolism in the brain and gut. Untargeted metabolomic profiling further identified the bile acid metabolites taurocholate and deoxycholic acid as direct <em>A. muciniphila</em>-derived molecules that are, individually, sufficient to rescue the CRS-induced impaired 5-HT metabolism and depression-like behaviors. Thus, we report metformin reprograms 5-HT metabolism via microbiome-brain interactions to mitigate depressive syndromes, providing novel insights into gut microbiota-derived bile acids as potential therapeutic candidates for depressive mood disorders from bench to bedside.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"123 ","pages":"Pages 442-455"},"PeriodicalIF":8.8,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142280417","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ernesto Griego , Camila Cerna , Isabel Sollozo-Dupont , Marco Fuenzalida , Emilio J. Galván
{"title":"Maternal immune activation alters temporal precision of spike generation of CA1 pyramidal neurons by unbalancing GABAergic inhibition in the Offspring","authors":"Ernesto Griego , Camila Cerna , Isabel Sollozo-Dupont , Marco Fuenzalida , Emilio J. Galván","doi":"10.1016/j.bbi.2024.09.012","DOIUrl":"10.1016/j.bbi.2024.09.012","url":null,"abstract":"<div><p>Infection during pregnancy represents a risk factor for neuropsychiatric disorders associated with neurodevelopmental alterations. A growing body of evidence from rodents and non-human primates shows that maternal inflammation induced by viral or bacterial infections results in several neurobiological alterations in the offspring. These changes may play an important role in the pathophysiology of psychiatric disorders like schizophrenia and autism spectrum disorders, whose clinical features include impairments in cognitive processing and social performance. Such alterations are causally associated with the maternal inflammatory response to infection rather than with the infection itself. Previously, we reported that CA1 pyramidal neurons of mice exposed to MIA exhibit increased excitability accompanied by a reduction in dendritic complexity. However, potential alterations in cellular and synaptic rules that shape the neuronal computational properties of the offspring remain to be determined. In this study, using mice as subjects, we identified a series of cellular and synaptic alterations endured by CA1 pyramidal neurons of the dorsal hippocampus in a lipopolysaccharide-induced maternal immune activation (MIA) model. Our data indicate that MIA reshapes the excitation-inhibition balance by decreasing the perisomatic GABAergic inhibition predominantly mediated by cholecystokinin-expressing Interneurons but not parvalbumin-expressing interneurons impinging on CA1 pyramidal neurons. These alterations yield a dysregulated amplification of the temporal and spatial synaptic integration. In addition, MIA-exposed offspring displayed social and anxiety-like abnormalities. These findings collectively contribute to understanding the cellular and synaptic alterations underlying the behavioral symptoms present in neurodevelopmental disorders associated with MIA.</p></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"123 ","pages":"Pages 211-228"},"PeriodicalIF":8.8,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0889159124006160/pdfft?md5=476831e42ccdb4ee53e7fb836a2472b5&pid=1-s2.0-S0889159124006160-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142271482","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Bethany A. Masson , Pamudika Kiridena , Da Lu , Elizabeth A. Kleeman , Sonali N. Reisinger , Wendy Qin , William J. Davies , Rikeish R. Muralitharan , Hamdi A. Jama , Simona Antonacci , Francine Z. Marques , Carolina Gubert , Anthony J. Hannan
{"title":"Depletion of the paternal gut microbiome alters sperm small RNAs and impacts offspring physiology and behavior in mice","authors":"Bethany A. Masson , Pamudika Kiridena , Da Lu , Elizabeth A. Kleeman , Sonali N. Reisinger , Wendy Qin , William J. Davies , Rikeish R. Muralitharan , Hamdi A. Jama , Simona Antonacci , Francine Z. Marques , Carolina Gubert , Anthony J. Hannan","doi":"10.1016/j.bbi.2024.09.020","DOIUrl":"10.1016/j.bbi.2024.09.020","url":null,"abstract":"<div><div>The paternal environment prior to conception has been demonstrated to influence offspring physiology and behavior, with the sperm epigenome (including noncoding RNAs) proposed as a potential facilitator of non-genetic inheritance. Whilst the maternal gut microbiome has been established as an important influence on offspring development, the impact of the paternal gut microbiome on offspring development, health and behavior is largely unknown. Gut microbiota have major influences on immunity, and thus we hypothesized that they may be relevant to paternal immune activation (PIA) modulating epigenetic inheritance in mice. Therefore, male C57BL/6J mice (F0) were orally administered non-absorbable antibiotics via drinking water in order to substantially deplete their gut microbiome. Four weeks after administration of the antibiotics (gut microbiome depletion), F0 male mice were then mated with naïve female mice. The F1 offspring of the microbiome-depleted males had reduced body weight as well as altered gut morphology (shortened colon length). F1 females showed significant alterations in affective behaviors, including measures of anxiety and depressive-like behaviors, indicating altered development. Analysis of small noncoding RNAs in the sperm of F0 mice revealed that gut microbiome depletion is associated with differential expression of 8 different PIWI-interacting RNAs (piRNAs), each of which has the potential to modulate the expression of multiple downstream gene targets, and thus influence epigenetic inheritance and offspring development. This study demonstrates that the gut-germline axis influences sperm small RNA profiles and offspring physiology, with specific impacts on offspring affective and/or coping behaviors. These findings may have broader implications for other animal species with comparable gut microbiota, intergenerational epigenetics and developmental biology, including humans.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"123 ","pages":"Pages 290-305"},"PeriodicalIF":8.8,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142253449","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}