bioRxiv - Pathology最新文献

{"title":"Mpox virus (MPXV) vertical transmission and fetal demise in a pregnant rhesus macaque model","authors":"Nicholas P Krabbe, Ann M Mitzey, Saswati Bhattacharya, Elaina R Razo, Xiankun Zeng, Nell Bekiares, Amy Moy, Amy Kamholz, Julie A Karl, Gregory Daggett, Grace VanSleet, Terry Morgan, Saverio V Capuano, Heather A Simmons, Puja Basu, Andrea M Weiler, David H O'Connor, Thomas C Friedrich, Thaddeus G Golos, Emma L. Mohr","doi":"10.1101/2024.05.29.596240","DOIUrl":"https://doi.org/10.1101/2024.05.29.596240","url":null,"abstract":"Infection with clade I Mpox virus (MPXV) results in adverse pregnancy outcomes, yet the potential for vertical transmission resulting in fetal harm with clade IIb MPXV, the clade that is currently circulating in the Western Hemisphere, remains unknown. We established a rhesus macaque model of vertical MPXV transmission with early gestation inoculation. Three pregnant rhesus macaques were inoculated intradermally with 1.5 x 10^5 plaque forming units (PFU) of clade IIb MPXV near gestational day (GD) 30 and animals were monitored for viremia and maternal and fetal well-being. Animals were euthanized to collect tissues at 5, 14, or 25 days post-inoculation (dpi). Tissues were evaluated for viral DNA (vDNA) loads, infectious virus titers, histopathology, MPXV mRNA and protein localization, as well as MPXV protein co-localization with placental cells including, Hofbauer cells, mesenchymal stromal cells, endothelial cells, and trophoblasts. vDNA was detected in maternal blood and skin lesions by 5 dpi. Lack of fetal heartbeat was observed at 14 or 25 dpi for two dams indicating fetal demise; the third dam developed significant vaginal bleeding at 5 dpi and was deemed an impending miscarriage. vDNA was detected in placental and fetal tissue in both fetal demise cases. MPXV localized to placental villi by ISH and IHC. Clade IIb MPXV infection in pregnant rhesus macaques results in vertical transmission to the fetus and adverse pregnancy outcomes, like clade I MPXV. Further studies are needed to determine whether antiviral therapy with tecovirimat will prevent vertical transmission and improve pregnancy outcomes.","PeriodicalId":501471,"journal":{"name":"bioRxiv - Pathology","volume":"36 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141198093","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":"mTOR inhibition in Q175 Huntington’s disease model mice facilitates neuronal autophagy and mutant huntingtin clearance","authors":"Philip Stavrides, Chris N. Goulbourne, James Peddy, Chunfeng Huo, Mala Rao, Vinod Khetarpal, Deanna M. Marchionini, Ralph A. Nixon, Dun-Sheng Yang","doi":"10.1101/2024.05.29.596471","DOIUrl":"https://doi.org/10.1101/2024.05.29.596471","url":null,"abstract":"Huntington’s disease (HD) is caused by expansion of the polyglutamine stretch in huntingtin protein (HTT) resulting in hallmark aggresomes/inclusion bodies (IBs) composed of mutant huntingtin protein (mHTT) and its fragments. Stimulating autophagy to enhance mHTT clearance is considered a potential therapeutic strategy for HD. Our recent evaluation of the autophagic-lysosomal pathway (ALP) in human HD brain reveals upregulated lysosomal biogenesis and relatively normal autophagy flux in early Vonsattel grade brains, but impaired autolysosome clearance in late grade brains, suggesting that autophagy stimulation could have therapeutic benefits as an earlier clinical intervention. Here, we tested this hypothesis by crossing the Q175 HD knock-in model with our autophagy reporter mouse TRGL (<strong>T</strong>hy-1-<strong>R</strong>FP-<strong>G</strong>FP-<strong>L</strong>C3) to investigate <em>in vivo</em> neuronal ALP dynamics. In the Q175 and/or TRGL/Q175 mice, mHTT was detected in autophagic vacuoles and also exhibited high level colocalization with autophagy receptors p62/SQSTM1 and ubiquitin in the IBs. Compared to the robust lysosomal pathology in late-stage human HD striatum, ALP alterations in Q175 models are also late-onset but milder that included a lowered phospho-p70S6K level, lysosome depletion and autolysosome elevation including more poorly acidified autolysosomes and larger-sized lipofuscin granules, reflecting impaired autophagic flux. Administration of a mTOR inhibitor to 6-mo-old TRGL/Q175 normalized lysosome number, ameliorated aggresome pathology while reducing mHTT-, p62- and ubiquitin-immunoreactivities, suggesting beneficial potential of autophagy modulation at early stages of disease progression.","PeriodicalId":501471,"journal":{"name":"bioRxiv - Pathology","volume":"34 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141196843","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":"Pathobiology of the autophagy-lysosomal pathway in the Huntington's disease brain","authors":"Martin J Berg, Veeranna, Corrinne M Rosa, Asok Kumar, Panaiyur S Mohan, Philip Stavrides, Deanna M Marchionini, Dun-Sheng Yang, Ralph A Nixon","doi":"10.1101/2024.05.29.596470","DOIUrl":"https://doi.org/10.1101/2024.05.29.596470","url":null,"abstract":"Accumulated levels of mutant huntingtin protein (mHTT) and its fragments are considered contributors to the pathogenesis of Huntington's disease (HD). Although lowering mHTT by stimulating autophagy has been considered a possible therapeutic strategy, the role and competence of autophagy-lysosomal pathway (ALP) during HD progression in the human disease remains largely unknown. Here, we used multiplex confocal and ultrastructural immunocytochemical analyses of ALP functional markers in relation to mHTT aggresome pathology in striatum and the less affected cortex of HD brains staged from HD2 to HD4 by Vonsattel neuropathological criteria compared to controls. Immunolabeling revealed the localization of HTT/mHTT in ALP vesicular compartments labeled by autophagy-related adaptor proteins p62/SQSTM1 and ubiquitin, and cathepsin D (CTSD) as well as HTT-positive inclusions. Although comparatively normal at HD2, neurons at later HD stages exhibited progressive enlargement and clustering of CTSD-immunoreactive autolysosomes/lysosomes and, ultrastructurally, autophagic vacuole/lipofuscin granules accumulated progressively, more prominently in striatum than cortex. These changes were accompanied by rises in levels of HTT/mHTT and p62/SQSTM1, particularly their fragments, in striatum but not in the cortex, and by increases of LAMP1 and LAMP2 RNA and LAMP1 protein. Importantly, no blockage in autophagosome formation and autophagosome-lysosome fusion was detected, thus pinpointing autophagy substrate clearance deficits as a basis for autophagic flux declines. The findings collectively suggest that upregulated lysosomal biogenesis and preserved proteolysis maintain autophagic clearance in early-stage HD, but failure at advanced stages contributes to progressive HTT build-up and potential neurotoxicity. These findings support the prospect that ALP stimulation applied at early disease stages, when clearance machinery is fully competent, may have therapeutic benefits in HD patients.","PeriodicalId":501471,"journal":{"name":"bioRxiv - Pathology","volume":"43 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141196824","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":"The effects of iron deficient and high iron diets on SARS-CoV-2 lung infection and disease","authors":"Agnes Carolin, David Frazer, Kexin Yan, Cameron R. Bishop, Bing Tang, Wilson Nguyen, Sheridan L. Helman, Jay Horvat, Thibaut Larcher, Daniel J. Rawle, Andreas Suhrbier","doi":"10.1101/2024.05.29.596393","DOIUrl":"https://doi.org/10.1101/2024.05.29.596393","url":null,"abstract":"The severity of Coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is often dictated by a range of comorbidities. A considerable literature suggests iron deficiency and iron overload may contribute to increased infection, inflammation and disease severity, although direct causal relationships have been difficult to establish. Here we generate iron deficient and iron loaded C57BL/6J mice by feeding low and high iron diets, with mice on a normal iron diet representing controls. All mice were infected with a primary omicron XXB SARS-CoV-2 isolate and lung inflammatory responses were analyzed by histology, immunohistochemistry and RNA-Seq. Compared with controls, iron deficient mice showed no significant changes in lung viral loads or histopathology, whereas, iron loaded mice showed slightly, but significantly, reduced lung viral loads and histopathology. Transcriptional changes were modest, but illustrated widespread dysregulation of inflammation signatures for both iron deficient vs. controls, and iron loaded vs. controls. Some of these changes could be associated with detrimental outcomes, whereas others would be viewed as beneficial. Diet-associated iron deficiency or overload thus induced modest modulations of inflammatory signatures, but no significant histopathologically detectable disease exacerbations.","PeriodicalId":501471,"journal":{"name":"bioRxiv - Pathology","volume":"43 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141196845","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":"The frequency dependence of prestin-mediated fast electromotility for mammalian cochlear amplification","authors":"Satoe Takahashi, Yingjie Zhou, Mary Ann Cheatham, Kazuaki Homma","doi":"10.1101/2024.05.22.595389","DOIUrl":"https://doi.org/10.1101/2024.05.22.595389","url":null,"abstract":"Prestin^,s voltage-driven motor activity confers sound-elicited somatic electromotility in auditory outer hair cells (OHCs) and is essential for the exquisite sensitivity and frequency selectivity of mammalian hearing. Lack of prestin results in hearing threshold shifts across frequency, supporting the causal association of variants in the prestin-coding gene, SLC26A5, with human hearing loss, DFNB61. However, cochlear function can tolerate reductions in prestin-mediated OHC electromotility. We found that two deafness-associated prestin variants, p.A100T and p.P119S, do not deprive prestin of its fast motor function but significantly reduce membrane expression, leading to large reductions in OHC electromotility that were only ~30% of wildtype (WT). Mice harboring these missense variants suffered congenital hearing loss that was worse at high frequencies; however, they retained WT-like auditory brainstem response thresholds at 8 kHz, which is processed at the apex of the mouse cochlea. This observation suggests the increasing importance of prestin-driven cochlear amplification at higher frequencies relevant to mammalian hearing. The observation also suggests the promising clinical possibility that small enhancements of OHC electromotility could significantly ameliorate DFNB61 hearing loss in human patients.","PeriodicalId":501471,"journal":{"name":"bioRxiv - Pathology","volume":"11 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141165872","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":"Functions of the AP2/ERF family transcription factor AIL7 in immunity against soilborne clubroot pathogen in Arabidopsis","authors":"Kethmi Jayawardhane, Tharangani Somarathna, Victor P Manoli, Sheau-Fang Hwang, Stephen E Strelkov, Stacy D Singer, Guanqun Gavin Chen","doi":"10.1101/2024.05.22.595381","DOIUrl":"https://doi.org/10.1101/2024.05.22.595381","url":null,"abstract":"Soilborne pathogens can be highly devastating, and clubroot, caused by Plasmodiophora brassicae, is particularly destructive to cruciferous plants. Although many AP2/ERF family transcription factors (TFs) have crucial physiological functions, very little is known regarding their functions in the context of soilborne diseases. Here we investigated the roles of AINTEGUMENTA-LIKE 7 (AIL7), an AIL sub-family TF in the AP2/ERF family, in plant immunity against clubroot. Unexpectedly, both AIL7 overexpression and mutant Arabidopsis lines exhibited increased tolerance to P. brassicae. Subsequent analysis revealed significant transcriptional alterations in genes linked to pathogen response, along with notable differences in genes associated with salicylic acid (SA) and jasmonic acid (JA) defense pathways, compared to wild-type plants. Interestingly, there was a tendency for up-regulation of SA- and JA-related genes in AIL7 overexpression and mutant lines in the absence, rather than presence, of P. brassicae. Subsequent phytohormone analyses confirmed these results. Taken together, AIL7 has an important role in maintaining constitutive systemic acquired resistance, involving phytohormone mediated defense, and this, rather than an accumulation of SA following P. brassicae challenge, primes the plants for improved clubroot resistance, which would shed light on exploring the functions of other AP2/ERF family TFs in plant immunity against soilborne pathogens.","PeriodicalId":501471,"journal":{"name":"bioRxiv - Pathology","volume":"12 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141165659","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":"Quantification of rose rosette emaravirus (RRV) titers in eriophyoid mites: insights into viral dynamics and vector competency","authors":"Tobiasz Z Druciarek, Alejandro Rojas, Ioannis Tzanetakis","doi":"10.1101/2024.05.23.595398","DOIUrl":"https://doi.org/10.1101/2024.05.23.595398","url":null,"abstract":"Understanding the interaction between rose rosette emaravirus (RRV) and its vectors is pivotal in addressing the epidemic outbreak of rose rosette disease. This study employed quantitative real-time RT-PCR to assess RRV genome copy numbers in Phyllocoptes fructiphilus and P. adalius, providing insights into the viral dynamics and vector competency. Our findings suggest active virus replication within P. fructiphilus, a confirmed vector species, unlike P. adalius, highlighting its non-vector status. Furthermore, the study highlights the variability in virus concentration in mites over time, underlining possible developmental stage-specific response and influence of mite lifestyle on RRV retention and replication. This research is the first step in understanding the virus-mite interactome, which is essential for developing effective management strategies against rose rosette disease.","PeriodicalId":501471,"journal":{"name":"bioRxiv - Pathology","volume":"48 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141151972","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":"Radiation dermatitis in the hairless mouse model mimics human radiation dermatitis","authors":"Jessica Lawrence, Davis Seelig, Kimberly Demos-Davies, Clara Ferreira, Yanan Ren, Li Wang, Sk Kayum Alam, Rendong Yang, Alonso Guedes, Angela Craig, Luke H. Hoeppner","doi":"10.1101/2024.05.21.595074","DOIUrl":"https://doi.org/10.1101/2024.05.21.595074","url":null,"abstract":"Over half of all people diagnosed with cancer receive radiation therapy. Moderate to severe radiation dermatitis occurs in most human radiation patients, causing pain, aesthetic distress, and a negative impact on tumor control. No effective prevention or treatment for radiation dermatitis exists. The lack of well-characterized, clinically relevant animal models of human radiation dermatitis contributes to the absence of strategies to mitigate radiation dermatitis. Here, we establish and characterize a hairless SKH-1 mouse model of human radiation dermatitis by correlating temporal stages of clinical and pathological skin injury. We demonstrate that a single ionizing radiation treatment of 30 Gy using 6 MeV electrons induces severe clinical grade 3 peak toxicity at 12 days, defined by marked erythema, desquamation and partial ulceration, with resolution occurring by 25 days. Histopathology reveals that radiation-induced skin injury features temporally unique inflammatory changes. Upregulation of epidermal and dermal TGF-β1 and COX-2 protein expression occurs at peak dermatitis, with sustained epidermal TGF-β1 expression beyond resolution. Specific histopathological variables that remain substantially high at peak toxicity and early clinical resolution, including epidermal thickening, hyperkeratosis and dermal fibroplasia/fibrosis, serve as specific measurable parameters for in vivo interventional preclinical studies that seek to mitigate radiation-induced skin injury.","PeriodicalId":501471,"journal":{"name":"bioRxiv - Pathology","volume":"220 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141151945","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":"Learning precise segmentation of neurofibrillary tangles from rapid manual point annotations","authors":"Sina Ghandian, Liane Albarghouthi, Kiana Nava, Shivam R. Rai Sharma, Lise Minaud, Laurel Beckett, Naomi Saito, Charles DeCarli, Robert A. Rissman, Andrew F. Teich, Lee-Way Jin, Brittany N. Dugger, Michael J. Keiser","doi":"10.1101/2024.05.15.594372","DOIUrl":"https://doi.org/10.1101/2024.05.15.594372","url":null,"abstract":"Accumulation of abnormal tau protein into neurofibrillary tangles (NFTs) is a pathologic hallmark of Alzheimer disease. Accurate and efficient detection and quantification of NFTs in tissue samples aids in deeper phenotyping of Alzheimer disease and may reveal relationships with clinical, demographic, and genetic features. However, expert manual analysis can be time-consuming, subject to observer variability, and limited in handling the large amounts of data generated by modern imaging techniques. We present a scalable, open access, deep learning-based approach to quantify the NFT burden in digital whole slide images (WSIs) of post-mortem human brain tissue. We trained a UNet model on 45 annotated 2400 μm by 1200 μm regions of interest (ROIs) selected from 15 unique WSIs of temporal cortex from Alzheimer disease cases from three institutes (University of California (UC)-Davis, UC-San Diego, and Columbia University). We developed a method to generate detailed segmentation ground truth masks at the pixel level directly from simple point annotations. The model achieved a precision of 0.53, recall of 0.60, and F1 score of 0.53 on a held-out test set of 7 WSIs, providing researchers with an efficient and reliable tool for NFT burden quantification. We compared this to an object detection model on the same dataset, which achieved comparable but more coarse-grained performance. Both models correlated with expert semi-quantitative scores at the whole-slide level. Our approach provides an open deep learning pipeline for detailed and scalable NFT spatial distribution and morphology analysis across large cohorts, which is not feasible through manual assessment.","PeriodicalId":501471,"journal":{"name":"bioRxiv - Pathology","volume":"30 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141058733","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":"A foundation model for generalizable cancer diagnosis and survival prediction from histopathological images","authors":"Zhangsheng Yu, Zhaochang Yang, Ting Wei, Ying Liang, Xin Yuan, Ruitian Gao, Yujia Xia, Jie Zhou, Yue Zhang","doi":"10.1101/2024.05.16.594499","DOIUrl":"https://doi.org/10.1101/2024.05.16.594499","url":null,"abstract":"Computational pathology, utilizing whole slide image (WSI) for pathological diagnosis, has advanced the development of intelligent healthcare. However, the scarcity of annotated data and histological differences hinder the general application of existing methods. Extensive\u0000histopathological data and the robustness of self-supervised models in small-scale data demonstrate promising prospects for developing foundation pathology models. In this work, we propose the BEPH (BEiT-based model Pre-training on Histopathological image), a general method that leverages self-supervised learning to learn meaningful representations from 11 million unlabeled\u0000histopathological images. These representations are then efficiently adapted to various tasks, including patch-level cancer recognition, WSI-level cancer classification, and survival prediction for multiple cancer subtypes. Experimental results demonstrate that our model consistently outperformsseveral comparative models, even with limited training data reduced to 50%. Especially\u0000when the downstream structure is the same, the model can improve ResNet and DINO by up to a maximum increase of 8.8% and 7.2% (WSI level classification), and 6.44% and 3.28% on average (survival prediction), respectively. Therefore, BEPH offers a universal solution to enhance model performance, reduce the burden of expert annotations, and enable widespread clinical applications of artificial intelligence. The code and models can be obtained at https://github.com/Zhcyoung/BEPH. And currently, online fine-tuning of WSI classification tasks\u0000is available for use on http://yulab-sjtu.natapp1.cc/BEPH.","PeriodicalId":501471,"journal":{"name":"bioRxiv - Pathology","volume":"66 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141058734","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}