The Journal of Clinical Investigation最新文献

{"title":"Postprandial metabolomics analysis reveals disordered serotonin metabolism in post-bariatric hypoglycemia.","authors":"Rafael Ferraz-Bannitz,Berkcan Ozturk,Cameron J Cummings,Vissarion Efthymiou,Pilar Casanova Querol,Lindsay Poulos,Hanna J Wang,Valerie Navarrete,Hamayle Saeed,Christopher M Mulla,Hui Pan,Jonathan M Dreyfuss,Donald C Simonson,Darleen A Sandoval,Mary-Elizabeth Patti","doi":"10.1172/jci180157","DOIUrl":"https://doi.org/10.1172/jci180157","url":null,"abstract":"BACKGROUNDBariatric surgery is a potent therapeutic approach for obesity and type 2 diabetes but can be complicated by post-bariatric hypoglycemia (PBH). PBH typically occurs 1 to 3 hours after meals, in association with exaggerated postprandial levels of incretins and insulin.METHODSTo identify mediators of disordered metabolism in PBH, we analyzed plasma metabolome in fasting state and 30 and 120 minutes after mixed meal in 3 groups: PBH (n = 13), asymptomatic post-RYGB (n = 10), and non-surgical controls (n = 8).RESULTSIn the fasting state, multiple tricarboxylic acid cycle intermediates and the ketone beta-hydroxybutyrate were increased by 30% to 80% in PBH vs. asymptomatic. Conversely, multiple amino acids (BCAA, tryptophan) and polyunsaturated lipids were reduced by 20% to 50% in PBH versus asymptomatic. Tryptophan-related metabolites, including kynurenate, xanthurenate, and serotonin, were reduced by 2- to 10-fold in PBH in fasting state. Postprandially, plasma serotonin was uniquely increased by 1.9-fold in PBH versus asymptomatic post-RYGB. In mice, serotonin administration lowered glucose and increased plasma insulin and GLP-1. Moreover, serotonin-induced hypoglycemia in mice was blocked by the nonspecific serotonin receptor antagonist cyproheptadine and the specific serotonin receptor 2 antagonist ketanserin.CONCLUSIONTogether these data suggest that increased postprandial serotonin may contribute to the pathophysiology of PBH and provide a potential therapeutic target.FUNDINGNIH grant R01 DK121995, NIH grant P30 DK036836 (Diabetes Research Center grant, Joslin Diabetes Center), and Fundação de Amparo à Pesquisa do Estado de São Paulo-FAPESP grant 2018/22111-2.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142231323","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":"Longitudinal analysis of viral dynamics in HIV+ to HIV+ HOPE Act kidney-transplant recipients.","authors":"Tatianna Travieso,Hannah Stadtler,Naseem Alavian,Feng Gao,Mary Klotman,Cameron R Wolfe,Maria Blasi","doi":"10.1172/jci181560","DOIUrl":"https://doi.org/10.1172/jci181560","url":null,"abstract":"BACKGROUNDThe HIV Organ Policy Equity (HOPE) Act allows individuals living with HIV to accept organs from donors with HIV. This practice widens the pool of available organs, but also presents important virological questions, including the potential for HIV superinfection of the recipient, viral persistence in the kidney, and loss of virological control.METHODSWe addressed these questions by performing in-depth longitudinal viral sequence analyses on urine, blood, and urine-derived renal epithelial cells from twelve recipients of HIV+ kidney allografts.RESULTSWe amplified donor-derived HIV-1 env sequences in 5 out of 12 recipients post-transplant. These donor-derived env sequences were amplified from recipient urine, urine-derived renal epithelial cells, and plasma between 12 and 96-hours post-transplant and remained detectable up to 16-days post-transplant. Env sequences were also detected in kidney biopsies taken from the allografts before implantation in 6 out of the 12 transplant cases, indicating the presence of donor virus within the organ. One recipient had a viremic episode 3.5 years after transplantation as a result of ART interruption. Only recipient strain viral sequences were detected in blood, suggesting that the donor virus, if still present, was not reactivated during the temporary ART withdrawal.CONCLUSIONSThis study demonstrates that the HIV env sequences in a donor kidney can be amplified from biopsies taken from the allograft before implantation and can be detected transiently in blood and urine samples collected from the organ recipients post-transplantation.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142171099","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":"Il-13 induces loss of CFTR in ionocytes and reduces airway epithelial fluid absorption.","authors":"Guillermo S Romano Ibarra,Lei Lei,Wenjie Yu,Andrew L Thurman,Nicholas D Gansemer,David K Meyerholz,Alejandro A Pezzulo,Paul B McCray,Ian M Thornell,David A Stoltz","doi":"10.1172/jci181995","DOIUrl":"https://doi.org/10.1172/jci181995","url":null,"abstract":"The airway surface liquid (ASL) plays a crucial role in lung defense mechanisms, and its composition and volume are regulated by the airway epithelium. The cystic fibrosis transmembrane conductance regulator (CFTR) is abundantly expressed in a rare airway epithelial cell type called an ionocyte. Recently, we demonstrated that ionocytes can increase liquid absorption through apical CFTR and basolateral barttin/chloride channels, while airway secretory cells mediate liquid secretion through apical CFTR channels and basolateral NKCC1 transporters. Th2-driven (IL-4/IL-13) airway diseases, such as asthma, cause goblet cell metaplasia, accompanied by increased mucus production and airway secretions. In this study, we investigate the effect of IL-13 on chloride and liquid transport performed by ionocytes. IL-13 treatment of human airway epithelia was associated with reduced epithelial liquid absorption rates and increased ASL volume. Additionally, IL-13 treatment reduced the abundance of CFTR-positive ionocytes and increased the abundance of CFTR-positive secretory cells. Increasing ionocyte abundance attenuated liquid secretion caused by IL-13. Finally, CFTR-positive ionocytes were less common in asthma and COPD and associated with airflow obstruction. Our findings suggest that loss of CFTR in ionocytes contributes to the liquid secretion observed in IL-13-mediated airway diseases.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142171100","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":"Epigenetic regulation of cell state by H2AFY governs immunogenicity in high-risk neuroblastoma.","authors":"Divya Nagarajan,Rebeca T Parracho,David Corujo,Minglu Xie,Ginte Kutkaite,Thale K Olsen,Marta Rúbies Bedós,Maede Salehi,Ninib Baryawno,Michael P Menden,Xingqi Chen,Marcus Buschbeck,Yumeng Mao","doi":"10.1172/jci175310","DOIUrl":"https://doi.org/10.1172/jci175310","url":null,"abstract":"Childhood neuroblastoma with MYCN-amplification is classified as high-risk and often relapses after intensive treatments. Immune checkpoint blockade therapy against the PD-1/L1 axis shows limited efficacy in neuroblastoma patients and the cancer intrinsic immune regulatory network is poorly understood. Here, we leverage genome-wide CRISPR/Cas9 screens and identify H2AFY as a resistance gene to the clinically approved PD-1 blocking antibody, nivolumab. Analysis of single-cell RNA sequencing datasets reveals that H2AFY mRNA is enriched in adrenergic cancer cells and is associated with worse patient survival. Genetic deletion of H2afy in MYCN-driven neuroblastoma cells reverts in vivo resistance to PD-1 blockade by eliciting activation of the adaptive and innate immunity. Mapping of the epigenetic and translational landscape demonstrates that H2afy deletion promotes cell transition to a mesenchymal-like state. With a multi-omics approach, we uncover H2AFY-associated genes that are functionally relevant and prognostic in patients. Altogether, our study elucidates the role of H2AFY as an epigenetic gatekeeper for cell states and immunogenicity in high-risk neuroblastoma.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142171102","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":"Antibiotic use during influenza infection augments lung eosinophils that impair immunity against secondary bacterial pneumonia.","authors":"Marilia Sanches Santos Rizzo Zuttion,Tanyalak Parimon,Stephanie A Bora,Changfu Yao,Katherine Lagree,Catherine A Gao,Richard G Wunderink,Georgios D Kitsios,Alison Morris,Yingze Zhang,Bryan J McVerry,Matthew E Modes,Alberto M Marchevsky,Barry R Stripp,Christopher M Soto,Ying Wang,Kimberly Merene,Silvia Cho,Blandine L Victor,Ivan Vujkovic-Cvijin,Suman Gupta,Suzanne Cassel,Fayyaz S Sutterwala,Suzanne Devkota,David M Underhill,Peter Chen","doi":"10.1172/jci180986","DOIUrl":"https://doi.org/10.1172/jci180986","url":null,"abstract":"A leading cause of mortality after influenza infection is the development of a secondary bacterial pneumonia. In the absence of a bacterial superinfection, prescribing antibacterial therapies is not indicated but has become a common clinical practice for those presenting with a respiratory viral illness. In a murine model, we found that antibiotic use during influenza infection impaired the lung innate immunologic defenses toward a secondary challenge with methicillin-resistant Staphylococcus aureus (MRSA). Antibiotics augment lung eosinophils, which have inhibitory effects on macrophage function through the release of major basic protein. Moreover, we demonstrated antibiotic treatment during influenza infection causes a fungal dysbiosis that drive lung eosinophilia and impair MRSA clearance. Finally, we evaluated three cohorts of hospitalized patients and found eosinophils positively correlated with antibiotic use, systemic inflammation, and worsened outcomes. Altogether, our work demonstrates a detrimental effect of antibiotic treatment during influenza infection that has harmful immunologic consequences via recruitment of eosinophils to the lungs thereby increasing the risk of developing a secondary bacterial infection.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142171101","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":"Metabolic rewiring during bone development underlies tRNA m7G-associated primordial dwarfism.","authors":"Qiwen Li,Shuang Jiang,Kexin Lei,Hui Han,Yaqian Chen,Weimin Lin,Qiuchan Xiong,Xingying Qi,Xinyan Gan,Rui Sheng,Yuan Wang,Yarong Zhang,Jieyi Ma,Tao Li,Shuibin Lin,Chenchen Zhou,Demeng Chen,Quan Yuan","doi":"10.1172/jci177220","DOIUrl":"https://doi.org/10.1172/jci177220","url":null,"abstract":"Translation of mRNA to protein is tightly regulated by tRNAs, which are subject to various chemical modifications that maintain the structure, stability and function. Deficiency of tRNA N7-methylguanosine (m7G) modification in patients causes a type of primordial dwarfism, but the underlying mechanism remains unknown. Here we report the loss of m7G rewires cellular metabolism, leading to the pathogenesis of primordial dwarfism. Conditional deletion of the catalytic enzyme Mettl1 or missense mutation of the scaffold protein Wdr4 severely impaired endochondral bone formation and bone mass accrual. Mechanistically, Mettl1 knockout decreased abundance of m7G-modified tRNAs and inhibited translation of mRNAs relating to cytoskeleton and Rho GTPase signaling. Meanwhile, Mettl1 knockout enhanced cellular energy metabolism despite of incompetent proliferation and osteogenic commitment. Further exploration revealed that impaired Rho GTPase signaling upregulated branched-chain amino acid transaminase 1 (BCAT1) level that rewired cell metabolism and restricted intracellular α-ketoglutarate (αKG). Supplementation of αKG ameliorated the skeletal defect of Mettl1-deficient mice. In addition to the selective translation of metabolism-related mRNAs, we further revealed that Mettl1 knockout globally regulated translation via integrated stress response (ISR) and mammalian target of rapamycin complex 1 (mTORC1) signaling. Restoring translation either by targeting ISR or mTORC1 aggravated bone defects of Mettl1-deficient mice. Overall, our study unveils a critical role of m7G tRNA modification in bone development by regulating cellular metabolism, and indicates that suspension of translation initiation as quality control mechanism in response to tRNA dysregulation.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142171098","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":"Lactate supports Treg function and immune balance via MGAT1 effects on N-glycosylation in the mitochondria.","authors":"Jinren Zhou,Jian Gu,Qufei Qian,Yigang Zhang,Tianning Huang,Xiangyu Li,Zhuoqun Liu,Qing Shao,Yuan Liang,Lei Qiao,Xiaozhang Xu,Qiuyang Chen,Zibo Xu,Yu Li,Ji Gao,Yufeng Pan,Yiming Wang,Roddy O'Connor,Keli L Hippen,Ling Lu,Bruce R Blazar","doi":"10.1172/jci175897","DOIUrl":"https://doi.org/10.1172/jci175897","url":null,"abstract":"Current research reports that lactate affects Treg metabolism, although the precise mechanism has only been partially elucidated. In this study, we presented evidence demonstrating that elevated lactate levels enhanced cell proliferation, suppressive capabilities, and oxidative phosphorylation (OXPHOS) in human Tregs. The expression levels of Monocarboxylate Transporters 1/2/4 (MCT1/2/4) regulate intracellular lactate concentration, thereby influencing the varying responses observed in naive Tregs and memory Tregs. Through mitochondrial isolation, sequencing, and analysis of human Tregs, we determined that Alpha-1,3-Mannosyl-Glycoprotein 2-Beta-N-Acetylglucosaminyltransferase (MGAT1) served as the pivotal driver initiating downstream N-glycosylation events involving progranulin (GRN) and hypoxia-upregulated 1 (HYOU1), consequently enhancing Treg OXPHOS. The mechanism by which MGAT1 was upregulated in mitochondria depended on elevated intracellular lactate that promoted the activation of XBP1s, which, in turn, supported MGAT1 transcription as well as the interaction of lactate with the translocase of the mitochondrial outer membrane 70 (TOM70) import receptor, facilitating MGAT1 translocation into mitochondria. Pre-treatment of Tregs with lactate reduced mortality in a xenogeneic graft-versus-host disease (GvHD) model. Together, these findings underscored the active regulatory role of lactate in human Treg metabolism through the upregulation of MGAT1 transcription and its facilitated translocation into the mitochondria.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142231324","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":"Neutralizing activity of anti–SARS-CoV-2 hyperimmune immunoglobulins and intravenous immunoglobulins against currently circulating SARS-CoV-2 variants","authors":"Lorenza Bellusci, Hana Golding, Surender Khurana","doi":"10.1172/jci182919","DOIUrl":"https://doi.org/10.1172/jci182919","url":null,"abstract":"<p><b>To the Editor:</b> Prophylactic or early post-exposure treatments with SARS-CoV-2–specific monoclonal antibodies (mAbs) were useful early in the COVID-19 pandemic. However, the currently circulating SARS-CoV-2 Omicron subvariants (e.g., XBB.1, JN.1 and its derivatives) are resistant to all approved mAb therapies (<span>1</span>). Immunoglobulin products (IGs) manufactured from pooled human plasma are widely used for treatment of patients with several immunodeficiency syndromes. Most IGs are administered intravenously and are called IVIGs.</p>\u0000<p>Polyclonal hyperimmune anti–SARS-CoV-2 IVIGs (pi-hCoV-2IG) were manufactured in 2021 by fractionation of pooled plasma from COVID-19 convalescent patients with virus neutralization titers of 1:320 or greater against the ancestral WA-1 strain and contain IgG at 10-fold higher concentration than in individual convalescent plasma (CP). Vx-hCoV-2IG was generated from pooled plasma of SARS-CoV-2–vaccinated individuals (2021) (<span>2</span>). Some vaccinated individuals also reported prior SARS-CoV-2 infection. Since 2022, more than 90% of the blood donations in the United States had anti–SARS-CoV-2 antibodies, suggesting prior exposure by vaccination, infections, or both (hybrid immunity) (<span><span></span>3</span>). Therefore, we hypothesized that IVIG lots manufactured from unscreened plasma donors from 2022 onwards may contain anti–SARS-CoV-2 neutralizing antibodies against circulating Omicron subvariants.</p>\u0000<p>To evaluate therapeutic potential of multiple lots of IVIG, pi-hCoV-2IG, and Vx-hCoV-2IG against circulating Omicron variants (Supplemental Table 1; supplemental material available online with this article; https://doi.org/10.1172/JCI182919DS1), we followed the STROBE reporting guideline (https://www.strobe-statement.org/) for cross-sectional studies. We tested 17 lots of pi-hCoV-2IG prepared from pooled plasma of convalescent individuals infected with SARS-CoV-2 in 2020 and one available Vx-hCoV-2IG lot manufactured from screened pooled plasma with high SARS-CoV-2 neutralization titers of mRNA-vaccinated individuals (hybrid immunity) who reported prior SARS-CoV-2 infection in 2021. Additionally, 20 IVIG preparations manufactured in 2019 from healthy plasma donations (2019-IVIG) before the COVID-19 pandemic, 8 IVIG lots manufactured in 2020 (2020-IVIG), 9 IVIG lots manufactured in 2023 (2023-IVIG), 5 IVIG lots manufactured in 2024 (2024-IVIG), 7 CP from recovered COVID-19 patients in early 2020 (2020-CP), and 8 CP from Omicron vaccine breakthrough infections in 2022 (2022-CP), all collected approximately 30 days after diagnosis, were analyzed for neutralization of SARS-CoV-2 WA-1 and 9 circulating Omicron subvariants (BA.2.86, XBB.1.16, XBB.2.3, EG.5, HV.1, HK.3, JN.1, JN.4, and JD.1.1) in a pseudovirus neutralization assay (PsVNA) (<span>4</span>).</p>\u0000<p>CP collected from recovered COVID-19 patients in 2020 and 2022 as well post-infection hyperimmunoglobulin lots (pi-hCoV-2IG) show high ","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142440505","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":"Immune-related events in individuals with solid tumors on immunotherapy associate with Th17 and Th2 signatures","authors":"Chester J. Kao, Soren Charmsaz, Stephanie L. Alden, Madelena Brancati, Howard L. Li, Aanika Balaji, Kabeer Munjal, Kathryn Howe, Sarah Mitchell, James Leatherman, Ervin Griffin, Mari Nakazawa, Hua-Ling Tsai, Ludmila Danilova, Chris Thoburn, Jennifer Gizzi, Nicole E. Gross, Alexei Hernandez, Erin M. Coyne, Sarah M. Shin, Jayalaxmi Suresh Babu, George W. Apostol, Jennifer Durham, Brian J. Christmas, Maximilian F. Konig, Evan J. Lipson, Jarushka Naidoo, Laura C. Cappelli, Aliyah Pabani, Yasser Ged, Marina Baretti, Julie Brahmer, Jean Hoffman-Censits, Tanguy Y. Seiwert, Rachel Garonce-Hediger, Aditi Guha, Sanjay Bansal, Laura Tang, Elizabeth M. Jaffee, G. Scott Chandler, Rajat Mohindra, Won Jin Ho, Mark Yarchoan","doi":"10.1172/jci176567","DOIUrl":"https://doi.org/10.1172/jci176567","url":null,"abstract":"<b>BACKGROUND. </b>Immune-related adverse events (irAEs) and their associated morbidity/mortality are a key concern for patients receiving immune checkpoint inhibitors (ICIs). Prospective evaluation of the drivers of irAEs in a diverse pan-tumor cohort is needed to identify patients at greatest risk and to develop rational treatment and interception strategies.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142440388","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}