Journal of Clinical Investigation最新文献

{"title":"Implications of gene × environment interactions in post-traumatic stress disorder risk and treatment.","authors":"Carina Seah, Anne Elizabeth Sidamon-Eristoff, Laura M Huckins, Kristen J Brennand","doi":"10.1172/JCI185102","DOIUrl":"10.1172/JCI185102","url":null,"abstract":"<p><p>Exposure to traumatic stress is common in the general population. Variation in the brain's molecular encoding of stress potentially contributes to the heterogeneous clinical outcomes in response to traumatic experiences. For instance, only a minority of those exposed to trauma will develop post-traumatic stress disorder (PTSD). Risk for PTSD is at least partially heritable, with a growing number of genetic factors identified through GWAS. A major limitation of genetic studies is that they capture only the genetic component of risk, whereas PTSD by definition requires an environmental traumatic exposure. Furthermore, the extent, timing, and type of trauma affects susceptibility. Here, we discuss the molecular mechanisms of PTSD risk together with gene × environment interactions, with a focus on how either might inform genetic screening for individuals at high risk for disease, reveal biological mechanisms that might one day yield novel therapeutics, and impact best clinical practices even today. To close, we discuss the interaction of trauma with sex, gender, and race, with a focus on the implications for treatment. Altogether, we suggest that predicting, preventing, and treating PTSD will require integrating both genotypic and environmental information.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":"135 5","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11870735/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143542204","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cathepsin K cleavage of Angiopoietin-2 creates detrimental Tie2 antagonist fragments in sepsis.","authors":"Takashi Suzuki, Erik Loyde, Sara Chen, Valerie Etzrodt, Temitayo O Idowu, Amanda J Clark, Marie Christelle Saade, Brenda Mendoza Flores, Shulin Lu, Gabriel Birrane, Vamsidhara Vemireddy, Benjamin Seeliger, Sascha David, Samir M Parikh","doi":"10.1172/JCI174135","DOIUrl":"https://doi.org/10.1172/JCI174135","url":null,"abstract":"<p><p>Elevated Angiopoietin-2 is associated with diverse inflammatory conditions including sepsis, a leading global cause of mortality. During inflammation, Angiopoietin-2 antagonizes the endothelium-enriched receptor Tie2 to destabilize the vasculature. In other contexts, Angiopoietin-2 stimulates Tie2. The basis for context-dependent antagonism remains incompletely understood. Here we show that inflammation-induced proteolytic cleavage of Angiopoietin-2 converts this ligand from Tie2 agonist to antagonist. Conditioned media from stimulated macrophages induced endothelial Angiopoietin-2 secretion. Unexpectedly, this was associated with reduction of the 75 kDa full-length protein and appearance of new 25 and 50 kDa C-terminal fragments. Peptide sequencing proposed cathepsin K as a candidate protease. Cathepsin K was necessary and sufficient to cleave Angiopoietin-2. Recombinant 25 and 50 kDa Angiopoietin-2 fragments (cANGPT225, cANGPT250) bound and antagonized Tie2. Cathepsin K inhibition with the Phase-3 small molecule inhibitor odanacatib improved survival in distinct murine sepsis models. Full-length Angiopoietin-2 enhanced survival in endotoxemic mice administered odanacatib and, conversely, increased mortality in the drug's absence. Odanacatib's benefit was reversed by heterologous cANGPT225. Septic humans accumulated circulating Angiopoietin-2 fragments, which were associated with adverse outcomes. These results identify cathepsin K as a candidate marker of sepsis and a proteolytic mechanism for the conversion of Angiopoietin-2 from Tie2 agonist to antagonist with therapeutic implications for inflammatory conditions associated with Angiopoietin-2 induction.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143542134","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multimodal single-cell analyses reveal molecular markers of neuronal senescence in human drug-resistant epilepsy.","authors":"Qianqian Ge, Jiachao Yang, Fei Huang, Xinyue Dai, Chao Chen, Jingxin Guo, Mi Wang, Mengyue Zhu, Yijie Shao, Yuxian Xia, Yu Zhou, Jieqiao Peng, Suixin Deng, Jiachen Shi, Yiqi Hu, Huiying Zhang, Yi Wang, Xiaoqun Wang, Xiao-Ming Li, Zhong Chen, Yousheng Shu, Jun-Ming Zhu, Jianmin Zhang, Ying Shen, Shumin Duan, Shengjin Xu, Li Shen, Jiadong Chen","doi":"10.1172/JCI188942","DOIUrl":"10.1172/JCI188942","url":null,"abstract":"<p><p>The histopathological neurons in the brain tissue of drug-resistant epilepsy exhibit aberrant cytoarchitecture and imbalanced synaptic circuit function. However, the gene expression changes of these neurons remain unknown, making it difficult to determine the diagnosis or to dissect the mechanism of drug-resistant epilepsy. By integrating whole-cell patch clamp recording and single-cell RNA-seq approaches, we identified a transcriptionally distinct subset of cortical pyramidal neurons. These neurons highly expressed genes CDKN1A (P21), CCL2, and NFKBIA, which associate with mTOR pathway, inflammatory response, and cellular senescence. We confirmed the expression of senescent marker genes in a subpopulation of cortical pyramidal neurons with enlarged soma size in the brain tissue of drug-resistant epilepsy. We further revealed the expression of senescent cell markers P21, P53, COX2, γ-H2AX, and β-Gal, and reduction of nuclear integrity marker Lamin B1 in histopathological neurons in the brain tissue of patients with drug-resistant epilepsy with different pathologies, but not in control brain tissue with no history of epilepsy. Additionally, chronic, but not acute, epileptic seizures induced senescent marker expression in cortical neurons in mouse models of drug-resistant epilepsy. These results provide important molecular markers for histopathological neurons and what we believe to be new insights into the pathophysiological mechanisms of drug-resistant epilepsy.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":"135 5","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11870744/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143542205","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Endothelial OX40 activation facilitates tumor cell escape from T cell surveillance through S1P/YAP-mediated angiogenesis.","authors":"Baoyu He, Rou Zhao, Baogui Zhang, Hongli Pan, Jilan Liu, Lunhua Huang, Yingying Wei, Dong Yang, Jing Liang, Mingyi Wang, Mingsheng Zhao, Sen Wang, Fengyun Dong, Junfeng Zhang, Yanhua Zhang, Xu Zhang, Xiao Zhang, Guanjun Dong, Huabao Xiong, Qingli Bie, Bin Zhang","doi":"10.1172/JCI186291","DOIUrl":"10.1172/JCI186291","url":null,"abstract":"<p><p>Understanding the complexity of the tumor microenvironment is vital for improving immunotherapy outcomes. Here, we report that the T cell costimulatory molecule OX40 was highly expressed in tumor endothelial cells (ECs) and was negatively associated with the prognosis of patients, which is irrelevant to T cell activation. Analysis of conditional OX40 loss- and gain-of-function transgenic mice showed that OX40 signal in ECs counteracted the antitumor effects produced in T cells by promoting angiogenesis. Mechanistically, leucine-rich repeat-containing GPCR5 (Lgr5+ ) cancer stem cells induced OX40 expression in tumor ECs via EGF/STAT3 signaling. Activated OX40 interacted with Spns lysolipid transporter 2 (Spns2), obstructing the export of sphingosine 1-phosphate (S1P) and resulting in S1P intracellular accumulation. Increased S1P directly bound to Yes 1-associated protein (YAP), disrupting its interaction with large tumor suppressor kinase 1 (LATS1) and promoting YAP nuclear translocation. Finally, the YAP inhibitor verteporfin enhanced the antitumor effects of the OX40 agonist. Together, these findings reveal an unexpected protumor role of OX40 in ECs, highlighting the effect of nonimmune cell compartments on immunotherapy.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":"135 5","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11870743/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143542202","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Zombie neurons in epilepsy: a burgeoning role for senescence in drug-resistant epilepsy.","authors":"Gemma L Carvill","doi":"10.1172/JCI189519","DOIUrl":"10.1172/JCI189519","url":null,"abstract":"<p><p>Cellular senescence is a cell state induced by irreparable cellular damage. The hallmark of senescence is cell cycle exit, yet neurons, which are postmitotic from birth, have also been found to undergo senescence. Neuronal senescence is prevalent in aging as well as in neurodegenerative disease. However, a role for senescence in epilepsy is virtually unexplored. In this issue of the JCI, Ge and authors used resected brain tissue from individuals with drug-resistant epilepsy, a genetic knockout mouse model, and a chemoconvulsant mouse model, to demonstrate a subset of cortical pyramidal senescent neurons that likely contribute to the pathophysiology of epilepsy. These findings highlight senescence as a possible target in precision-therapy approaches for epilepsy and warrant further investigation.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":"135 5","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11870726/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143542207","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A multi-analyte blood test for acute spinal cord injury.","authors":"Tej D Azad, Kathleen R Ran, Joshua D Materi, Divyaansh Raj, Timour Al-Khindi, Sameer Gabbita, Marvin Li, Elizabeth T Wang, A Karim Ahmed, Megan Parker, Anita L Kalluri, Daniel Lubelski, Christopher M Jackson, Daniel M Sciubba, Jon D Weingart, Ali Bydon, Timothy F Witham, David W Nauen, Srinivasan Yegnasubramanian, Nicholas Theodore, Chetan Bettegowda","doi":"10.1172/JCI185463","DOIUrl":"10.1172/JCI185463","url":null,"abstract":"<p><p>BACKGROUNDRapid diagnosis to facilitate urgent intervention is critical for treatment of acute spinal cord injury (SCI). We hypothesized that a multi-analyte blood biomarker would support point-of-care SCI diagnosis, correlate with injury severity, and predict long-term neurologic outcomes.METHODSDroplet digital PCR (ddPCR) assays were designed to amplify differentially hypomethylated genomic loci in spinal cord tissue. An optimized ddPCR assay was applied to cell-free DNA (cfDNA) from plasma samples collected from prospectively enrolled acute SCI patients. Targeted proteomic profiling was also performed. Spinal cord-derived cfDNA and plasma proteins were tested for their association with SCI and ability to predict conversion in American Spinal Injury Association (ASIA) score at 6 months.RESULTSA bespoke ddPCR assay detected spinal cord-derived cfDNA in plasma of 50 patients with acute SCI (AUC: 0.89, 95% CI 0.83-0.95, P < 0.0001). Levels of cfDNA were highest in patients with the most severe injury, i.e., ASIA A, compared with those with ASIA B (P = 0.04), ASIA C (P = 0.009), and ASIA D injuries (P < 0.001). Dimensionality reduction identified 4 candidate proteins (FABP3, REST, IL-6, NF-H) that were integrated with spinal cord-derived cfDNA to derive the Spinal Cord Injury Index (SCII), which has high sensitivity and specificity for SCI diagnosis (AUC: 0.91, 95% CI 0.82-0.99, P < 0.0001), correlates with injury severity (P < 0.0001), and predicts 6-month neurologic improvement (AUC: 0.77, 95% CI 0.61-0.93, P = 0.006).CONCLUSIONThe detection of spinal cord-derived cfDNA and plasma protein alterations as part of a multi-analyte blood test can inform SCI diagnosis and prognosis.FUNDINGNorth American Spine Society Young Investigator Award; Morton Cure Paralysis Fund.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":"135 5","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11870727/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143542138","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bridging the gap: insights into sensorimotor deficits in NMDA receptor antibody encephalitis.","authors":"Puneet Opal, Geoffrey T Swanson","doi":"10.1172/JCI188251","DOIUrl":"10.1172/JCI188251","url":null,"abstract":"<p><p>N-methyl-d-aspartate (NMDA) receptor-mediated autoimmune encephalitis (NMDAR-AE) is the most common cause of autoimmune encephalitis, especially in children and young adults. The disorder is caused by antibodies directed against the GluN1 protein, an obligatory constituent of NMDA receptors, which are key signaling molecules in brain development, learning and memory, and executive function. The manuscript by Zhou et al. offers key insights into aberrant development of cortical pathways that may underly persistent sensorimotor deficits associated with this encephalitis in a newly generated mouse model. This study convincingly links transient exposure to a patient-derived anti-GluN1 mAb during a critical developmental period to lasting disruptions in interhemispheric connectivity through callosal projections. These findings provide insight into the impact of a prevalent autoimmune disorder on fundamental aspects of brain development and establish a model system that could be further employed to probe other aspects of NMDAR-AE pathogenesis.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":"135 5","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11870722/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143542199","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Acetylsalicylic acid aggravates anaphylaxis in a PGE2-dependent manner.","authors":"Philipp Globig, Payam Morakabati, Veronika Höfer, Diana M Willmes, Magda Babina, Margitta Worm","doi":"10.1172/JCI175397","DOIUrl":"10.1172/JCI175397","url":null,"abstract":"<p><p>Acetylsalicylic acid (ASA) can exert proanaphylactic effects, but the extent of this phenomenon and its underlying mechanisms are undefined. Yet, low homeostatic prostaglandin E2 (PGE2) levels have been associated with anaphylaxis. In this study, we investigated whether the proanaphylactic effect of ASA is PGE2 dependent. We assessed the effect of ASA in experimental anaphylaxis models, analyzed a large dataset of patients with anaphylaxis, and performed titrated allergen challenges in ASA-treated allergic individuals. Registry data indicated an increased risk for severe anaphylaxis in patients with ASA comedication. ASA pretreatment aggravated allergen-dependent anaphylaxis in mice, whereas histamine-induced anaphylaxis remained unaffected. Exacerbation was due to reduced PGE2, as its stabilization or the use of prostanoid E receptor (EP) agonists reversed the proanaphylactic effects of ASA. EP2-, EP3-, and EP4 receptor-deficient mice revealed that each receptor individually contributed to ASA susceptibility. In patients with allergy, prior ASA intake increased skin responsiveness to allergen but not to histamine. Conversely, the responses of basophils to ex vivo FcεRI aggregation remained unaltered, indicating that ASA operated by enhancing the stimulability of mast cells in a PGE2-dependent manner. Collectively, our data reveal a central role of the PGE2 network in ASA-aggravated anaphylaxis. EP receptors could be potential targets to prevent or alter the outcome of anaphylaxis.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":"135 5","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11870728/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143542065","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Imatinib on target in stroke recovery.","authors":"Hae Ryong Kwon, Lorin E Olson","doi":"10.1172/JCI190024","DOIUrl":"10.1172/JCI190024","url":null,"abstract":"<p><p>Ischemic stroke causes scars in the CNS that impede functional recovery, and there is a need for therapeutics to improve recovery after the acute phase. Scar-resident myofibroblasts and the PDGF pathway have been implicated in stroke pathology. In this issue of the JCI, Protzmann et al. report that inhibition of PDGF-CC or its receptor, PDGFRα, reduces the myofibroblast population and improves functional recovery after ischemic stroke in mice. Importantly, PDGFRα inhibition was effective in improving functional recovery even when initiated 24 hours after stroke, which suggests opportunities for later treatment by targeting the PDGF pathway. This study demonstrates the therapeutic potential of enhancing stroke recovery even after acute damage and blood-brain barrier dysfunction has already occurred.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":"135 5","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11870721/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143542203","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CRISPR-mediated detection of Pneumocystis transcripts in bronchoalveolar, oropharyngeal, and serum specimens for Pneumocystis pneumonia diagnosis.","authors":"Brady M Youngquist, Ayanda Trevor Mnguni, Dora Pungan, Rachel Pj Lai, Guixiang Dai, Chun Fai Ng, Amy Samson, Yasmean Abdelgaliel, Christopher J Lyon, Bo Ning, Shahid Husain, Sean Wasserman, Jay K Kolls, Tony Y Hu","doi":"10.1172/JCI177241","DOIUrl":"https://doi.org/10.1172/JCI177241","url":null,"abstract":"<p><strong>Background: </strong>Pneumocystis jirovecii pneumonia (PCP) is a leading cause of fungal pneumonia, but its diagnosis primarily relies on invasive bronchoalveolar lavage (BAL) specimens that are difficult to obtain. Oropharyngeal swabs and serum could improve the PCP diagnostic workflow, and we hypothesized that CRISPR could enhance assay sensitivity to allow robust P. jirovecii diagnosis using swabs and serum. Herein we describe the development of an ultrasensitive RT-PCR-coupled CRISPR assay with high active-infection specificity in infant swabs and adult BAL and serum.</p><p><strong>Methods: </strong>Mouse analyses employed an RT-PCR CRISPR assay to analyze P. murina transcripts in wild-type and Rag2-/- mouse lung RNA, BAL, and serum at 2-, 4-, and 6-weeks post-infection. Human studies used an optimized RT-PCR CRISPR assay to detect P. jirovecii transcripts in infant oropharyngeal swab samples, adult serum, and adult BAL specimens from P. jirovecii-infected and P. jirovecii-non-infected patients.</p><p><strong>Results: </strong>The P. murina assays sensitively detected Pneumocystis RNA in the serum of infected mice throughout infection. Oropharyngeal swab CRISPR assay results identified infants infected with P. jirovecii with greater sensitivity (96.3% vs. 66.7%) and specificity (100% vs. 90.6%) than RT-qPCR compared to mtLSU standard marker, and CRISPR results achieved higher sensitivity than RT-qPCR results (93.3% vs. 26.7%) in adult serum specimens.</p><p><strong>Conclusion: </strong>Since swabs are routinely collected in pediatric pneumonia patients and serum is easier to obtain than BAL, this assay approach could improve the accuracy and timing of pediatric and adult Pneumocystis diagnosis by achieving specificity for active infection and potentially avoiding the requirement for BAL specimens.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143605179","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}