Circulation: Genomic and Precision Medicine最新文献

{"title":"Polygenic Scoring for Detection of Ascending Thoracic Aortic Dilation.","authors":"John DePaolo, Gina Biagetti, Renae Judy, Grace J Wang, John J Kelly, Amit Iyengar, Nicholas J Goel, Nimesh D Desai, Wilson Y Szeto, Joseph E Bavaria, Michael G Levin, Scott M Damrauer","doi":"10.1161/CIRCGEN.123.004512","DOIUrl":"10.1161/CIRCGEN.123.004512","url":null,"abstract":"<p><strong>Background: </strong>Ascending thoracic aortic dilation is a complex heritable trait that involves modifiable and nonmodifiable risk factors. Polygenic scores (PGS) are increasingly used to assess risk for complex diseases. The degree to which a PGS can improve aortic diameter prediction in diverse populations is unknown. Presently, we tested whether adding a PGS to clinical prediction algorithms improves performance in a diverse biobank.</p><p><strong>Methods: </strong>The analytic cohort comprised 6235 Penn Medicine Biobank participants with available echocardiography and clinical data linked to genome-wide genotype data. Linear regression models were used to integrate PGS weights derived from a genome-wide association study of thoracic aortic diameter performed in the UK Biobank and were compared with the performance of the previously published aorta optimized regression for thoracic aneurysm (AORTA) score.</p><p><strong>Results: </strong>Cohort participants had a median age of 61 years (IQR, 53-70) and a mean ascending aortic diameter of 3.36 cm (SD, 0.49). Fifty-five percent were male, and 33% were genetically similar to an African reference population. Compared with the AORTA score, which explained 30.6% (95% CI, 29.9%-31.4%) of the variance in aortic diameter, AORTA score+UK Biobank-derived PGS explained 33.1%, (95% CI, 32.3%-33.8%), the reweighted AORTA score explained 32.5% (95% CI, 31.8%-33.2%), and the reweighted AORTA score+UK Biobank-derived PGS explained 34.9% (95% CI, 34.2%-35.6%). When stratified by population, models including the UK Biobank-derived PGS consistently improved upon the clinical AORTA score among individuals genetically similar to a European reference population but conferred minimal improvement among individuals genetically similar to an African reference population. Comparable performance disparities were observed in models developed to discriminate cases/noncases of thoracic aortic dilation (≥4.0 cm).</p><p><strong>Conclusions: </strong>We demonstrated that inclusion of a UK Biobank-derived PGS to the AORTA score confers a clinically meaningful improvement in model performance only among individuals genetically similar to European reference populations and may exacerbate existing health care disparities.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004512"},"PeriodicalIF":6.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11540195/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142342758","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":"Common <i>SYNE2</i> Genetic Variant Associated With Atrial Fibrillation Lowers Expression of Nesprin-2α1 With Downstream Effects on Nuclear and Electrophysiological Traits.","authors":"Nana Liu, Jeffrey Hsu, Gautam Mahajan, Han Sun, Kenneth R Laurita, Sathyamangla V Naga Prasad, John Barnard, David R Van Wagoner, Chandrasekhar R Kothapalli, Mina K Chung, Jonathan D Smith","doi":"10.1161/CIRCGEN.124.004750","DOIUrl":"10.1161/CIRCGEN.124.004750","url":null,"abstract":"<p><strong>Background: </strong>Atrial fibrillation GWAS (genome-wide association studies) identified significant associations for rs1152591 and linked variants in the <i>SYNE2</i> gene encoding Nesprin-2, which connects the nuclear membrane with the cytoskeleton.</p><p><strong>Methods: </strong>Reporter gene vector transfection and CRISPR-Cas9 editing were used to identify the causal variant regulating the expression of <i>SYNE2α1</i>. After <i>SYNE2</i> knockdown or <i>SYNE2α1</i> overexpression in human stem cell-derived cardiomyocytes, nuclear phenotypes were assessed by imaging and atomic force microscopy. Gene expression was assessed by RNAseq and gene set enrichment analysis. Fura-2 AM staining assessed calcium transients. Optical mapping assessed action potential duration and conduction velocity.</p><p><strong>Results: </strong>The risk allele of rs1152591 had lower promoter and enhancer activity and was significantly associated with lower expression of the short <i>SYNE2α1</i> isoform in human stem cell-derived cardiomyocytes, without an effect on the expression of the full-length <i>SYNE2</i> mRNA. <i>SYNE2α1</i> overexpression had dominant negative effects on the nucleus with its overexpression or <i>SYNE2</i> knockdown leading to increased nuclear area and decreased nuclear stiffness. Gene expression results from <i>SYNE2α1</i> overexpression demonstrated both concordant and nonconcordant effects with <i>SYNE2</i> knockdown. <i>SYNE2α1</i> overexpression had a gain of function on electrophysiology, leading to significantly faster calcium reuptake and decreased assessed action potential duration, while <i>SYNE2</i> knockdown showed both shortened assessed action potential duration and decreased conduction velocity.</p><p><strong>Conclusions: </strong>rs1152591 was identified as a causal atrial fibrillation variant, with the risk allele decreasing <i>SYNE2α1</i> expression. Downstream effects of <i>SYNE2α1</i> overexpression include changes in nuclear stiffness and electrophysiology, which may contribute to the mechanism for the risk allele's association with AF.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004750"},"PeriodicalIF":6.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11522946/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142361226","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":"Role of Calmodulin in Cardiac Disease: Insights on Genotype and Phenotype.","authors":"Peter J Schwartz, Lia Crotti, Mette Nyegaard, Michael Toft Overgaard","doi":"10.1161/CIRCGEN.124.004542","DOIUrl":"10.1161/CIRCGEN.124.004542","url":null,"abstract":"<p><p>Calmodulin, a protein critically important for the regulation of all major cardiac ion channels, is the quintessential cellular calcium sensor and plays a key role in preserving cardiac electrical stability. Its unique importance is highlighted by the presence of 3 genes in 3 different chromosomes encoding for the same protein and by their extreme conservation. Indeed, all 3 calmodulin (<i>CALM</i>) genes are among the most constrained genes in the human genome, that is, the observed variants are much less than expected by chance. Not surprisingly, <i>CALM</i> variants are poorly tolerated and accompany significant clinical phenotypes, of which the most important are those associated with increased risk for life-threatening arrhythmias. Here, we review the current knowledge about calmodulin, its specific physiological, structural, and functional characteristics, and its importance for cardiovascular disease. Given our role in the development of this knowledge, we also share some of our views about currently unanswered questions, including the rational approaches to the clinical management of the affected patients. Specifically, we present some of the most critical information emerging from the International Calmodulinopathy Registry, which we established 10 years ago. Further progress clearly requires deep phenotypic information on as many carriers as possible through international contributions to the registry, in order to expand our knowledge about Calmodulinopathies and guide clinical management.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004542"},"PeriodicalIF":6.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142153270","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":"Proteome- and Transcriptome-Wide Genetic Analysis Identifies Biological Pathways and Candidate Drug Targets for Preeclampsia.","authors":"Maddalena Ardissino, Buu Truong, Eric A W Slob, Art Schuermans, Satoshi Yoshiji, Alec P Morley, Stephen Burgess, Fu Siong Ng, Antonio de Marvao, Pradeep Natarajan, Kypros Nicolaides, Liam Gaziano, Adam Butterworth, Michael C Honigberg","doi":"10.1161/CIRCGEN.124.004755","DOIUrl":"10.1161/CIRCGEN.124.004755","url":null,"abstract":"<p><strong>Background: </strong>Preeclampsia is a leading cause of maternal and perinatal morbidity and mortality. However, the current understanding of its underlying biological pathways remains limited.</p><p><strong>Methods: </strong>In this study, we performed a cross-platform proteome- and transcriptome-wide genetic analysis aimed at evaluating the causal relevance of >2000 circulating proteins with preeclampsia, supported by data on the expression of over 15 000 genes across 36 tissues leveraging large-scale preeclampsia genetic association data from women of European ancestry.</p><p><strong>Results: </strong>We demonstrate genetic associations of 18 circulating proteins with preeclampsia (SULT1A1 [sulfotransferase 1A1], SH2B3 [SH2B adapter protein 3], SERPINE2 [serpin family E member 2], RGS18 [regulator of G-protein signaling 18], PZP [pregnancy zone protein], NOTUM [notum, palmitoleoyl-protein carboxylesterase], METAP1 [methionyl aminopeptidase 1], MANEA [mannosidase endo-alpha], jun-D [JunD proto-oncogene], GDF15 [growth differentiation factor 15], FGL1 [fibrinogen like 1], FGF5 [fibroblast growth factor 5], FES [FES proto-oncogene], APOBR [apolipoprotein B receptor], ANP [natriuretic peptide A], ALDH-E2 [aldehyde dehydrogenase 2 family member], ADAMTS13 [ADAM metallopeptidase with thrombospondin type 1 motif 13], and 3MG [N-methylpurine DNA glycosylase]), among which 11 were either directly or indirectly supported by gene expression data, 9 were supported by Bayesian colocalization analyses, and 5 (SERPINE2, PZP, FGF5, FES, and ANP) were supported by all lines of evidence examined. Protein interaction mapping identified potential shared biological pathways through natriuretic peptide signaling, blood pressure regulation, immune tolerance, and thrombin activity regulation.</p><p><strong>Conclusions: </strong>This investigation identified multiple targetable proteins linked to cardiovascular, inflammatory, and coagulation pathways, with SERPINE2, PZP, FGF5, FES, and ANP identified as pivotal proteins with likely causal roles in the development of preeclampsia. The identification of these potential targets may guide the development of targeted therapies for preeclampsia.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004755"},"PeriodicalIF":6.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7616531/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141906035","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":"Exercise Intolerance and Low Cardiac Filling Pressures in a Woman With a Novel eNOS Mutation.","authors":"Sarah McGarrity, David R Ziehr, Christina A Austin-Tse, Marc N Wein, Raghu R Chivukula, William M Oldham","doi":"10.1161/CIRCGEN.124.004741","DOIUrl":"10.1161/CIRCGEN.124.004741","url":null,"abstract":"","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004741"},"PeriodicalIF":6.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142342756","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":"How Normal Is Low-Normal Left Ventricular Ejection Fraction in Familial Dilated Cardiomyopathy?","authors":"Stacey A Peters, Leah Wright, Samuel J Fogarty, Lauren McCall, Maraed Rosa, Subodh B Joshi, Elaine Lui, Dominica Zentner, Tom Marwick, Diane Fatkin","doi":"10.1161/CIRCGEN.124.004603","DOIUrl":"10.1161/CIRCGEN.124.004603","url":null,"abstract":"","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004603"},"PeriodicalIF":6.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141901115","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":"Polygenic Risk and Coronary Artery Disease Severity.","authors":"Alborz Sherafati, Kristjan Norland, Mohammadreza Naderian, Daniel J Schaid, Iftikhar J Kullo","doi":"10.1161/CIRCGEN.123.004470","DOIUrl":"10.1161/CIRCGEN.123.004470","url":null,"abstract":"<p><strong>Background: </strong>Coronary atherosclerotic burden and adverse coronary heart disease events are related phenotypes with likely shared genetic cause.</p><p><strong>Methods: </strong>We analyzed 6021 patients with available coronary angiography, genotyping, and exome sequencing data. We tested for associations of polygenic risk scores for coronary heart disease (PRS_CHD) with multiple measures of coronary artery disease (CAD) severity. We assessed the joint associations of PRS_CHD and pathogenic/likely pathogenic variants in 3 familial hypercholesterolemia genes, with CAD severity. We performed mediation analyses to explore whether CAD severity mediated the association of PRS_CHD with prevalent coronary heart disease and incident myocardial infarction.</p><p><strong>Results: </strong>A 1-SD increase in PRS_CHD was associated with multiple measures of CAD severity, including the log Gensini score (β, 0.31 [95% CI, 0.28-0.33]). Carrying a pathogenic/likely pathogenic familial hypercholesterolemia variant was associated with a higher log Gensini score after adjustment for PRS_CHD (β, 0.21 [95% CI, 0.03-0.38]). A 1-SD increase in PRS_CHD was associated with incident myocardial infarction over a mean follow-up of 9.2 years (hazard ratio, 1.20 [95% CI, 1.13-1.27]; <i>P</i>=5×10^-¹⁰), and the Gensini score mediated 90% of this association.</p><p><strong>Conclusions: </strong>PRS_CHD was associated with multiple measures of CAD severity. The association of PRS_CHD with incident myocardial infarction was almost fully mediated by CAD severity, indicating a considerable genetic overlap between the 2 phenotypes.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004470"},"PeriodicalIF":6.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141901116","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":"Clinical Utility of Protein Language Models in Resolution of Variants of Uncertain Significance in <i>KCNQ1, KCNH2</i>, and <i>SCN5A</i> Compared With Patch-Clamp Functional Characterization.","authors":"Dan Ye, Ramin Garmany, Estefania Martinez-Barrios, Xiaozhi Gao, Raquel Almeida Lopes Neves, David J Tester, Sahej Bains, Wei Zhou, John R Giudicessi, Michael J Ackerman","doi":"10.1161/CIRCGEN.124.004584","DOIUrl":"10.1161/CIRCGEN.124.004584","url":null,"abstract":"<p><strong>Background: </strong>Genetic testing for cardiac channelopathies is the standard of care. However, many rare genetic variants remain classified as variants of uncertain significance (VUS) due to lack of epidemiological and functional data. Whether deep protein language models may aid in VUS resolution remains unknown. Here, we set out to compare how 2 deep protein language models perform at VUS resolution in the 3 most common long-QT syndrome-causative genes compared with the gold-standard patch clamp.</p><p><strong>Methods: </strong>A total of 72 rare nonsynonymous VUS (9 <i>KCNQ1,</i> 19 <i>KCNH2</i>, and 50 <i>SCN5A</i>) were engineered by site-directed mutagenesis and expressed in either HEK293 cells or TSA201 cells. Whole-cell patch-clamp technique was used to functionally characterize these variants. The protein language models, evolutionary scale modeling, version 1b and AlphaMissense, were used to predict the variant effect of missense variants and compared with patch clamp.</p><p><strong>Results: </strong>Considering variants in all 3 genes, the evolutionary scale modeling, version 1b model had a receiver operating characteristic curve-area under the curve of 0.75 (<i>P</i>=0.0003). It had a sensitivity of 88% and a specificity of 50%. AlphaMissense performed well compared with patch-clamp with an receiver operating characteristic curve-area under the curve of 0.85 (<i>P</i><0.0001), sensitivity of 80%, and specificity of 76%.</p><p><strong>Conclusions: </strong>Deep protein language models aid in VUS resolution with high sensitivity but lower specificity. Thus, these tools cannot fully replace functional characterization but can aid in reducing the number of variants that may require functional analysis.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004584"},"PeriodicalIF":6.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141906034","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":"Circulating Blood Plasma Profiling Reveals Proteomic Signature and a Causal Role for SVEP1 in Sudden Cardiac Death.","authors":"ThuyVy Duong, Thomas R Austin, Jennifer A Brody, Ali Shojaie, Alexis Battle, Joel S Bader, Yun Soo Hong, Christie M Ballantyne, Josef Coresh, Robert E Gerszten, Russell P Tracy, Bruce M Psaty, Nona Sotoodehnia, Dan E Arking","doi":"10.1161/CIRCGEN.123.004494","DOIUrl":"10.1161/CIRCGEN.123.004494","url":null,"abstract":"","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004494"},"PeriodicalIF":6.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11479847/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142132031","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":"Invasive Assessment of Coronary Artery Disease in Clonal Hematopoiesis of Indeterminate Potential.","authors":"J Brett Heimlich, Michael A Raddatz, John Wells, Caitlyn Vlasschaert, Sydney Olson, Marcus Threadcraft, Kristoff Foster, Emmanuel Boateng, Kelsey Umbarger, Yan Ru Su, Dan M Roden, Colin M Barker, Alexander G Bick","doi":"10.1161/CIRCGEN.123.004415","DOIUrl":"10.1161/CIRCGEN.123.004415","url":null,"abstract":"<p><strong>Background: </strong>Clonal hematopoiesis of indeterminate potential (CHIP) occurs due to acquired mutations in bone marrow progenitor cells. CHIP confers a 2-fold risk of atherosclerotic cardiovascular disease. However, there are limited data regarding specific cardiovascular phenotypes. The purpose of this study was to define the coronary artery disease phenotype of the CHIP population-based on coronary angiography.</p><p><strong>Methods: </strong>We recruited 1142 patients from the Vanderbilt University Medical Center cardiac catheterization laboratory and performed DNA sequencing to determine CHIP status. Multivariable logistic regression models and proportional odds models were used to assess the association between CHIP status and angiography phenotypes.</p><p><strong>Results: </strong>We found that 18.4% of patients undergoing coronary angiography had a CHIP mutation. Those with CHIP had a higher risk of having obstructive left main (odds ratio, 2.44 [95% CI, 1.40-4.27]; <i>P</i>=0.0018) and left anterior descending (odds ratio, 1.59 [1.12-2.24]; <i>P</i>=0.0092) coronary artery disease compared with non-CHIP carriers. We additionally found that a specific CHIP mutation, ten eleven translocase 2 <i>(TET2</i>), has a larger effect size on left main stenosis compared with other CHIP mutations.</p><p><strong>Conclusions: </strong>This is the first invasive assessment of coronary artery disease in CHIP and offers a description of a specific atherosclerotic phenotype in CHIP wherein there is an increased risk of obstructive left main and left anterior descending artery stenosis, especially among <i>TET2</i> mutation carriers. This serves as a basis for understanding enhanced morbidity and mortality in CHIP.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004415"},"PeriodicalIF":6.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11338040/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141466600","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}