Genome BiologyPub Date : 2025-05-19DOI: 10.1186/s13059-025-03568-9
Yanlin Zhang, Rola Dali, Mathieu Blanchette
{"title":"RobusTAD: reference panel based annotation of nested topologically associating domains","authors":"Yanlin Zhang, Rola Dali, Mathieu Blanchette","doi":"10.1186/s13059-025-03568-9","DOIUrl":"https://doi.org/10.1186/s13059-025-03568-9","url":null,"abstract":"Topologically associating domains (TADs) are fundamental units of 3D genomes and play essential roles in gene regulation. Hi-C data suggests a hierarchical organization of TADs. Accurately annotating nested TADs from Hi-C data remains challenging, both in terms of the precise identification of boundaries and the correct inference of hierarchies. While domain boundary is relatively well conserved across cells, few approaches have taken advantage of this fact. Here, we present RobusTAD to annotate TAD hierarchies. It incorporates additional Hi-C data to refine boundaries annotated from the study sample. RobusTAD outperforms existing tools at boundary and domain annotation across several benchmarking tasks.","PeriodicalId":12611,"journal":{"name":"Genome Biology","volume":"55 1","pages":""},"PeriodicalIF":12.3,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144088313","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Genome BiologyPub Date : 2025-05-19DOI: 10.1186/s13059-025-03602-w
Pedro G. Nachtigall, Brett R. Hamilton, Taline D. Kazandjian, Paolo Stincone, Daniel Petras, Nicholas R. Casewell, Eivind A. B. Undheim
{"title":"The gene regulatory mechanisms shaping the heterogeneity of venom production in the Cape coral snake","authors":"Pedro G. Nachtigall, Brett R. Hamilton, Taline D. Kazandjian, Paolo Stincone, Daniel Petras, Nicholas R. Casewell, Eivind A. B. Undheim","doi":"10.1186/s13059-025-03602-w","DOIUrl":"https://doi.org/10.1186/s13059-025-03602-w","url":null,"abstract":"Venoms and their associated glands and delivery structures have evolved numerous times among animals. Within these venom systems, the molecular, cellular, and morphological components interact and co-evolve to generate distinct, venom phenotypes that are increasingly recognized as models for studying adaptive evolution. However, toxins are often unevenly distributed across venom-producing tissues in patterns that are not necessarily adaptive but instead likely result from constraints associated with protein secretion. We generate a high-quality draft genome of the Cape coral snake (Aspidelaps lubricus) and combine analyses of venom gland single-cell RNA-seq data with spatial venom gland in situ toxin distributions. Our results reveal that while different toxin families are produced by distinct populations of cells, toxin expression is fine-tuned by regulatory modules that result in further specialization of toxin production within each cell population. We also find that the evolution of regulatory elements closely mirrors the evolution of their associated toxin genes, resulting in spatial association of closely related and functionally similar toxins in the venom gland. While this compartmentalization is non-adaptive, the modularity of the underlying regulatory network likely facilitated the repeated evolution of defensive venom in spitting cobras. Our results provide new insight into the variability of toxin regulation across snakes, reveal the molecular mechanisms underlying the heterogeneous toxin production in snake venom glands, and provide an example of how constraints can result in non-adaptive character states that appear to be adaptive, which may nevertheless facilitate evolutionary innovation and novelty.","PeriodicalId":12611,"journal":{"name":"Genome Biology","volume":"32 1","pages":""},"PeriodicalIF":12.3,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144088316","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Genome BiologyPub Date : 2025-05-14DOI: 10.1186/s13059-025-03604-8
Bingchao Wu, Dan Luo, Yuesen Yue, Haidong Yan, Min He, Xixi Ma, Bingyu Zhao, Bin Xu, Jie Zhu, Jing Wang, Jiyuan Jia, Min Sun, Zheni Xie, Xiaoshan Wang, Linkai Huang
{"title":"New insights into the cold tolerance of upland switchgrass by integrating a haplotype-resolved genome and multi-omics analysis","authors":"Bingchao Wu, Dan Luo, Yuesen Yue, Haidong Yan, Min He, Xixi Ma, Bingyu Zhao, Bin Xu, Jie Zhu, Jing Wang, Jiyuan Jia, Min Sun, Zheni Xie, Xiaoshan Wang, Linkai Huang","doi":"10.1186/s13059-025-03604-8","DOIUrl":"https://doi.org/10.1186/s13059-025-03604-8","url":null,"abstract":"Switchgrass (Panicum virgatum L.) is a bioenergy and forage crop. Upland switchgrass exhibits superior cold tolerance compared to the lowland ecotype, but the underlying molecular mechanisms remain unclear. Here, we present a high-quality haplotype-resolved genome of the upland ecotype “Jingji31.” We then conduct multi-omics analysis to explore the mechanism underlying its cold tolerance. By comparative transcriptome analysis of the upland and lowland ecotypes, we identify many genes with ecotype-specific differential expression, particularly members of the cold-responsive (COR) gene family, under cold stress. Notably, AFB1, ATL80, HOS10, and STRS2 gene families show opposite expression changes between the two ecotypes. Based on the haplotype-resolved genome of “Jingji31,” we detect more cold-induced allele-specific expression genes in the upland ecotype than in the lowland ecotype, and these genes are significantly enriched in the COR gene family. By genome-wide association study, we detect an association signal related to the overwintering rate, which overlaps with a selective sweep region containing a cytochrome P450 gene highly expressed under cold stress. Heterologous overexpression of this gene in rice alleviates leaf chlorosis and wilting under cold stress. We also verify that expression of this gene is suppressed by a structural variation in the promoter region. Based on the high-quality haplotype-resolved genome and multi-omics analysis of upland switchgrass, we characterize candidate genes responsible for cold tolerance. This study advances our understanding of plant cold tolerance, which provides crop breeding for improved cold tolerance.","PeriodicalId":12611,"journal":{"name":"Genome Biology","volume":"10 1","pages":""},"PeriodicalIF":12.3,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143945974","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Genome BiologyPub Date : 2025-05-12DOI: 10.1186/s13059-025-03582-x
Judith Hyle, Wenjie Qi, Mohamed Nadhir Djekidel, Wojciech Rosikiewicz, Beisi Xu, Chunliang Li
{"title":"Deciphering the role of RNA in regulating CTCF’s DNA binding affinity in leukemia cells","authors":"Judith Hyle, Wenjie Qi, Mohamed Nadhir Djekidel, Wojciech Rosikiewicz, Beisi Xu, Chunliang Li","doi":"10.1186/s13059-025-03582-x","DOIUrl":"https://doi.org/10.1186/s13059-025-03582-x","url":null,"abstract":"CTCF, a highly studied transcription factor, is essential for chromatin interaction maintenance. Several independent studies report that CTCF interacts with RNAs in vitro and in cells. Yet continuous debates about the authenticity of the RNA-binding affinity of CTCF and its biological role remain in large part due to limited research techniques available, such as CLIP-seq. Here, we investigate RNA’s role in CTCF’s transcription factor function through its chromatin occupancy. To systematically explore whether RNAs affect CTCF’s ability to bind DNA, we perturb CTCF-RNA interactions by three independent approaches and examine CTCF genome occupancy by ChIP-seq. Although RNase A and triptolide treatment each affect a certain number of CTCF-binding peaks, few peaks overlap between treatment groups indicating the effect of RNA in regulating CTCF’s DNA binding affinity is variable between loci. In addition, limited transcriptional or chromatin accessibility changes occur between cells expressing wild-type CTCF or CTCF lacking the RNA binding region. Our data provide a complementary approach and in silico evidence to consider the significance of RNA affecting CTCF’s DNA binding affinity globally.","PeriodicalId":12611,"journal":{"name":"Genome Biology","volume":"32 1","pages":""},"PeriodicalIF":12.3,"publicationDate":"2025-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143933587","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Genome BiologyPub Date : 2025-05-09DOI: 10.1186/s13059-025-03579-6
Tevfik Umut Dincer, Jason Ernst
{"title":"ChromActivity: integrative epigenomic and functional characterization assay based annotation of regulatory activity across diverse human cell types","authors":"Tevfik Umut Dincer, Jason Ernst","doi":"10.1186/s13059-025-03579-6","DOIUrl":"https://doi.org/10.1186/s13059-025-03579-6","url":null,"abstract":"We introduce ChromActivity, a computational framework for predicting and annotating regulatory activity across the genome through integration of multiple epigenomic maps and various functional characterization datasets. ChromActivity generates genomewide predictions of regulatory activity associated with each functional characterization dataset across many cell types based on available epigenomic data. It then for each cell type produces ChromScoreHMM genome annotations based on the combinatorial and spatial patterns within these predictions and ChromScore tracks of overall predicted regulatory activity. ChromActivity provides a resource for analyzing and interpreting the human regulatory genome across diverse cell types.","PeriodicalId":12611,"journal":{"name":"Genome Biology","volume":"31 1","pages":""},"PeriodicalIF":12.3,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143926676","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Genome BiologyPub Date : 2025-05-09DOI: 10.1186/s13059-025-03591-w
Jamie T. Carrington, Rosemary H. C. Wilson, Eduardo de La Vega, Sathish Thiyagarajan, Tom Barker, Leah Catchpole, Alex Durrant, Vanda Knitlhoffer, Chris Watkins, Karim Gharbi, Conrad A. Nieduszynski
{"title":"Most human DNA replication initiation is dispersed throughout the genome with only a minority within previously identified initiation zones","authors":"Jamie T. Carrington, Rosemary H. C. Wilson, Eduardo de La Vega, Sathish Thiyagarajan, Tom Barker, Leah Catchpole, Alex Durrant, Vanda Knitlhoffer, Chris Watkins, Karim Gharbi, Conrad A. Nieduszynski","doi":"10.1186/s13059-025-03591-w","DOIUrl":"https://doi.org/10.1186/s13059-025-03591-w","url":null,"abstract":"The identification of sites of DNA replication initiation in mammalian cells has been challenging. Here, we present unbiased detection of replication initiation events in human cells using BrdU incorporation and single-molecule nanopore sequencing. Increases in BrdU incorporation allow us to measure DNA replication dynamics, including identification of replication initiation, fork direction, and termination on individual nanopore sequencing reads. Importantly, initiation and termination events are identified on single molecules with high resolution, throughout S-phase, genome-wide, and at high coverage at specific loci using targeted enrichment. We find a significant enrichment of initiation sites within the broad initiation zones identified by population-level studies. However, these focused initiation sites only account for ~ 20% of all identified replication initiation events. Most initiation events are dispersed throughout the genome and are missed by cell population approaches. This indicates that most initiation occurs at sites that, individually, are rarely used. These dispersed initiation sites contrast with the focused sites identified by population studies, in that they do not show a strong relationship to transcription or a particular epigenetic signature. We show here that single-molecule sequencing enables unbiased detection and characterization of DNA replication initiation events, including the numerous dispersed initiation events that replicate most of the human genome.","PeriodicalId":12611,"journal":{"name":"Genome Biology","volume":"28 1","pages":""},"PeriodicalIF":12.3,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143926677","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Genome BiologyPub Date : 2025-05-09DOI: 10.1186/s13059-025-03596-5
Sebastian Gregoricchio, Aleksandar Kojic, Marlous Hoogstraat, Karianne Schuurman, Suzan Stelloo, Tesa M. Severson, Tracy A. O’Mara, Marjolein Droog, Abhishek A. Singh, Dylan M. Glubb, Lodewyk F. A. Wessels, Michiel Vermeulen, Flora E. van Leeuwen, Wilbert Zwart
{"title":"Endometrial tumorigenesis involves epigenetic plasticity demarcating non-coding somatic mutations and 3D-genome alterations","authors":"Sebastian Gregoricchio, Aleksandar Kojic, Marlous Hoogstraat, Karianne Schuurman, Suzan Stelloo, Tesa M. Severson, Tracy A. O’Mara, Marjolein Droog, Abhishek A. Singh, Dylan M. Glubb, Lodewyk F. A. Wessels, Michiel Vermeulen, Flora E. van Leeuwen, Wilbert Zwart","doi":"10.1186/s13059-025-03596-5","DOIUrl":"https://doi.org/10.1186/s13059-025-03596-5","url":null,"abstract":"The incidence and mortality of endometrial cancer (EC) is on the rise. Eighty-five percent of ECs depend on estrogen receptor alpha (ERα) for proliferation, but little is known about its transcriptional regulation in these tumors. We generate epigenomics, transcriptomics, and Hi-C datastreams in healthy and tumor endometrial tissues, identifying robust ERα reprogramming and profound alterations in 3D genome organization that lead to a gain of tumor-specific enhancer activity during EC development. Integration with endometrial cancer risk single-nucleotide polymorphisms and whole-genome sequencing data from primary tumors and metastatic samples reveals a striking enrichment of risk variants and non-coding somatic mutations at tumor-enriched ERα sites. Through machine learning-based predictions and interaction proteomics analyses, we identify an enhancer mutation which alters 3D genome conformation, impairing recruitment of the transcriptional repressor EHMT2/G9a/KMT1C, thereby alleviating transcriptional repression of ESR1 in EC. In summary, we identify a complex genomic-epigenomic interplay in EC development and progression, altering 3D genome organization to enhance expression of the critical driver ERα.","PeriodicalId":12611,"journal":{"name":"Genome Biology","volume":"11 1","pages":""},"PeriodicalIF":12.3,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143926678","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Parent-of-origin regulation by maternal auts2 shapes neurodevelopment and behavior in fish","authors":"Antoine Emile Clément, Constance Merdrignac, Sergi Roig Puiggros, Dorine Sévère, Aurélien Brionne, Thomas Lafond, Thaovi Nguyen, Jérôme Montfort, Cervin Guyomar, Alexandra Dauvé, Amaury Herpin, Denis Jabaudon, Violaine Colson, Florent Murat, Julien Bobe","doi":"10.1186/s13059-025-03600-y","DOIUrl":"https://doi.org/10.1186/s13059-025-03600-y","url":null,"abstract":"Parental experience can influence progeny behavior through gamete-mediated non-genetic inheritance, that is, mechanisms that do not involve changes in inherited DNA sequence. However, underlying mechanisms remain poorly understood in vertebrates, especially for maternal effects. Here, we use the medaka, a model fish species, to investigate the role of auts2a, the ortholog of human AUTS2, a gene repressed in the fish oocyte following maternal stress and associated with neurodevelopmental disorders. We show that auts2a expression in the oocyte influences long-term progeny behavior, including anxiety-like behavior and environment recognition capabilities. Using single-nuclei RNA-sequencing, we reveal that maternal auts2a influences gene expression in neural cell populations during neurodevelopment. We also show that maternal auts2a knock-out triggers differences in maternally inherited factors, including early embryonic transcriptional and post-transcriptional regulators. Together, our results reveal the unsuspected role of an autism-related gene expressed in the mother’s oocyte in shaping progeny neurodevelopment and behavior. Finally, we report that auts2a/AUTS2 is part of a group of evolutionarily conserved genes associated with human neurodevelopmental disorders and expressed in oocytes across species, from fish to mammals. These findings raise important questions about their potential role in the non-genetic regulation of progeny neurodevelopment and behavior in vertebrates.","PeriodicalId":12611,"journal":{"name":"Genome Biology","volume":"49 1","pages":""},"PeriodicalIF":12.3,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143927009","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Long-read sequencing reveals novel isoform-specific eQTLs and regulatory mechanisms of isoform expression in human B cells","authors":"Yuya Nagura, Mihoko Shimada, Ryoji Kuribayashi, Ko Ikemoto, Hiroki Kiyose, Arisa Igarashi, Tadashi Kaname, Motoko Unoki, Akihiro Fujimoto","doi":"10.1186/s13059-025-03583-w","DOIUrl":"https://doi.org/10.1186/s13059-025-03583-w","url":null,"abstract":"Genetic variations linked to changes in gene expression are known as expression quantitative loci (eQTLs). The identification of eQTLs helps to understand the mechanisms governing gene expression. However, prior studies have primarily utilized short-read sequencing techniques, and the analysis of eQTLs on isoforms has been relatively limited. In this study, we employ long-read sequencing technology (Oxford Nanopore) on B cells from 67 healthy Japanese individuals to explore genetic variations associated with isoform expression levels, referred to as isoform eQTLs (ieQTLs). Our analysis reveals 17,119 ieQTLs, with 70.6% remaining undetected by a gene-level analysis. Additionally, we identify ieQTLs that have significantly different effects on isoform expression levels within a gene. A functional feature analysis demonstrates a significant enrichment of ieQTLs at splice sites and specific histone marks, such as H3K36me3, H3K4me1, H3K4me3, and H3K79me2. Through an experimental validation using genome editing, we observe that a distant genomic region can modulate isoform-specific expression. Moreover, an ieQTL analysis and minigene splicing assays unveils functionally crucial variants in splicing that splicing prediction software did not assign a high prediction score. A comparison with GWAS data reveals a higher number of colocalizations between ieQTLs and GWAS findings compared to gene eQTLs. These findings highlight the substantial contribution of ieQTLs identified through long-read analysis in our understanding of the functional implications of genetic variations and the regulatory mechanisms governing isoforms.","PeriodicalId":12611,"journal":{"name":"Genome Biology","volume":"25 1","pages":""},"PeriodicalIF":12.3,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143920838","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Genome BiologyPub Date : 2025-05-08DOI: 10.1186/s13059-025-03595-6
Hongji Yang, Guorong Yu, Zhidong Lv, Tonghui Li, Xi Wang, Ying Fu, Zhangsheng Zhu, Guangjun Guo, Hang He, Ming Wang, Guochen Qin, Feng Liu, Zhenhui Zhong, Yan Xue
{"title":"Epigenome profiling reveals distinctive regulatory features and cis-regulatory elements in pepper","authors":"Hongji Yang, Guorong Yu, Zhidong Lv, Tonghui Li, Xi Wang, Ying Fu, Zhangsheng Zhu, Guangjun Guo, Hang He, Ming Wang, Guochen Qin, Feng Liu, Zhenhui Zhong, Yan Xue","doi":"10.1186/s13059-025-03595-6","DOIUrl":"https://doi.org/10.1186/s13059-025-03595-6","url":null,"abstract":"Pepper (Capsicum annuum) is one of the earliest and most widely cultivated vegetable crops worldwide. While the large and complex genome of pepper severely hampered the understanding of its functional genome, it also indicates a rich yet unexplored reservoir of regulatory elements (REs). In fact, variations in the REs represent a major driving force in evolution and domestication in both plants and animals. However, identification of the REs remains difficult especially for plants with complex genomes. Here, we present a comprehensive epigenomic landscape of Capsicum annuum, Zhangshugang (ST-8), including chromatin accessibility, histone modifications, DNA methylation, and transcriptome. We also develop comparative crosslinked immunoprecipitation mass spectrometry to reveal the proteome associated with certain chromatin features. Through integrated analysis of these epigenetic features, we profile promoters and enhancers involved in development, heat stress and cucumber mosaic virus challenges. We generate stress responsive expression networks composed of potential transcription activators and their target genes. Through population genetics analysis, we demonstrate that some regulatory elements show lower nucleotide diversity compare to other genomic regions during evolution. We demonstrate that variations in the REs may contribute to more diversified and agronomically desired phenotypes. Our study provides a foundation not only for studying gene regulation, but also for targeted genetic and epigenetic manipulation for pepper improvement.","PeriodicalId":12611,"journal":{"name":"Genome Biology","volume":"12 1","pages":""},"PeriodicalIF":12.3,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143920830","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}