bioRxiv - Genetics最新文献

{"title":"Discovery and functional analysis of a novel ALPK1 variant causing ROSAH syndrome","authors":"Tom Snelling, Leo Olory-Garnotel, Isabella Jeru, Maud Tusseau, Laurence Cuisset, Antoinette Perlat, Geoffrey Minard, Thibaut Benquey, Yann Maucourant, Nicola T Wood, Philip Cohen, Alban Ziegler","doi":"10.1101/2024.09.13.612837","DOIUrl":"https://doi.org/10.1101/2024.09.13.612837","url":null,"abstract":"ROSAH syndrome is an autosomal dominant autoinflammatory disorder characterised by visual disturbance caused by pathogenic variation in the protein kinase ALPK1. Only two such variants have been reported to cause ROSAH syndrome to date: 66 out of 67 patients harbour the Thr237Met variant, while a single patient carries a Tyr254Cys variant. Here we identify a family in which ROSAH syndrome is caused by a Ser277Phe variant in ALPK1. The phenotypic variability in this family is high, with four of the seven individuals legally blind. Hypohidrosis, splenomegaly and arthritis were present in several family members. In contrast to wildtype ALPK1, which is activated specifically by the bacterial metabolite ADP-heptose during bacterial infection, ALPK1[Ser277Phe] was also activated by the human metabolites UDP-mannose and ADP-ribose, even more strongly than the ALPK1[Thr237Met] variant. However, unlike ALPK1[Thr237Met], ALPK1[Ser277Phe] could additionally be activated by GDP-mannose. These observations can explain why these ALPK1 variants are active in cells in the absence of ADP-heptose and hence why patients have episodes of autoinflammation. Examination of the three-dimensional structure of ALPK1 revealed that the sidechains of Ser277 and Tyr254 interact but mutational analysis established that this interaction is not critical for the integrity of the ADP-heptose binding site. Instead, it is the replacement of Ser277 by a large hydrophobic phenylalanine residue or the replacement of Tyr254 by a much smaller cysteine residue that is responsible for altering the specificity of the ADP-heptose-binding pocket. The characterisation of ALPK1 variants that cause ROSAH syndrome suggests ways in which drugs that inhibit these disease- causing variants selectively can be developed.","PeriodicalId":501246,"journal":{"name":"bioRxiv - Genetics","volume":"13 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142247602","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Comprehensive Proteogenomic and Spatial Analysis of Innate and Acquired Resistance of Metastatic Melanoma to Immune Checkpoint Blockade Therapies","authors":"shiyou wei, Kuang Du, Hongbin Lan, Zhenyu Yang, Yulan Deng, Zhi Wei, Dennie T Frederick, Jinho Lee, Marilyne Labrie, Tian Tian, Tabea Moll, Yeqing Chen, Ryan J. Sullivan, Gordon B Mills, Genevieve M Boland, Keith Flaherty, lunxu liu, Meenhard Herlyn, Gao Zhang","doi":"10.1101/2024.09.12.612675","DOIUrl":"https://doi.org/10.1101/2024.09.12.612675","url":null,"abstract":"While a subset of patients with metastatic melanoma achieves durable responses to immune checkpoint blockade (ICB) therapies, the majority ultimately exhibit either innate or acquired resistance to these treatments. However, the molecular mechanisms underlying resistance to ICB therapies remain elusive and are warranted to elucidate. Here, we comprehensively investigated the tumor and tumor immune microenvironment (TIME) of paired pre- and post-treatment tumor specimens from metastatic melanoma patients who were primary or secondary resistance to anti-CTLA-4 and/or anti-PD-1/PD-L1 therapies. Differentially expressed gene (DEG) analysis and single-sample gene set enrichment analysis (ssGSEA) with transcriptomic data identified cell cycle and c-MYC signaling as pathway-based resistance signatures. And weighted gene co-expression network analysis (WGCNA) revealed the activation of a cross-resistance meta-program involving key signaling pathways related to tumor progression in ICB resistant melanoma. Moreover, spatially-resolved, image-based immune monitoring analysis by using NanoString digital spatial profiling (DSP) and Cyclic Immunofluorescence (CyCIF) showed infiltration of suppressive immune cells in the tumor microenvironment of melanoma with resistance to ICB therapies. Our study reveals the molecular mechanisms underlying resistance to ICB therapies in patients with metastatic melanoma by conducting such integrated analyses of multi-dimensional data, and provides rationale for salvage therapies that will potentially overcome resistance to ICB therapies.","PeriodicalId":501246,"journal":{"name":"bioRxiv - Genetics","volume":"10 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142247598","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":"Homoploid Hybridization Resolves the Origin of Octoploid Strawberries","authors":"Zhen Fan, Aaron Liston, Douglas Soltis, Pamela Sue Soltis, Tia-Lynn Ashman, Vance M Whitaker","doi":"10.1101/2024.09.12.612680","DOIUrl":"https://doi.org/10.1101/2024.09.12.612680","url":null,"abstract":"The identity of the diploid progenitors of octoploid cultivated strawberry (Fragaria × ananassa) has been subject to much debate. Past work identified four subgenomes and consistent evidence for F. californica (previously named F. vesca subsp. bracteata) and F. iinumae as donors for subgenomes A and B, respectively, with conflicting results for the origins of subgenomes C and D. Here, reticulate phylogeny and admixture analysis support hybridization between F. viridis and F. vesca in the ancestry of subgenome A, and between F. nipponica and F. iinumae in the ancestry of subgenome B. Using an LTR-age-distribution-based approach, we estimate that the octoploid and its intermediate hexaploid and tetraploid ancestors emerged approximately 0.8, 2, and 3 million years ago, respectively. These results provide an explanation for previous reports of F. viridis and F. nipponica as donors of the C and D subgenomes and unify conflicting hypotheses about the evolutionary origin of octoploid Fragaria.","PeriodicalId":501246,"journal":{"name":"bioRxiv - Genetics","volume":"3 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142247601","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":"SMARCAD1 Regulates R-Loops at Active Replication Forks Linked to Cancer Mutation Hotspots","authors":"Sidrit Uruci, Nicole M Hoitsma, Maria E. Soler-Oliva, Aleix Bayona-Feliu, Vincent Gaggioli, Maria L. Garcia Rubio, Calvin S.Y. Lo, Collin Bakker, Jessica Marinello, Eleni Maria Manolika, Giovanni Capranico, Martijn S. Luijsterburg, Karolin Luger, Andres Aguilera, Nitika Taneja","doi":"10.1101/2024.09.13.612941","DOIUrl":"https://doi.org/10.1101/2024.09.13.612941","url":null,"abstract":"DNA replication often encounters obstacles like the stalled transcription machinery and R-loops. While ribonucleases and DNA-RNA helicases can resolve these structures, the role of chromatin remodelers remains understudied. Through a series of in vitro and in vivo experiments, we show that the chromatin remodeler SMARCAD1, which associates with active replication forks, is crucial for resolving nearby R-loops to maintain fork stability. SMARCAD1 directly binds R-loops via its ATPase domain and associates with the replisome through its N-terminus region. Both interactions are critical for resolving R-loops within cells. Genome-wide assays reveal that cells expressing mutant SMARCAD1 accumulate significantly more R-loops than wild-type cells, particularly in regions distinct from known fork blockage-prone sites. These R-loop-enriched regions in SMARCAD1 mutants also exhibit increased mutagenesis in germline tumors, suggesting they are mutation hotspots in cancer. Therefore, SMARCAD1 acts as an R-loop sensor and resolvase at actively progressing forks, maintaining genome stability and preventing tumorigenesis.","PeriodicalId":501246,"journal":{"name":"bioRxiv - Genetics","volume":"21 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142247562","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":"Tenascin C Deletion Impairs Tendon Healing and Functional Recovery After Rotator Cuff Repair","authors":"ROBERT TASHJIAN, Jared Zitnay, Nikolas Kazmers, Shivakumar Veerabhadraiah, Antonio Zelada, Matthew Honeggar, Matthew Smith, Peter Chalmers, Heath Henninger, Michael Jurynec","doi":"10.1101/2024.09.11.612543","DOIUrl":"https://doi.org/10.1101/2024.09.11.612543","url":null,"abstract":"The biological factors that affect healing after rotator cuff repair (RCR) are not well understood. Genetic variants in the extracellular matrix protein Tenascin C (TNC) are associated with impaired tendon healing and it is expressed in rotator cuff tendon tissue after injury, suggesting it may have a role in the repair process. The purpose of the current study was to determine the role of TNC on tendon healing after RCR in a murine model. The supraspinatus tendon was transected and repaired on the left shoulder of Wild-Type (WT-RCR), Tenascin C null (Tnc--RCR) and Tnc heterozygous (Tnc+/--RCR) mice. Controls included the unoperated, contralateral shoulder of WT-RCR, Tnc-RCR, Tnc+/--RCR mice and unoperated shoulders from age and genotype matched controls. We performed histologic, activity testing, RNA-seq, and biomechanical analyses. At 8-weeks post-RCR, Tnc- and Tnc+/- mice had severe bone and tendon defects following rotator cuff repair. Tnc--RCR mice had reduced activity after rotator cuff repair including reduced wheel rotations, wheel duration, and wheel episode average velocity compared with WT-RCR. Loss of Tnc following RCR altered gene expression in the shoulder, including upregulation of sex hormone and WNT pathways and a downregulation of inflammation and cell cycle pathways. Tnc- mice had similar biomechanical properties after repair as WT. Further research is required to evaluate tissue specific alterations of Tnc, the interactions of Tnc and sex hormone and inflammation pathways as well as possible adjuvants to improve enthesis healing in the setting of reduced TNC function.","PeriodicalId":501246,"journal":{"name":"bioRxiv - Genetics","volume":"196 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142247597","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":"Solanum pan-genomics and pan-genetics reveal paralogs as contingencies in crop engineering","authors":"Matthias Benoit, Katharine M Jenike, James W Satterlee, Srividya Ramakrishnan, Iacopo Gentile, Anat Hendelman, Michael J Passalacqua, Hamsini Suresh, Hagai Shohat, Gina M Robitaille, Blaine Fitzgerald, Michael M Alonge, Xingang Wang, Ryan Santos, Jia He, Shujun Ou, Hezi Golan, Yumi Green, Kerry Swartwood, Gina P Sierra, Andres Orejuela, Federico Fornaguera, Sara Goodwin, William Richard McCombie, Elizabeth Balyejusa Kizito, Edeline Gagnon, Sandra Knapp, Tiina Sarkinen, Amy Frary, Jesse Gillis, Joyce Van Eck, Michael C Schatz, Zachary B Lippman","doi":"10.1101/2024.09.10.612244","DOIUrl":"https://doi.org/10.1101/2024.09.10.612244","url":null,"abstract":"Pan-genomics and genome editing technologies are revolutionizing the breeding of globally cultivated crops. A transformative opportunity lies in the reciprocal exchange of genotype-to-phenotype knowledge of agricultural traits between these major crops and hundreds of locally cultivated indigenous crops, thereby enhancing the diversity and resilience of our food system. However, species-specific genetic variants and their interactions with desired natural or engineered mutations pose barriers to achieving predictable phenotypic effects, even between closely related crops or genotypes. Here, by establishing a pan-genome of the crop-rich genus Solanum and integrating functional genomics and genetics, we show that gene duplication and subsequent paralog diversification are a major obstacle to genotype-phenotype predictability. Despite broad conservation of gene macrosynteny among chromosome-scale references for 22 species, including 13 indigenous crops, hundreds of global and lineage-specific gene duplications exhibited dynamic evolutionary trajectories in paralog sequence, expression, and function, including among members of key domestication gene families. Extending our pan-genome with 10 cultivars of African eggplant and leveraging quantitative genetics and genome editing, we uncovered an intricate history of paralog emergence and evolution within this indigenous crop. The loss of an ancient redundant paralog of the classical regulator of stem cell proliferation and fruit organ number, CLAVATA3 (CLV3), was compensated by a lineage-specific tandem duplication. Subsequent pseudogenization of the derived copy followed by a cultivar-specific structural variant resulted in a single fused functional copy of CLV3 that modifies locule number alongside a newly identified gene controlling the same trait. Our findings demonstrate that paralog diversifications over short evolutionary periods are critical yet underexplored contingencies in trait evolvability and independent crop domestication histories. Unraveling these contingencies is crucial for translating genotype-to-phenotype relationships across related species.","PeriodicalId":501246,"journal":{"name":"bioRxiv - Genetics","volume":"61 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142247605","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":"SCAMPI: A scalable statistical framework for genome-wide interaction testing harnessing cross-trait correlations","authors":"Shijia Bian, Andrew J. Bass, Yue Liu, Aliza P. Wingo, Thomas Wingo, David J. Cutler, Michael P. Epstein","doi":"10.1101/2024.09.10.612314","DOIUrl":"https://doi.org/10.1101/2024.09.10.612314","url":null,"abstract":"Family-based heritability estimates of complex traits are often considerably larger than their single-nucleotide polymorphism (SNP) heritability estimates. This discrepancy may be due to non-additive effects of genetic variation, including variation that interacts with other genes or environmental factors to influence the trait. Variance-based procedures provide a computationally efficient strategy to screen for SNPs with potential interaction effects without requiring the specification of the interacting variable. While valuable, such variance-based tests consider only a single trait and ignore likely pleiotropy among related traits that, if present, could improve power to detect such interaction effects. To fill this gap, we propose SCAMPI (Scalable Cauchy Aggregate test using Multiple Phenotypes to test Interactions), which screens for variants with interaction effects across multiple traits. SCAMPI is motivated by the observation that SNPs with pleiotropic interaction effects induce genotypic differences in the patterns of correlation among traits. By studying such patterns across genotype categories among multiple traits, we show that SCAMPI has improved performance over traditional univariate variance-based methods. Like those traditional variance-based tests, SCAMPI permits the screening of interaction effects without requiring the specification of the interaction variable and is further computationally scalable to biobank data. We employed SCAMPI to screen for interacting SNPs associated with four lipid-related traits in the UK Biobank and identified multiple gene regions missed by existing univariate variance-based tests. SCAMPI is implemented in software for public use.","PeriodicalId":501246,"journal":{"name":"bioRxiv - Genetics","volume":"21 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142268419","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":"EBAX-1/ZSWIM8 destabilizes miRNAs resulting in transgenerational memory of a predatory trait","authors":"Shiela Pearl Quiobe, Ata Kalirad, Waltraud Roeseler, Hanh Witte, Yinan Wang, Christian Roedelsperger, Ralf J. Sommer","doi":"10.1101/2024.09.10.612280","DOIUrl":"https://doi.org/10.1101/2024.09.10.612280","url":null,"abstract":"Environmental influences on traits and associated transgenerational epigenetic inheritance have widespread implications, but remain controversial and underlying mechanisms poorly understood. We introduce long-term environmental induction experiments on alternative diets in <em>Pristionchus pacificus</em>, a nematode exhibiting mouth-form plasticity including predation, by propagating 110 isogenic lines for 101 generations with associated food-reversal experiments. We found dietary induction and subsequent transgenerational memory of the predatory morph and identified a role of ubiquitin ligase EBAX-1/ZSWIM8 in this process. <em>Ppa-ebax-1</em> mutants have no memory and <em>Ppa</em>-EBAX-1 destabilizes the clustered microRNA family <em>miR-2235a/miR-35</em>. Deletions of a cluster of 44 identical <em>miR-2235a</em> copies resulted in precocious and extended transgenerational inheritance of the predatory morph. These findings indicate that EBAX-1/ZSWIM8 destabilizes miRNAs resulting in transgenerational memory, suggesting a role for target-directed miRNA degradation.","PeriodicalId":501246,"journal":{"name":"bioRxiv - Genetics","volume":"21 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142268414","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":"Pushing the limits of single molecule transcript sequencing to uncover the largest disease-associated transcript isoforms in the human neural retina","authors":"Merel Stemerdink, Tabea Riepe, Nick Zomer, Renee Salz, Michael Kwint, Raoul Timmermans, Barbara Ferrari, Stefano Ferrari, Alfredo Duenas Rey, Emma Delanote, Suzanne E de Bruijn, Hannie Kremer, Susanne Roosing, Frauke Coppieters, Alexander Hoischen, Frans P.M. Cremers, Peter A.C. 't Hoen, Erwin van Wijk, Erik de Vrieze","doi":"10.1101/2024.09.10.612265","DOIUrl":"https://doi.org/10.1101/2024.09.10.612265","url":null,"abstract":"Sequencing technologies have long limited the comprehensive investigation of large transcripts associated with inherited retinal diseases (IRDs) like Usher syndrome, which involves 11 associated genes with transcripts up to 19.6 kb. To address this, we used PacBio long-read mRNA isoform sequencing (Iso-Seq) following standard library preparation and an optimized workflow to enrich for long transcripts in the human neural retina. While our workflow achieved sequencing of transcripts up to 15 kb, this was insufficient for Usher syndrome-associated genes USH2A and ADGRV1, with transcripts of 18.9 kb and 19.6 kb, respectively. To overcome this, we employed the Samplix Xdrop System for indirect target enrichment of cDNA, a technique typically used for genomic DNA capture. This method facilitated the successful capture and sequencing of ADGRV1 transcripts as well as the full-length 18.9 kb USH2A transcripts. By combining algorithmic analysis with detailed manual curation of sequenced reads, we identified novel isoforms and alternative splicing events across the 11 Usher syndrome-associated genes, with implications for diagnostics and therapy development. Our findings demonstrate the Xdrop systems adaptability for cDNA capture and the advantages of integrating computational and manual transcript analyses. The full neural retina sequencing dataset is available via EGA under identifier EGAD50000000720.","PeriodicalId":501246,"journal":{"name":"bioRxiv - Genetics","volume":"77 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142268420","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":"Stabilising selection enriches the tails of complex traits with rare alleles of large effect","authors":"Anil PS Ori, Carla Giner-Delgado, Clive Julian Hoggart, Paul F O'Reilly","doi":"10.1101/2024.09.12.612687","DOIUrl":"https://doi.org/10.1101/2024.09.12.612687","url":null,"abstract":"Establishing the relative contribution of common and rare variants to complex trait heritability is a key goal of biomedical research. Recent statistical genetics inference suggests that common variants explain most complex trait heritability, but little is known about how genetic architecture varies across the trait continuum. If rare variants make a small contribution to heritability but have their effects concentrated in the tails of complex traits, where disease typically manifests, then they may have a greater clinical impact than previously inferred. Here, we perform simulations using the forward-in-time simulator SLiM to generate realistic population genetic and complex trait data, in which traits evolve under neutrality or stabilising selection. Recent studies suggest that stabilising selection is the dominant force shaping the genetic architecture of complex traits, consistent with our simulations in that data simulated under stabilising selection here more closely resembles real data. Moreover, we observe a shift of rare, large-effect alleles towards the tails of the complex trait distribution under stabilising selection. In our simulations, individuals in the tails of complex traits are, depending on the strength of selection, 10-20x more likely to harbour singleton or extremely rare alleles of large effect under stabilising selection than neutrality. Such an enrichment of rare, large-effect alleles in the tails of real complex traits subject to stabilising selection could have important implications for the design of studies to detect rare variants, as well as for the prediction and prevention of complex disease.","PeriodicalId":501246,"journal":{"name":"bioRxiv - Genetics","volume":"109 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142179732","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}