Journal of Human Genetics最新文献_第7页

New insights into the clinical and molecular spectrum of the MADD-related neurodevelopmental disorder 对与 MADD 相关的神经发育障碍的临床和分子谱的新认识。

IF 3.5 3区生物学

Journal of Human Genetics Pub Date : 2024-03-08 DOI: 10.1038/s10038-024-01236-7

Ghada M. H. Abdel-Salam, Mohamed S. Abdel-Hamid

{"title":"New insights into the clinical and molecular spectrum of the MADD-related neurodevelopmental disorder","authors":"Ghada M. H. Abdel-Salam, Mohamed S. Abdel-Hamid","doi":"10.1038/s10038-024-01236-7","DOIUrl":"10.1038/s10038-024-01236-7","url":null,"abstract":"Biallelic pathogenic variants in MADD lead to a very rare neurodevelopmental disorder which is phenotypically pleiotropic grossly ranging from severe neonatal hypotonia, failure to thrive, multiple organ dysfunction, and early lethality to a similar but milder phenotype with better survival. Here, we report 5 patients from 3 unrelated Egyptian families in whom 4 patients showed the severe end of the spectrum displaying neonatal respiratory distress, hypotonia and chronic diarrhea while one patient presented with the mild form displaying moderate intellectual disability and myopathy. In addition, we observed distal arthrogryposis and nonspecific structural brain anomalies in all our patients. Interestingly, cerebellar and brainstem hypoplasia were noted in one patient. Whole exome sequencing identified three novel homozygous variants in the MADD gene: two likely pathogenic [c.4321delC p.(Gln1441ArgfsTer46) and c.2620 C > T p.(Arg874Ter)] and one variant of uncertain significance (c.4307 G > A, p.Arg1436Gln). The variants segregated with the disease in all available family members. Our findings confirm that arthrogryposis, genital, cardiac and structural brain anomalies are manifestations of MADD which expand the spectrum of MADD-related neurodevelopmental disorder. Moreover, they further highlight the convergence of MADD variants on different organ systems leading to complex phenotypes.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s10038-024-01236-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140065255","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A bird’s eye view on the use of whole exome sequencing in rare congenital ophthalmic diseases 鸟瞰全外显子测序在罕见先天性眼科疾病中的应用。

IF 3.5 3区生物学

Journal of Human Genetics Pub Date : 2024-03-08 DOI: 10.1038/s10038-024-01237-6

Jessica Zucco, Federica Baldan, Lorenzo Allegri, Elisa Bregant, Nadia Passon, Alessandra Franzoni, Angela Valentina D’Elia, Flavio Faletra, Giuseppe Damante, Catia Mio

{"title":"A bird’s eye view on the use of whole exome sequencing in rare congenital ophthalmic diseases","authors":"Jessica Zucco, Federica Baldan, Lorenzo Allegri, Elisa Bregant, Nadia Passon, Alessandra Franzoni, Angela Valentina D’Elia, Flavio Faletra, Giuseppe Damante, Catia Mio","doi":"10.1038/s10038-024-01237-6","DOIUrl":"10.1038/s10038-024-01237-6","url":null,"abstract":"Phenotypic and genotypic heterogeneity in congenital ocular diseases, especially in anterior segment dysgenesis (ASD), have created challenges for proper diagnosis and classification of diseases. Over the last decade, genomic research has indeed boosted our understanding in the molecular basis of ASD and genes associated with both autosomal dominant and recessive patterns of inheritance have been described with a wide range of expressivity. Here we describe the molecular characterization of a cohort of 162 patients displaying isolated or syndromic congenital ocular dysgenesis. Samples were analyzed with diverse techniques, such as direct sequencing, multiplex ligation-dependent probe amplification, and whole exome sequencing (WES), over 20 years. Our data reiterate the notion that PAX6 alterations are primarily associated with ASD, mostly aniridia, since the majority of the cohort (66.7%) has a pathogenic or likely pathogenic variant in the PAX6 locus. Unexpectedly, a high fraction of positive samples (20.3%) displayed deletions involving the 11p13 locus, either partially/totally involving PAX6 coding region or abolishing its critical regulatory region, underlying its significance. Most importantly, the use of WES has allowed us to both assess variants in known ASD genes (i.e., CYP1B1, ITPR1, MAB21L1, PXDN, and PITX2) and to identify rarer phenotypes (i.e., MIDAS, oculogastrointestinal-neurodevelopmental syndrome and Jacobsen syndrome). Our data clearly suggest that WES allows expanding the analytical portfolio of ocular dysgenesis, both isolated and syndromic, and that is pivotal for the differential diagnosis of those conditions in which there may be phenotypic overlaps and in general in ASD.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s10038-024-01237-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140065297","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Correction: The c.1617del variant of TMEM260 is identified as the most frequent single gene determinant for Japanese patients with a specific type of congenital heart disease 更正：TMEM260的c.1617del变异被确定为日本特定类型先天性心脏病患者最常见的单基因决定因素。

IF 3.5 3区生物学

Journal of Human Genetics Pub Date : 2024-03-08 DOI: 10.1038/s10038-024-01238-5

Tadashi Inoue, Ryuta Takase, Keiko Uchida, Kazuki Kodo, Kenji Suda, Yoriko Watanabe, Koh-Ichiro Yoshiura, Masaya Kunimatsu, Reina Ishizaki, Kenko Azuma, Kei Inai, Jun Muneuchi, Yoshiyuki Furutani, Hiroyuki Akagawa, Hiroyuki Yamagishi

引用次数: 0

Weighted burden analysis of rare coding variants in 470,000 exome-sequenced UK Biobank participants characterises effects on hyperlipidaemia risk 对英国生物库中 47 万名外显子组测序参与者的罕见编码变异进行加权负担分析，以确定其对高脂血症风险的影响。

IF 3.5 3区生物学

Journal of Human Genetics Pub Date : 2024-03-07 DOI: 10.1038/s10038-024-01235-8

David Curtis

{"title":"Weighted burden analysis of rare coding variants in 470,000 exome-sequenced UK Biobank participants characterises effects on hyperlipidaemia risk","authors":"David Curtis","doi":"10.1038/s10038-024-01235-8","DOIUrl":"10.1038/s10038-024-01235-8","url":null,"abstract":"A previous study of 200,000 exome-sequenced UK Biobank participants investigating the association between rare coding variants and hyperlipidaemia had implicated four genes, LDLR, PCSK9, APOC3 and IFITM5, at exome-wide significance. In addition, a further 43 protein-coding genes were significant with an uncorrected p value of <0.001. Exome sequence data has become available for a further 270,000 participants and weighted burden analysis to test for association with hyperlipidaemia was carried out in this sample for the 47 genes highlighted by the previous study. There was no evidence to implicate IFITM5 but LDLR, PCSK9, APOC3, ANGPTL3, ABCG5 and NPC1L1 were all statistically significant after correction for multiple testing. These six genes were also all exome-wide significant in the combined sample of 470,000 participants. Variants impairing function of LDLR and ABCG5 were associated with increased risk whereas variants in the other genes were protective. Variant categories associated with large effect sizes are cumulatively very rare and the main benefit of this kind of study seems to be to throw light on the molecular mechanisms impacting hyperlipidaemia risk, hopefully supporting attempts to develop improved therapies.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s10038-024-01235-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140059587","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Combined exome and whole transcriptome sequencing identifies a de novo intronic SRCAP variant causing DEHMBA syndrome with severe sleep disorder 外显子组和全转录组联合测序确定了一个导致严重睡眠障碍的DEHMBA综合征的全新SRCAP内含子变异体。

IF 3.5 3区生物学

Journal of Human Genetics Pub Date : 2024-03-07 DOI: 10.1038/s10038-024-01240-x

Silvia Morlino, Lorenzo Vaccaro, Maria Pia Leone, Grazia Nardella, Luigi Bisceglia, Rocco Pio Ortore, Giannandrea Verzicco, Lazzaro Cassano, Marco Castori, Davide Cacchiarelli, Lucia Micale

{"title":"Combined exome and whole transcriptome sequencing identifies a de novo intronic SRCAP variant causing DEHMBA syndrome with severe sleep disorder","authors":"Silvia Morlino, Lorenzo Vaccaro, Maria Pia Leone, Grazia Nardella, Luigi Bisceglia, Rocco Pio Ortore, Giannandrea Verzicco, Lazzaro Cassano, Marco Castori, Davide Cacchiarelli, Lucia Micale","doi":"10.1038/s10038-024-01240-x","DOIUrl":"10.1038/s10038-024-01240-x","url":null,"abstract":"Rare heterozygous variants in exons 33-34 of the SRCAP gene are associated with Floating-Harbor syndrome and have a dominant-negative mechanism of action. At variance, heterozygous null alleles falling in other parts of the same gene cause developmental delay, hypotonia, musculoskeletal defects, and behavioral abnormalities (DEHMBA) syndrome. We report an 18-year-old man with DEHMBA syndrome and obstructive sleep apnea, who underwent exome sequencing (ES) and whole transcriptome sequencing (WTS) on peripheral blood. Trio analysis prioritized the de novo heterozygous c.5658+5 G > A variant. WTS promptly demostrated four different abnormal transcripts affecting >40% of the reads, three of which leading to a frameshift. This study demonstrated the efficacy of a combined ES-WTS approach in solving undiagnosed cases. We also speculated that sleep respiratory disorder may be an underdiagnosed complication of DEHMBA syndrome.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140049674","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Correction: Genetic association and functional validation of ZFP36L2 in non-syndromic orofacial cleft subtypes 更正：ZFP36L2在非综合征口面裂亚型中的遗传关联和功能验证。

IF 3.5 3区生物学

Journal of Human Genetics Pub Date : 2024-03-05 DOI: 10.1038/s10038-024-01239-4

Jialin Sun, Mujia Li, Huaqin Sun, Ziyuan Lin, Bing Shi, Zhonglin Jia

引用次数: 0

Potential drug targets for gastroesophageal reflux disease and Barrett’s esophagus identified through Mendelian randomization analysis 通过孟德尔随机分析确定胃食管反流病和巴雷特食管的潜在药物靶点

IF 3.5 3区生物学

Journal of Human Genetics Pub Date : 2024-03-01 DOI: 10.1038/s10038-024-01234-9

Yun-Lu Lin, Tao Yao, Ying-Wei Wang, Zhi-Xiang Zhou, Ze-Chao Hong, Yu Shen, Yu Yan, Yue-Chun Li, Jia-Feng Lin

{"title":"Potential drug targets for gastroesophageal reflux disease and Barrett’s esophagus identified through Mendelian randomization analysis","authors":"Yun-Lu Lin, Tao Yao, Ying-Wei Wang, Zhi-Xiang Zhou, Ze-Chao Hong, Yu Shen, Yu Yan, Yue-Chun Li, Jia-Feng Lin","doi":"10.1038/s10038-024-01234-9","DOIUrl":"10.1038/s10038-024-01234-9","url":null,"abstract":"Gastroesophageal reflux disease (GERD) is a prevalent chronic ailment, and present therapeutic approaches are not always effective. This study aimed to find new drug targets for GERD and Barrett’s esophagus (BE). We obtained genetic instruments for GERD, BE, and 2004 plasma proteins from recently published genome-wide association studies (GWAS), and Mendelian randomization (MR) was employed to explore potential drug targets. We further winnowed down MR-prioritized proteins through replication, reverse causality testing, colocalization analysis, phenotype scanning, and Phenome-wide MR. Furthermore, we constructed a protein-protein interaction network, unveiling potential associations among candidate proteins. Simultaneously, we acquired mRNA expression quantitative trait loci (eQTL) data from another GWAS encompassing four different tissues to identify additional drug targets. Meanwhile, we searched drug databases to evaluate these targets. Under Bonferroni correction (P < 4.8 × 10−5), we identified 11 plasma proteins significantly associated with GERD. Among these, 7 are protective proteins (MSP, GPX1, ERBB3, BT3A3, ANTR2, CCM2, and DECR2), while 4 are detrimental proteins (TMEM106B, DUSP13, C1-INH, and LINGO1). Ultimately, C1-INH and DECR2 successfully passed the screening process and exhibited similar directional causal effects on BE. Further analysis of eQTLs highlighted 4 potential drug targets, including EDEM3, PBX3, MEIS1-AS3, and NME7. The search of drug databases further supported our conclusions. Our study indicated that the plasma proteins C1-INH and DECR2, along with 4 genes (EDEM3, PBX3, MEIS1-AS3, and NME7), may represent potential drug targets for GERD and BE, warranting further investigation.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140001542","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Advances in AI and machine learning for predictive medicine 人工智能和机器学习在预测医学方面的进展。

IF 2.6 3区生物学

Journal of Human Genetics Pub Date : 2024-02-29 DOI: 10.1038/s10038-024-01231-y

Alok Sharma, Artem Lysenko, Shangru Jia, Keith A. Boroevich, Tatsuhiko Tsunoda

{"title":"Advances in AI and machine learning for predictive medicine","authors":"Alok Sharma, Artem Lysenko, Shangru Jia, Keith A. Boroevich, Tatsuhiko Tsunoda","doi":"10.1038/s10038-024-01231-y","DOIUrl":"10.1038/s10038-024-01231-y","url":null,"abstract":"The field of omics, driven by advances in high-throughput sequencing, faces a data explosion. This abundance of data offers unprecedented opportunities for predictive modeling in precision medicine, but also presents formidable challenges in data analysis and interpretation. Traditional machine learning (ML) techniques have been partly successful in generating predictive models for omics analysis but exhibit limitations in handling potential relationships within the data for more accurate prediction. This review explores a revolutionary shift in predictive modeling through the application of deep learning (DL), specifically convolutional neural networks (CNNs). Using transformation methods such as DeepInsight, omics data with independent variables in tabular (table-like, including vector) form can be turned into image-like representations, enabling CNNs to capture latent features effectively. This approach not only enhances predictive power but also leverages transfer learning, reducing computational time, and improving performance. However, integrating CNNs in predictive omics data analysis is not without challenges, including issues related to model interpretability, data heterogeneity, and data size. Addressing these challenges requires a multidisciplinary approach, involving collaborations between ML experts, bioinformatics researchers, biologists, and medical doctors. This review illuminates these complexities and charts a course for future research to unlock the full predictive potential of CNNs in omics data analysis and related fields.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":null,"pages":null},"PeriodicalIF":2.6,"publicationDate":"2024-02-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s10038-024-01231-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139996432","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Dyssegmental dysplasia Rolland–Desbuquois type is caused by pathogenic variants in HSPG2 - a founder haplotype shared in five patients Rolland-Desbuquois型发育不良是由HSPG2的致病变体引起的，这是五名患者共有的一个创始单倍型。

IF 3.5 3区生物学

Journal of Human Genetics Pub Date : 2024-02-29 DOI: 10.1038/s10038-024-01229-6

Paniz Farshadyeganeh, Takahiro Yamada, Hirofumi Ohashi, Gen Nishimura, Hiroki Fujita, Yuriko Oishi, Misa Nunode, Shuku Ishikawa, Jun Murotsuki, Yuri Yamashita, Shiro Ikegawa, Tomoo Ogi, Eri Arikawa-Hirasawa, Kinji Ohno

{"title":"Dyssegmental dysplasia Rolland–Desbuquois type is caused by pathogenic variants in HSPG2 - a founder haplotype shared in five patients","authors":"Paniz Farshadyeganeh, Takahiro Yamada, Hirofumi Ohashi, Gen Nishimura, Hiroki Fujita, Yuriko Oishi, Misa Nunode, Shuku Ishikawa, Jun Murotsuki, Yuri Yamashita, Shiro Ikegawa, Tomoo Ogi, Eri Arikawa-Hirasawa, Kinji Ohno","doi":"10.1038/s10038-024-01229-6","DOIUrl":"10.1038/s10038-024-01229-6","url":null,"abstract":"Dyssegmental dysplasia (DD) is a severe skeletal dysplasia comprised of two subtypes: lethal Silverman–Handmaker type (DDSH) and nonlethal Rolland–Desbuquois type (DDRD). DDSH is caused by biallelic pathogenic variants in HSPG2 encoding perlecan, whereas the genetic cause of DDRD remains undetermined. Schwartz–Jampel syndrome (SJS) is also caused by biallelic pathogenic variants in HSPG2 and is an allelic disorder of DDSH. In SJS and DDSH, 44 and 8 pathogenic variants have been reported in HSPG2, respectively. Here, we report that five patients with DDRD carried four pathogenic variants in HSPG2: c.9970 G > A (p.G3324R), c.559 C > T (p.R187X), c7006 + 1 G > A, and c.11562 + 2 T > G. Two patients were homozygous for p.G3324R, and three patients were heterozygous for p.G3324R. Haplotype analysis revealed a founder haplotype spanning 85,973 bp shared in the five patients. SJS, DDRD, and DDSH are allelic disorders with pathogenic variants in HSPG2.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-02-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s10038-024-01229-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139996433","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Identifying the genetic associations among the psoriasis patients in eastern India 确定印度东部银屑病患者的遗传关联。

IF 3.5 3区生物学

Journal of Human Genetics Pub Date : 2024-02-27 DOI: 10.1038/s10038-024-01227-8

Shantanab Das, Aditi Chandra, Anamika Das, Swapan Senapati, Gobinda Chatterjee, Raghunath Chatterjee

{"title":"Identifying the genetic associations among the psoriasis patients in eastern India","authors":"Shantanab Das, Aditi Chandra, Anamika Das, Swapan Senapati, Gobinda Chatterjee, Raghunath Chatterjee","doi":"10.1038/s10038-024-01227-8","DOIUrl":"10.1038/s10038-024-01227-8","url":null,"abstract":"Psoriasis is a multifactorial genetic disorder manifested by hyperproliferation and abnormal differentiation of epidermal keratinocytes, along with the infiltration of inflammatory cells into the skin. Although ~80 genetic susceptibility variants were reported in psoriasis, many loci showed population-specific associations, warranting the need for more population-specific association studies in psoriasis. We determined the association of forty single nucleotide polymorphisms (SNPs) among 2136 psoriasis patients and normal individuals from eastern India. We investigated the expression of corresponding genes and evaluated the protein structure stability for the genes with susceptible coding variants. We found fifteen SNPs significantly associated with psoriasis, while additional three SNPs showed significant association when we classified the patients based on the presence of HLA-Cw6 allele. Epistatic interaction between HLA-Cw6 and other associated loci showed significant association with the SNPs at PSORS1 region, along with other five SNPs outside PSORS1. Three genes showed significant differential expression in psoriatic tissues compared to the adjacent normal skin tissues but were not differential when classified the patients based on their genotypes. SNP rs495337 at SPATA2 (Spermatogenesis Associated 2) showed a 1.2-fold increased risk among the HLA-Cw6 patients compared to combined samples. We found significant downregulation of SPATA2 among the patients with risk genotypes and HLA-Cw6 allele compared to the non-risk genotypes. Protein structure stability analysis showed reduced structural stability for all the mutant residues caused by the associated coding variants. Our study evaluated the genetic associations of psoriasis-susceptible variants in India and evaluated the possible functional significance of these associated variants in psoriasis.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139972188","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0