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Complete reference genome and pangenome improve genome-wide detection and interpretation of DNA methylation using sequencing and array data

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Cell Reports 2025年第6期44卷

作者： Zheng Dong Joanne Whitehead Maggie Fu Julia L. MacIsaac David H. Rehkopf Luis Rosero-Bixby Michael S. Kobor Keegan Korthauer Centre for Molecular Medicine and Therapeutics University of British Columbia 950 West 28th Avenue Vancouver BC V5Z 4H4 Canada BC Children’s Hospital Research Institute University of British Columbia 950 West 28th Avenue Vancouver BC V5Z 4H4 Canada Genome Science and Technology Graduate Program University of British Columbia 100-570 West 7th Avenue Vancouver BC V5Z 4S6 Canada Division of General Medical Disciplines Department of Medicine School of Medicine Stanford University 1070 Arastradero Road Suite 300 Palo Alto CA 94304 USA Centro Centroamericano de Población (CCP) Universidad de Costa Rica San José 2060 Costa Rica Department of Medical Genetics University of British Columbia 950 West 28th Avenue Vancouver BC V5Z 4H4 Canada Edwin S. H. Leong Centre for Healthy Aging University of British Columbia 117-2194 Health Science Mall Vancouver BC V6T 1Z3 Canada Department of Statistics University of British Columbia 2207 Main Mall Vancouver BC V6T 1Z4 Canada

The complete telomere-to-telomere human genome assembly (T2T-CHM13) and the draft human pangenome reference provide unique opportunities to refine DNA methylation (DNAm) studies. Here, we find that T2T-CHM13 calls 7.4% more CpGs genome wide compared to GRCh38 across four widely used short-read DNAm profiling methods and improves the evaluation of probe cross-reactivity and mismatch for Illumina DNAm arrays, yielding new and more reproducible sets of unambiguous probes. The pangenome reference further expands CpG calling by 4.5% in short-read sequencing data and identifies cross-population and population-specific unambiguous probes in DNAm arrays, owing to its improved representation of genetic diversity. These benefits facilitate the discovery of biologically relevant DNAm alterations in epigenome-wide association studies (EWASs). For instance, additional DNAm alterations enriched in cancer-related genes and pathways are identified in cancer EWASs. Together, this study highlights the practical applications of T2T-CHM13 and pangenome for genome biology and provides a basis for expansion of DNAm investigations.

关键词： T2T-CHM13 pangenome epigenetics bisulfite sequencing cross-reactive probe Illumina Infinium HumanMethylation BeadChips annotation Illumina HumanMethylationEPIC BeadChip Infinium MethylationEPIC v.2.0 EPICv2 epigenome-wide association study cancer

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k-mer-based approaches to bridging pangenomics and population genetics

arXiv

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arXiv 2024年

作者： Roberts, Miles D. Davis, Olivia Josephs, Emily B. Williamson, Robert J. Genetics and Genome Sciences Program Michigan State University East LansingMI48824 United States Department of Computer Science and Software Engineering Rose-Hulman Institute of Technology Terre HauteIN47803 United States Department of Biology and Biomedical Engineering Rose-Hulman Institute of Technology Terre HauteIN47803 United States Department of Plant Biology Michigan State University East LansingMI48824 United States Ecology Evolution and Behavior Program Michigan State University East LansingMI48824 United States Plant Resilience Institute Michigan State University East LansingMI48824 United States

Many commonly studied species now have more than one chromosome-scale genome assembly, revealing a large amount of genetic diversity previously missed by approaches that map short reads to a single reference. However, many species still lack multiple reference genomes and correctly aligning references to build pangenomes is challenging, limiting our ability to study this missing genomic variation in population genetics. Here, we argue that k-mers are a crucial stepping stone to bridging the reference-focused paradigms of population genetics with the reference-free paradigms of pangenomics. We review current literature on the uses of k-mers for performing three core components of most population genetics analyses: identifying, measuring, and explaining patterns of genetic variation. We also demonstrate how different k-mer-based measures of genetic variation behave in population genetic simulations according to the choice of k, depth of sequencing coverage, and degree of data compression. Overall, we find that k-mer-based measures of genetic diversity scale consistently with pairwise nucleotide diversity (π) up to values of about π = 0.025 (R2 = 0.97) for neutrally evolving populations. For populations with even more variation, using shorter k-mers will maintain the scalability up to at least π = 0.1. Furthermore, in our simulated populations, k-mer dissimilarity values can be reliably approximated from counting bloom filters, highlighting a potential avenue to decreasing the memory burden of k-mer based genomic dissimilarity analyses. For future studies, there is a great opportunity to further develop methods to identifying selected loci using k-mers. © 2024, CC BY.

关键词： genome

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Ontology engineering

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Nature Biotechnology 2010年第2期28卷 128-130页

作者： Alterovitz, Gil Xiang, Michael Hill, David P. Lomax, Jane Liu, Jonathan Cherkassky, Michael Dreyfuss, Jonathan Mungall, Chris Harris, Midori A. Dolan, Mary E. Blake, Judith A. Ramoni, Marco F. Children's Hospital Informatics Program Harvard-MIT Division of Health Sciences and Technology Harvard Medical School Boston MA United States Partners Healthcare Center for Personalized Genetic Medicine Boston MA United States Department of Electrical Engineering and Computer Science Massachusetts Institute of Technology Cambridge MA United States Jackson Laboratory Bar Harbor ME United States EMBL-EBI Wellcome Trust Genome Campus Hinxton United Kingdom Department of Biology Massachusetts Institute of Technology Cambridge MA United States Lawrence Berkeley National Laboratory Berkeley CA United States

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Single-nucleus chromatin accessibility profiling highlights regulatory mechanisms of coronary artery disease risk (vol 54, pg 804, 2022)

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NATURE GENETICS 2022年第8期54卷 1259-1259页

作者： Turner, Adam W. Hu, Shengen Shawn Mosquera, Jose Verdezoto Ma, Wei Feng Hodonsky, Chani J. Wong, Doris Auguste, Gaelle Song, Yipei Sol-Church, Katia Farber, Emily Kundu, Soumya Kundaje, Anshul Lopez, Nicolas G. Ma, Lijiang Ghosh, Saikat Kumar B. Onengut-Gumuscu, Suna Ashley, Euan A. Quertermous, Thomas Finn, Aloke V. Leeper, Nicholas J. Kovacic, Jason C. Bjorkegren, Johan L. M. Zang, Chongzhi Miller, Clint L. Center for Public Health Genomics University of Virginia Charlottesville VA USA Department of Biochemistry and Molecular Genetics University of Virginia Charlottesville VA USA Medical Scientist Training Program University of Virginia Charlottesville VA USA Department of Pathology University of Virginia Charlottesville VA USA Robert M. Berne Cardiovascular Research Center University of Virginia Charlottesville VA USA Genome Analysis & Technology Core University of Virginia Charlottesville VA USA Genome Sciences Laboratory University of Virginia Charlottesville VA USA Department of Genetics Stanford University School of Medicine Stanford CA USA Department of Computer Science Stanford University Stanford CA USA Division of Vascular Surgery Department of Surgery Stanford University Stanford CA USA Department of Genetics and Genomic Sciences Icahn Institute for Genomics and Multiscale Biology Icahn School of Medicine at Mount Sinai New York NY USA CVPath Institute Gaithersburg MD USA Department of Public Health Sciences University of Virginia Charlottesville VA USA Division of Cardiovascular Medicine Department of Medicine Stanford University Stanford CA USA Cardiovascular Research Institute Icahn School of Medicine at Mount Sinai New York NY USA Victor Chang Cardiac Research Institute Darlinghurst New South Wales Australia St. Vincent’s Clinical School University of New South Wales Sydney New South Wales Australia Integrated Cardio Metabolic Centre Department of Medicine Karolinska Institutet Huddinge Sweden

Coronary artery disease (CAD) is a complex inflammatory disease involving genetic influences across cell types. genome-wide association studies have identified over 200 loci associated with CAD, where the majority of risk variants reside in noncoding DNA sequences impacting cis-regulatory elements. Here, we applied single-nucleus assay for transposase-accessible chromatin with sequencing to profile 28,316 nuclei across coronary artery segments from 41 patients with varying stages of CAD, which revealed 14 distinct cellular clusters. We mapped ~320,000 accessible sites across all cells, identified cell-type-specific elements and transcription factors, and prioritized functional CAD risk variants. We identified elements in smooth muscle cell transition states (for example, fibromyocytes) and functional variants predicted to alter smooth muscle cell- and macrophage-specific regulation of MRAS (3q22) and LIPA (10q23), respectively. We further nominated key driver transcription factors such as PRDM16 and TBX2. Together, this single-nucleus atlas provides a critical step towards interpreting regulatory mechanisms across the continuum of CAD risk.

关键词： Atherosclerosis Epigenomics Gene regulation

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Cell free translation in engineered picoliter volume containers

Cell free translation in engineered picoliter volume contain...

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Annual ORNL Biomedical science & Engineering Conference (BSEC)

作者： Piro Siuti Scott T. Retterer Chang Kyoung Choi Jason D. Fowlkes Mitchel J. Doktycz Genome Science and Technology program University of Tennessee Knoxville TN USA Biosciences Division and the Center of Nanophase Materials Sciences Oak Ridge National Laboratory USA Mechanical Engineering-Engineering Mechanics Michigan Technological University MI USA Oak Ridge National Laboratory USA Center of Nanophase Materials Sciences Oak Ridge National Laboratory USA Biosciences Division and the Center of Nanophase Materials Sciences Oak Ridge National Laboratory Oak Ridge TN USA

ISBN: (纸本)9781424438372

Engineers seek to use biological design principles to manipulate information and import new functionality to synthetic devices. Such devices inspired by natural systems could, in turn, play a crucial role in allowing biologists to explore the effects of physical transport and extreme conditions of temperature and pH on reaction systems. For example, engineered reaction containers can be physically and chemically defined to control the flux of molecules of different sizes and charge. The design and testing of such a container is described here. It has a volume of 19 pL with defined slits of 200 nm. The device successfully contained DNA and protein molecules and is evaluated for carrying out cell-free protein synthesis. The effect of DNA concentration and slit size on protein yield is discussed.

关键词： Containers Biological materials Nanostructured materials Nanobioscience Laboratories DNA Biomembranes Design engineering Protein engineering Size control

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genome-Wide Association Study in Thai Tsunami Survivors Identified Risk Alleles for Posttraumatic Stress Disorder

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Open Journal of Genetics 2015年第2期5卷 43-57页

作者： Nuntika Thavichachart Taisei Mushiroda Thongchai Thavichachart Ongart Charoensook Anchalee Prasansuklab Prathan Rutchatajumroon Sookjaroen Tangwongchai Puangsoi Worakul Buranee Kanchanatawan Siriluck Suppapitiporn Atapol Sughondhabirom Chutima Roomruangwong Wasun Chantratita Atsushi Takahashi Michiaki Kubo Naoyuki Kamatani Yusuke Nakamura Department of Psychiatry Faculty of Medicine Chulalongkorn University Bangkok Thailand Laboratory for Pharmacogenetics RIKEN Center for Genomic Medicine Kanagawa Japan Thailand Center of Excellence for Life Sciences (Public Organization) Ministry of Science and Technology Bangkok Thailand Ph.D. Program in Clinical Biochemistry and Molecular Medicine Department of Clinical Chemistry Faculty of Allied Health Sciences Chulalongkorn University Bangkok Thailand Department of Pathology Faculty of Medicine Mahidol University Bangkok Thailand Laboratory for Statistical Analysis RIKEN Center for Genomic Medicine Kanagawa Japan Laboratory for Genotyping Development RIKEN Center for Genomic Medicine Kanagawa Japan Laboratory of Molecular Medicine Human Genome Center Institute of Medical Science The University of Tokyo Tokyo Japan

Posttraumatic stress disorder (PTSD) is a psychiatric disorder found in individuals afflicted by a traumatic event. Multiple environmental and genetic factors can contribute to PTSD susceptibility. Since it is rare to find members of the same family afflicted by the same catastrophic event, it is not practical to determine PTSD susceptibility genes by a gene linkage analysis. A natural disaster, such as the 2004 Tsunami, provided us with a rare chance for a genetic analysis of PTSD. To identify SNPs associated with PTSD susceptibility, we conducted a genome-association study (GWAS) in Thai-Tsunami survivors. Initial phase of the study with 396 chronic PTSD patients and 457 controls, we identified top ninety SNPs (P -4), which were further assessed in the second phase with 395 chronic PTSD patients and 798 controls. Two SNPs (rs267950 and rs954406), were identified in the second phase, and subjected to fine mapping using a data set from both phases. SNP rs267943 showed the strongest association with PTSD susceptibility and was in complete linkage disequilibrium with SNP rs267950 with P = 6.15 × 10-8, OR = 1.46 and 95% CI = 1.19 - 1.79, reaching genome-wide significance. SNP rs267943 is located on chromosome 5 in the intron of the death-associated protein 1 (DAP1) gene and, when linked to a synthetic promoter, could regulate transcription. To our knowledge, this is the first GWAS for PTSD susceptibility in an Asian population which could provide an important insight into the genetic contribution of PTSD and may lead to new treatment strategies for PTSD.

关键词： Death-Associated Protein 1 Gene (DAP1) Genetics genome-Wide Association Study (GWAS) Posttraumatic Stress Disorder (PTSD) Tsunami

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Publisher Correction: The ENCODE Imputation Challenge: a critical assessment of methods for cross-cell type imputation of epigenomic profiles

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genome biology 2025年第1期26卷 31页

作者： Jacob Matthew Schreiber Carles A Boix Jin Wook Lee Hongyang Li Yuanfang Guan Chun-Chieh Chang Jen-Chien Chang Alex Hawkins-Hooker Bernhard Schölkopf Gabriele Schweikert Mateo Rojas Carulla Arif Canakoglu Francesco Guzzo Luca Nanni Marco Masseroli Mark James Carman Pietro Pinoli Chenyang Hong Kevin Y Yip Jefrey P Spence Sanjit Singh Batra Yun S Song Shaun Mahony Zheng Zhang Wuwei Tan Yang Shen Yuanfei Sun Minyi Shi Jessika Adrian Richard S Sandstrom Nina P Farrell Jessica M Halow Kristen Lee Lixia Jiang Xinqiong Yang Charles B Epstein J Seth Strattan Bradley E Bernstein Michael P Snyder Manolis Kellis William S Noble Anshul Bharat Kundaje Department of Genetics Stanford University Stanford CA USA. jmschreiber91@***. Computer Science and Artificial Intelligence Laboratory Massachusetts Institute of Technology Cambridge MA USA. Department of Genetics Stanford University Stanford CA USA. Department of Computational Medicine and Bioinformatics University of Michigan Ann Arbor MI USA. Department of Research and Development DeepSeq.AI San Francisco CA USA. RIKEN Center for Integrative Medical Sciences Yokohama Japan. Department of Empirical Inference Max Planck Institute for Intelligent Systems Stuttgart Germany. School of Life Sciences University of Dundee Dundee UK. Department of Electronics Information and Bioengineering Politecnico Di Milano Milan Italy. Department of Computational Biology University of Lausanne Lausanne Switzerland. Department of Computer Science and Engineering The Chinese University of Hong Kong Sha Tin Hong Kong. Sanford Burnham Prebys Medical Discovery Institute San Diego CA USA. Department of Electrical Engineering and Computer Sciences University of California Berkeley Berkeley CA USA. Department of Statistics University of California Berkeley Berkeley CA USA. Department of Biochemistry & Molecular Biology Center for Eukaryotic Gene Regulation Pennsylvania State University University Park PA USA. Department of Statistics Pennsylvania State University University Park PA USA. Department of Electrical and Computer Engineering Texas A&M University College Station TX USA. Altius Institute Seattle WA USA. Epigenomics Program The Broad Institute of MIT and Harvard Cambridge MA USA. Department of Genome Sciences University of Washington Seattle WA USA. Department of Computer Science Stanford University Stanford CA USA.

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A unified theory of grain growth in polycrystalline materials

arXiv

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arXiv 2018年

作者： Hu, Jianfeng Wang, Xianhao Zhang, Junzhan Shen, Zhijian Luo, Jun Luo, Jian School of Materials Science and Engineering Shanghai University Shanghai200444 China Carl Zeiss Co. Shanghai 60 Meiyue road Shanghai200131 China Department of Materials and Environmental Chemistry Arrhenius Laboratory Stockholm University StockholmS-106 91 Sweden College of Materials and Mineral Resources Xi'an University of Architecture and Technology 13 Yanta Road Xi'an710055 China Materials Genome Institute Shanghai University Shanghai200444 China Department of Nano Engineering Program of Materials Science and Engineering University of California San Diego San diegoCA92093 United States

Grain growth is a ubiquitous and fundamental phenomenon observed in the cellular structures with the grain assembly separated by a network of grain boundaries, including metals and ceramics. However, the underlying mechanism of grain growth has remained ambiguous for more than 60 years. The models for grain growth, based on the classically linear relationship between the grain boundary migration and capillary driving force, generally predict normal grain growth. Quantitative model for abnormal grain growth is lacking despite decades of efforts. Here, we present a unified model to reveal quantitatively how grain growth evolves, which predicts the normal, abnormal and stagnant behaviors of grain growth in polycrystalline materials. Our model indicates that the relationship between grain boundary migration and capillary driving force is generally nonlinear, but will switch to be the classically linear relationship in a specific case. Furthermore, the grain growth experiments observed in polycrystalline SrTiO3 demonstrates the validity of the unified model. Our study provides a unified, quantitative model to understand and predict grain growth in polycrystalline materials, and thus offers helpful guides for the microstructural design to optimize the properties of polycrystalline materials. © 2018, CC BY.

关键词： Grain growth

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Functional Analysis of Semi-conserved Transit Peptide Motifs and Mechanistic Implications in Precursor Targeting and Recognition

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Molecular Plant 2016年第9期9卷 1286-1301页

作者： Kristen Holbrook Chitra Subramanian Prakitchai Chotewutmontri L. Evan Reddick Sarah Wright Huixia Zhang Lily Moncrief Barry D. Bruce Department of Biochemistry Cellular and Molecular Biology Graduate Program in Plant Physiology and Genetics Graduate School of Genome Science and Technology Department of Botany Department of BotanyUniversity of Tennessee Knoxville TN 37996 USA Present address: Department of Infectious Disease St. Jude Children's Research Hospital Memphis TN 38105 USA Present address: Institute of Molecular Biology University of Oregon Eugene OR 97403 USA present address: Department of Microbiology University of Texas Southwestern Medical Center 5323 Harry Hines Boulevard Dallas TX 75390 USA Present address: Albert R. Mann Library Cornell University Ithaca NY 14850 USA present address: U.S. Food and Drug Administration 10903 New Hampshire Avenue Silver Spring MD 20993 USA

Over 95% of plastid proteins are nuclear-encoded as their precursors containing an N-terminal extension known as the transit peptide （TP）. Although highly variable, TPs direct the precursors through a conserved, posttranslational mechanism involving translocons in the outer （TOC） and inner envelope （TOC）. The organelle import specificity is mediated by one or more components of the Toc complex. However, the high TP diversity creates a paradox on how the sequences can be specifically recognized. An emerging model of TP design is that they contain multiple loosely conserved motifs that are recognized at different steps in the targeting and transport process. Bioinformatics has demonstrated that many TPs contain semiconserved physicochemical motifs, termed FGLK. In order to characterize FGLK motifs in TP recognition and import, we have analyzed two well-studied TPs from the precursor of RuBisCO small subunit （SStp） and ferredoxin （Fdtp）. Both SStp and Fdtp contain two FGLK motifs. Analysis of large set mutations （-85） in these two motifs using in vitro, in organello, and in vivo approaches support a model in which the FGLK domains mediate interaction with TOC34 and possibly other TOC components. In vivo import analysis suggests that multiple FGLK motifs are functionally redundant. Furthermore, we discuss how FGLK motifs are required for efficient precursor protein import and how these elements may permit a convergent function of this highly variable class of targeting sequences.

关键词： chloroplast biology protein translocation Toc34 transit peptide cell biology

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Ophthalmic characteristics and retinal vasculature changes in Williams syndrome, and its association with systemic diseases

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Eye (Basingstoke) 2023年第11期37卷 2265-2271页

作者： Yeh, Tsai-Chu Cheng, Hui-Chen Li, Hsing-Yuan Chi, Sheng Chu Yang, Hsin-Yu Yu, Jenn-Yah Niu, Dau-Ming Wang, An-Guor School of Medicine National Yang Ming Chiao Tung University Taipei Taiwan Department of Ophthalmology Taipei Veterans General Hospital Taipei Taiwan Department of Ophthalmology School of Medicine National Yang Ming Chiao Tung University Taipei Taiwan Program in Molecular Medicine College of Life Sciences National Yang Ming Chiao Tung University Taipei Taiwan Department of Life Sciences and Institute of Genome Sciences College of Life Sciences National Yang Ming Chiao Tung University Taipei Taiwan Brain Research Center National Yang Ming Chiao Tung University Taipei Taiwan Department of Pediatrics Taipei Veterans General Hospital Taipei Taiwan Department of Biological Science and Technology National Yang Ming Chiao Tung University Hsinchu Taiwan Institute of Biology and Anatomy National Defense Medical Center Taipei Taiwan Taipei Veterans General Hospital Yuanshan and Suao Branch Yilan Taiwan Institute of Clinical Medicine National Yang Ming Chiao Tung University Taipei Taiwan

Background: We aim to characterise the ophthalmic findings and retinal vasculature changes in patients with WS, and to analyse the correlation between ophthalmic manifestations and the associated systemic diseases. Methods: This retrospective case-control study included 27 WS patients and 28 age-matched healthy participants. Stellate pattern of iris, central macular thickness (CMT), foveal width, retinal vessel diameter, superficial vascular density (SVD) of macula and foveal avascular zone (FAZ) were compared between WS patients and healthy participants. Results: Twenty-five patients (93%) had the classic stellate iris presentation. Compared with healthy controls, WS patients had decreased CMT, increased foveal width and a lower SVD of macula (all P < 0.001). Significantly decreased mean retinal arterial (117.9 ± 9.9 µm vs. 133.0 ± 6.7 µm in WS and controls, respectively;p < 0.001) and venous (158.9 ± 11.2 µm vs. 174.0 ± 8.0 µm in WS and controls, respectively;p < 0.001) outer diameters, as well as mean arterial wall thickness (11.2 ± 1.3 µm vs. 12.2 ± 0.8 µm in WS and controls, respectively;p < 0.01) were found in WS. Stellate iris grading was significantly associated with CMT, foveal width, retinal vessel diameter (all p < 0.05), and a significant increase in the odds of having hypertension (Odds ratio (OR), 5.63;P < 0.05). The severity of stellate iris in WS seemed to have the trend of increasing risk of having pulmonary stenosis, tricuspid regurgitation and mitral regurgitation. Conclusions: This study provides the first in vivo evidence reflecting current knowledge on vessel morphology in WS patients that deficient circumferential growth is the predominant pathophysiologic changes resulting from elastin deficiency. The ophthalmic characteristics may serve as a complementary tool to diagnose and follow-up patients suffering from WS. © 2022, The Author(s), under exclusive licence to The Royal College of Ophthalmologists.

关键词： Eye manifestations Predictive markers

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