Abstract：
:Accurately modeling cellular response to perturbations is a central goal of computational biology. While such modeling has been based on statistical, mechanistic and machine learning models in specific settings, no generalization of predictions to phenomena absent from training data (out-of-sample) has yet been demonstrated. Here, we present scGen (https://github.com/theislab/scgen), a model combining variational autoencoders and latent space vector arithmetics for high-dimensional single-cell gene expression data. We show that scGen accurately models perturbation and infection response of cells across cell types, studies and species. In particular, we demonstrate that scGen learns cell-type and species-specific responses implying that it captures features that distinguish responding from non-responding genes and cells. With the upcoming availability of large-scale atlases of organs in a healthy state, we envision scGen to become a tool for experimental design through in silico screening of perturbation response in the context of disease and drug treatment.
journal_name
Nat Methodsjournal_title
Nature methodsauthors
Lotfollahi M,Wolf FA,Theis FJdoi
10.1038/s41592-019-0494-8subject
Has Abstractpub_date
2019-08-01 00:00:00pages
715-721issue
8eissn
1548-7091issn
1548-7105pii
10.1038/s41592-019-0494-8journal_volume
16pub_type
杂志文章相关文献
NATURE METHODS文献大全abstract：:We discuss the advantages and challenges of the open-source strategy in biological image analysis and argue that its full impact will not be realized without better support and recognition of software engineers' contributions to the biological sciences and more support of this development model from funders and instit...
journal_title：Nature methods
pub_type： 杂志文章
doi：10.1038/nmeth.2082
更新日期：2012-06-28 00:00:00
abstract：:A quantitative high-throughput FRET-based method of screening fluorescent protein fusion libraries brings the promise of more detailed interactome maps. ...
journal_title：Nature methods
pub_type： 杂志文章
doi：10.1038/nmeth0207-112b
更新日期：2007-02-01 00:00:00
abstract：:Bisulfite sequencing measures absolute levels of DNA methylation at single-nucleotide resolution, providing a robust platform for molecular diagnostics. We optimized bisulfite sequencing for genome-scale analysis of clinical samples: here we outline how restriction digestion targets bisulfite sequencing to hotspots of...
journal_title：Nature methods
pub_type： 杂志文章
doi：10.1038/nmeth.1414
更新日期：2010-02-01 00:00:00
abstract：:An outstanding challenge of epigenome-wide association studies (EWASs) performed in complex tissues is the identification of the specific cell type(s) responsible for the observed differential DNA methylation. Here we present a statistical algorithm called CellDMC ( https://github.com/sjczheng/EpiDISH ), which can ide...
journal_title：Nature methods
pub_type： 杂志文章
doi：10.1038/s41592-018-0213-x
更新日期：2018-12-01 00:00:00
abstract：:The normalization of RNA-seq data is essential for accurate downstream inference, but the assumptions upon which most normalization methods are based are not applicable in the single-cell setting. Consequently, applying existing normalization methods to single-cell RNA-seq data introduces artifacts that bias downstrea...
journal_title：Nature methods
pub_type： 杂志文章
doi：10.1038/nmeth.4263
更新日期：2017-06-01 00:00:00
abstract：:An amendment to this paper has been published and can be accessed via a link at the top of the paper. ...
journal_title：Nature methods
pub_type： 已发布勘误
doi：10.1038/s41592-019-0660-z
更新日期：2019-12-01 00:00:00
abstract：:The ribose of RNA nucleotides can be 2'-O-methylated (Nm). Despite advances in high-throughput detection, the inert chemical nature of Nm still limits sensitivity and precludes mapping in mRNA. We leveraged the differential reactivity of 2'-O-methylated and 2'-hydroxylated nucleosides to periodate oxidation to develop...
journal_title：Nature methods
pub_type： 杂志文章
doi：10.1038/nmeth.4294
更新日期：2017-07-01 00:00:00
abstract：:The analysis of structure and dynamics of biomolecules is important for understanding their function. Toward this aim, we introduce a method called 'switchable FRET', which combines single-molecule fluorescence resonance energy transfer (FRET) with reversible photoswitching of fluorophores. Typically, single-molecule ...
journal_title：Nature methods
pub_type： 杂志文章
doi：10.1038/nmeth.1502
更新日期：2010-10-01 00:00:00
abstract：:Protein function often depends on the exchange between conformational substates. Allosteric ligand binding or distal mutations can stabilize specific active-site conformations and consequently alter protein function. Observing alternative conformations at low levels of electron density, in addition to comparison of in...
journal_title：Nature methods
pub_type： 杂志文章
doi：10.1038/nmeth.2592
更新日期：2013-09-01 00:00:00
abstract：:We describe an engineered family of highly antigenic molecules based on GFP-like fluorescent proteins. These molecules contain numerous copies of peptide epitopes and simultaneously bind IgG antibodies at each location. These 'spaghetti monster' fluorescent proteins (smFPs) distributed well in neurons, notably into sm...
journal_title：Nature methods
pub_type： 杂志文章
doi：10.1038/nmeth.3365
更新日期：2015-06-01 00:00:00
abstract：:The need for automated and efficient systems for tracking full animal pose has increased with the complexity of behavioral data and analyses. Here we introduce LEAP (LEAP estimates animal pose), a deep-learning-based method for predicting the positions of animal body parts. This framework consists of a graphical inter...
journal_title：Nature methods
pub_type： 杂志文章
doi：10.1038/s41592-018-0234-5
更新日期：2019-01-01 00:00:00
abstract：:We demonstrate tracking of protein structural changes with time-resolved wide-angle X-ray scattering (TR-WAXS) with nanosecond time resolution. We investigated the tertiary and quaternary conformational changes of human hemoglobin under nearly physiological conditions triggered by laser-induced ligand photolysis. We a...
journal_title：Nature methods
pub_type： 杂志文章
doi：10.1038/nmeth.1255
更新日期：2008-10-01 00:00:00
abstract：: ...
journal_title：Nature methods
pub_type： 杂志文章
doi：10.1038/s41592-018-0270-1
更新日期：2019-01-01 00:00:00
abstract：:We achieve simultaneous two-photon excitation of three chromophores with distinct absorption spectra using synchronized pulses from a femtosecond laser and an optical parametric oscillator. The two beams generate separate multiphoton processes, and their spatiotemporal overlap provides an additional two-photon excitat...
journal_title：Nature methods
pub_type： 杂志文章
doi：10.1038/nmeth.2098
更新日期：2012-07-08 00:00:00
abstract：:Achieving information content of satisfactory breadth and depth remains a formidable challenge for proteomics. This problem is particularly relevant to the study of primary human specimens, such as tumor biopsies, which are heterogeneous and of finite quantity. Here we present a functional proteomics strategy that uni...
journal_title：Nature methods
pub_type： 杂志文章
doi：10.1038/nmeth778
更新日期：2005-09-01 00:00:00
abstract：:Photoconvertible fluorescent proteins are potential tools for investigating dynamic processes in living cells and for emerging super-resolution microscopy techniques. Unfortunately, most probes in this class are hampered by oligomerization, small photon budgets or poor photostability. Here we report an EosFP variant t...
journal_title：Nature methods
pub_type： 杂志文章
doi：10.1038/nmeth.1296
更新日期：2009-02-01 00:00:00
abstract：:The dynamic reshaping of tissues during morphogenesis results from a combination of individual cell behaviors and collective cell rearrangements. However, a comprehensive framework to unambiguously measure and link cell behavior to tissue morphogenesis is lacking. Here we introduce such a kinematic framework, bridging...
journal_title：Nature methods
pub_type： 杂志文章
doi：10.1038/nmeth.1327
更新日期：2009-06-01 00:00:00
abstract：:High-resolution optical imaging is critical to understanding brain function. We demonstrate that three-photon microscopy at 1,300-nm excitation enables functional imaging of GCaMP6s-labeled neurons beyond the depth limit of two-photon microscopy. We record spontaneous activity from up to 150 neurons in the hippocampal...
journal_title：Nature methods
pub_type： 杂志文章
doi：10.1038/nmeth.4183
更新日期：2017-04-01 00:00:00
abstract：:Electron cryotomography is currently the only method capable of visualizing cells in three dimensions at nanometer resolutions. While modern instruments produce massive amounts of tomography data containing extremely rich structural information, data processing is very labor intensive and the results are often limited...
journal_title：Nature methods
pub_type： 杂志文章
doi：10.1038/s41592-019-0591-8
更新日期：2019-11-01 00:00:00
abstract：:Focused-ion-beam scanning electron microscopy (FIB-SEM) has become an essential tool for studying neural tissue at resolutions below 10 nm × 10 nm × 10 nm, producing data sets optimized for automatic connectome tracing. We present a technical advance, ultrathick sectioning, which reliably subdivides embedded tissue sa...
journal_title：Nature methods
pub_type： 杂志文章
doi：10.1038/nmeth.3292
更新日期：2015-04-01 00:00:00
abstract：:Identifying groups of similar objects is a popular first step in biomedical data analysis, but it is error-prone and impossible to perform manually. Many computational methods have been developed to tackle this problem. Here we assessed 13 well-known methods using 24 data sets ranging from gene expression to protein d...
journal_title：Nature methods
pub_type： 杂志文章
doi：10.1038/nmeth.3583
更新日期：2015-11-01 00:00:00
abstract：:We report attainment of subdiffraction resolution using stimulated emission depletion (STED) microscopy with GFP-labeled samples. The approximately 70 nm lateral resolution attained in this study is demonstrated by imaging GFP-labeled viruses and the endoplasmic reticulum (ER) of a mammalian cell. Our results mark the...
journal_title：Nature methods
pub_type： 杂志文章,评审
doi：10.1038/nmeth922
更新日期：2006-09-01 00:00:00
abstract：:We present Omni-ATAC, an improved ATAC-seq protocol for chromatin accessibility profiling that works across multiple applications with substantial improvement of signal-to-background ratio and information content. The Omni-ATAC protocol generates chromatin accessibility profiles from archival frozen tissue samples and...
journal_title：Nature methods
pub_type： 杂志文章
doi：10.1038/nmeth.4396
更新日期：2017-10-01 00:00:00
abstract：:Generation of complex libraries of defined nucleic acid sequences can greatly aid the functional analysis of protein and gene function. Previously, such studies relied either on individually synthesized oligonucleotides or on cellular nucleic acids as the starting material. As each method has disadvantages, we have de...
journal_title：Nature methods
pub_type： 杂志文章
doi：10.1038/nmeth724
更新日期：2004-12-01 00:00:00
abstract：:Understanding how cells maintain genome integrity when challenged with DNA double-strand breaks (DSBs) is of major importance, particularly since the discovery of multiple links of DSBs with genome instability and cancer-predisposition disorders. Ionizing radiation is the agent of choice to produce DSBs in cells; howe...
journal_title：Nature methods
pub_type： 杂志文章
doi：10.1038/nmeth.f.206
更新日期：2008-03-01 00:00:00
abstract：:The analysis of synthetic genetic interaction networks can reveal how biological systems achieve a high level of complexity with a limited repertoire of components. Studies in yeast and bacteria have taken advantage of collections of deletion strains to construct matrices of quantitative interaction profiles and infer...
journal_title：Nature methods
pub_type： 杂志文章
doi：10.1038/nmeth.1581
更新日期：2011-04-01 00:00:00
abstract：:Despite widespread use of CRISPR, comprehensive data on the frequency and impact of Cas9-mediated off-targets in modified rodents are limited. Here we present deep-sequencing data from 81 genome-editing projects on mouse and rat genomes at 1,423 predicted off-target sites, 32 of which were confirmed, and show that hig...
journal_title：Nature methods
pub_type： 杂志文章
doi：10.1038/s41592-018-0011-5
更新日期：2018-07-01 00:00:00
abstract：:Spatiotemporal activity patterns in three-dimensionally organized cellular networks are fundamental to the function of the nervous system. Despite advances in functional imaging of cell populations, a method to resolve local network activity in three dimensions has been lacking. Here we introduce a three-dimensional (...
journal_title：Nature methods
pub_type： 杂志文章
doi：10.1038/nmeth989
更新日期：2007-01-01 00:00:00
abstract：:We describe a statistical analysis methodology designed to minimize the impact of off-target activities upon large-scale RNA interference (RNAi) screens in mammalian cells. Application of this approach enhances reconfirmation rates and facilitates the experimental validation of new gene activities through the probabil...
journal_title：Nature methods
pub_type： 杂志文章
doi：10.1038/nmeth1089
更新日期：2007-10-01 00:00:00
abstract：:We introduce CIBERSORT, a method for characterizing cell composition of complex tissues from their gene expression profiles. When applied to enumeration of hematopoietic subsets in RNA mixtures from fresh, frozen and fixed tissues, including solid tumors, CIBERSORT outperformed other methods with respect to noise, unk...
journal_title：Nature methods
pub_type： 杂志文章
doi：10.1038/nmeth.3337
更新日期：2015-05-01 00:00:00
