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Cell Systems

Nicolai J Wewer Albrechtsen, Philipp E Geyer, Sophia Doll, Peter V Treit, Kirstine N Bojsen-Møller, Christoffer Martinussen, Nils B Jørgensen, Signe S Torekov, Florian Meier, Lili Niu, Alberto Santos, Eva C Keilhauer, Jens J Holst, Sten Madsbad, Matthias Mann
Obesity-related diseases affect half of the global population, and bariatric surgery is one of the few interventions with long-lasting weight loss and cardio-metabolic effects. Here, we investigated the effect of Roux-en-Y gastric bypass surgery on the plasma proteome, hypothesizing that specific proteins or protein patterns may serve as key mediators and markers of the metabolic response. We performed mass spectrometry (MS)-based proteomics on two longitudinal studies encompassing 47 morbidly obese patients, generating quantitative information on more than 1,700 proteins...
November 30, 2018: Cell Systems
Yan Wu, Pablo Tamayo, Kun Zhang
High-throughput single-cell gene expression profiling has enabled the definition of new cell types and developmental trajectories. Visualizing these datasets is crucial to biological interpretation, and a popular method is t-stochastic neighbor embedding (t-SNE), which visualizes local patterns well but distorts global structure, such as distances between clusters. We developed similarity weighted nonnegative embedding (SWNE), which enhances interpretation of datasets by embedding the genes and factors that separate cell states on the visualization alongside the cells and maintains fidelity when visualizing local and global structure for both developmental trajectories and discrete cell types...
November 28, 2018: Cell Systems
Rea L Antoniou-Kourounioti, Jo Hepworth, Amélie Heckmann, Susan Duncan, Julia Qüesta, Stefanie Rosa, Torbjörn Säll, Svante Holm, Caroline Dean, Martin Howard
Many organisms need to respond to complex, noisy environmental signals for developmental decision making. Here, we dissect how Arabidopsis plants integrate widely fluctuating field temperatures over month-long timescales to progressively upregulate VERNALIZATION INSENSITIVE3 (VIN3) and silence FLOWERING LOCUS C (FLC), aligning flowering with spring. We develop a mathematical model for vernalization that operates on multiple timescales-long term (month), short term (day), and current (hour)-and is constrained by experimental data...
November 20, 2018: Cell Systems
Fabian Fröhlich, Thomas Kessler, Daniel Weindl, Alexey Shadrin, Leonard Schmiester, Hendrik Hache, Artur Muradyan, Moritz Schütte, Ji-Hyun Lim, Matthias Heinig, Fabian J Theis, Hans Lehrach, Christoph Wierling, Bodo Lange, Jan Hasenauer
Mechanistic models are essential to deepen the understanding of complex diseases at the molecular level. Nowadays, high-throughput molecular and phenotypic characterizations are possible, but the integration of such data with prior knowledge on signaling pathways is limited by the availability of scalable computational methods. Here, we present a computational framework for the parameterization of large-scale mechanistic models and its application to the prediction of drug response of cancer cell lines from exome and transcriptome sequencing data...
November 13, 2018: Cell Systems
Krystal K Lum, Bokai Song, Joel D Federspiel, Benjamin A Diner, Timothy Howard, Ileana M Cristea
Viral DNA sensing is an essential component of the mammalian innate immune response. Upon binding viral DNA, the cyclic-GMP-AMP synthase (cGAS) catalyzes the production of cyclic dinucleotides to induce type I interferons. However, little is known about how cGAS is homeostatically maintained or regulated upon infection. Here, we define cytoplasmic cGAS interactions with cellular and viral proteins upon herpes simplex virus type 1 (HSV-1) infection in primary human fibroblasts. We compare several HSV-1 strains (wild-type, d109, d106) that induce cytokine responses and apoptosis and place cGAS interactions in the context of temporal proteome alterations using isobaric-labeling mass spectrometry...
November 12, 2018: Cell Systems
Hiroyuki Kubota, Shinsuke Uda, Fumiko Matsuzaki, Yukiyo Yamauchi, Shinya Kuroda
No abstract text is available yet for this article.
November 28, 2018: Cell Systems
Quincey Justman
No abstract text is available yet for this article.
November 28, 2018: Cell Systems
Udit Parekh, Yan Wu, Dongxin Zhao, Atharv Worlikar, Neha Shah, Kun Zhang, Prashant Mali
Understanding the effects of genetic perturbations on the cellular state has been challenging using traditional pooled screens, which typically rely on the delivery of a single perturbation per cell and unidimensional phenotypic readouts. Here, we use barcoded open reading frame overexpression libraries coupled with single-cell RNA sequencing to assay cell state and fitness, a technique we call SEUSS (scalable functional screening by sequencing). Using SEUSS, we perturbed hPSCs with a library of developmentally critical transcription factors (TFs) and assayed the impact of TF overexpression on fitness and transcriptomic states...
November 28, 2018: Cell Systems
Noa Gil, Igor Ulitsky
Active enhancers in mammals produce enhancer RNAs (eRNAs) that are bidirectionally transcribed, unspliced, and unstable. Enhancer regions are also enriched with long noncoding RNA (lncRNA) transcripts, which are typically spliced and substantially more stable. In order to explore the relationship between these two classes of RNAs, we analyzed DNase hypersensitive sites with evidence of bidirectional transcription, which we termed eRNA-producing centers (EPCs). EPCs found very close to transcription start sites of lncRNAs exhibit attributes of both enhancers and promoters, including distinctive DNA motifs and a characteristic chromatin landscape...
November 28, 2018: Cell Systems
Denis Torre, Alexander Lachmann, Avi Ma'ayan
BioJupies is a web application that enables the automated creation, storage, and deployment of Jupyter Notebooks containing RNA-seq data analyses. Through an intuitive interface, novice users can rapidly generate tailored reports to analyze and visualize their own raw sequencing files, gene expression tables, or fetch data from >9,000 published studies containing >300,000 preprocessed RNA-seq samples. Generated notebooks have the executable code of the entire pipeline, rich narrative text, interactive data visualizations, differential expression, and enrichment analyses...
November 28, 2018: Cell Systems
James T Webber, Swati Kaushik, Sourav Bandyopadhyay
Leveraging insights from genomic studies of patient tumors is limited by the discordance between these tumors and the cell line models used for functional studies. We integrate omics datasets using functional networks to identify gene modules reflecting variation between tumors and show that the structure of these modules can be evaluated in cell lines to discover clinically relevant biomarkers of therapeutic responses. Applied to breast cancer, we identify 219 gene modules that capture recurrent alterations and subtype patients and quantitate various cell types within the tumor microenvironment...
November 28, 2018: Cell Systems
Erin Elizabeth Edwards, Katherine Gayle Birmingham, Meghan Jeanne O'Melia, Jaeho Oh, Susan Napier Thomas
Hematogenous metastasis is a multistep, selectin-regulated process whose mechanisms remain poorly understood. To investigate this biological pathway of cancer dissemination and better understand circulating cancer cells, we developed a high-throughput methodology that integrates organ-on-chip-like microfluidic and photoconvertible protein technologies. Our approach can ascribe single-cell velocity as a traceable cell property for off-chip analysis of the direct relationships between cell molecular profiles and adhesive phenotypes in the context of physiologically relevant fluid flow...
November 28, 2018: Cell Systems
Aleksandra Pękowska, Bernd Klaus, Wanqing Xiang, Jacqueline Severino, Nathalie Daigle, Felix A Klein, Małgorzata Oleś, Rafael Casellas, Jan Ellenberg, Lars M Steinmetz, Paul Bertone, Wolfgang Huber
The genome of pluripotent stem cells adopts a unique three-dimensional architecture featuring weakly condensed heterochromatin and large nucleosome-free regions. Yet, it is unknown whether structural loops and contact domains display characteristics that distinguish embryonic stem cells (ESCs) from differentiated cell types. We used genome-wide chromosome conformation capture and super-resolution imaging to determine nuclear organization in mouse ESC and neural stem cell (NSC) derivatives. We found that loss of pluripotency is accompanied by widespread gain of structural loops...
November 28, 2018: Cell Systems
Miaowei Mao, Yue Hu, Yun Yang, Yajie Qian, Huanhuan Wei, Wei Fan, Yi Yang, Xiaoling Li, Zefeng Wang
Alternative splicing (AS) is generally regulated by trans-splicing factors that specifically bind to cis-elements in pre-mRNAs. The human genome encodes ∼1,500 RNA binding proteins (RBPs) that potentially regulate AS, yet their functions remain largely unknown. To explore their potential activities, we fused the putative functional domains of RBPs to a sequence-specific RNA-binding domain and systemically analyzed how these engineered factors affect splicing. We discovered that ∼80% of low-complexity domains in endogenous RBPs displayed distinct context-dependent activities in regulating splicing, indicating that AS is under more extensive regulation than previously expected...
November 28, 2018: Cell Systems
Yi Liao, Michael J Rust
When resources are abundant, many rod-shaped bacteria reproduce through precise, symmetric divisions. However, realistic environments entail fluctuations between restrictive and permissive growth conditions. Here, we use time-lapse microscopy to study the division of the cyanobacterium Synechococcus elongatus as illumination intensity varies. We find that dim conditions produce elongated cells whose divisions follow a simple rule: cells shorter than ∼8 μm divide symmetrically, but above this length divisions become asymmetric, typically producing a short ∼3-μm daughter...
November 28, 2018: Cell Systems
Fangfei Li, Marc L Salit, Sasha F Levy
Standard practice for phenotyping complex cell pools is to measure the fold enrichment of genotype-specific amplicons after a period of competitive growth. Here, we show that fold-enrichment measures cannot be compared across genotype pools with different fitness distributions. We develop a method to calculate an unbiased estimate of relative fitness by tracking abundances over several time points and show how to optimize experimental protocols to minimize fitness measurement error.
November 28, 2018: Cell Systems
Markus A Seeliger
Co-evolution analysis reveals which amino acids within the protein kinase domain are working together to mediate catalysis, regulation, and substrate binding.
October 24, 2018: Cell Systems
Noah Olsman, Fangzhou Xiao, John Doyle
One snapshot of the peer review process for "Cytoplasmic Amplification of Transcriptional Noise Generates Substantial Cell-to-Cell Variability" (Hansen et al., 2018).
October 24, 2018: Cell Systems
Quincey Justman
No abstract text is available yet for this article.
October 24, 2018: Cell Systems
Doris Popovic, Birgit Koch, Moritz Kueblbeck, Jan Ellenberg, Lucas Pelkmans
A long-standing question in quantitative biology is the relationship between mRNA and protein levels of the same gene. Here, we measured mRNA and protein abundance, the phenotypic state, and the population context in thousands of single human cells for 23 genes by combining a unique collection of cell lines with fluorescently tagged endogenous genomic loci and quantitative immunofluorescence with branched DNA single-molecule fluorescence in situ hybridization and computer vision. mRNA and protein abundance displayed a mean single-cell correlation of 0...
October 24, 2018: Cell Systems
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