682 results match your criteria Cell systems[Journal]


A Single-Cell Transcriptomics CRISPR-Activation Screen Identifies Epigenetic Regulators of the Zygotic Genome Activation Program.

Cell Syst 2020 Jun 29. Epub 2020 Jun 29.

Epigenetics Programme, Babraham Institute, Cambridge CB22 3AT, UK; Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK; Centre for Trophoblast Research University of Cambridge, Cambridge CB2 3EG, UK. Electronic address:

Zygotic genome activation (ZGA) is an essential transcriptional event in embryonic development that coincides with extensive epigenetic reprogramming. Complex manipulation techniques and maternal stores of proteins preclude large-scale functional screens for ZGA regulators within early embryos. Here, we combined pooled CRISPR activation (CRISPRa) with single-cell transcriptomics to identify regulators of ZGA-like transcription in mouse embryonic stem cells, which serve as a tractable, in vitro proxy of early mouse embryos. Read More

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http://dx.doi.org/10.1016/j.cels.2020.06.004DOI Listing

Loss of TET2 Affects Proliferation and Drug Sensitivity through Altered Dynamics of Cell-State Transitions.

Cell Syst 2020 Jun 24. Epub 2020 Jun 24.

Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158, USA. Electronic address:

A persistent puzzle in cancer biology is how mutations, which neither alter growth signaling pathways nor directly interfere with drug mechanism, can still recur and persist in tumors. One example is the mutation of the DNA demethylase tet methylcytosine dioxygenase 2 (TET2) in acute myeloid leukemias (AMLs) that frequently persists from diagnosis through remission and relapse, but whose fitness advantage in chemotherapy is unclear. Here, we use isogenic human AML cell lines to show that TET2 loss of function alters the dynamics of transitions between differentiated and stem-like states. Read More

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http://dx.doi.org/10.1016/j.cels.2020.06.003DOI Listing

Quantitative Translation of Dog-to-Human Aging by Conserved Remodeling of the DNA Methylome.

Cell Syst 2020 Jul 1. Epub 2020 Jul 1.

Division of Genetics, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address:

All mammals progress through similar physiological stages throughout life, from early development to puberty, aging, and death. Yet, the extent to which this conserved physiology reflects underlying genomic events is unclear. Here, we map the common methylation changes experienced by mammalian genomes as they age, focusing on comparison of humans with dogs, an emerging model of aging. Read More

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http://dx.doi.org/10.1016/j.cels.2020.06.006DOI Listing

Ultra-High-Throughput Clinical Proteomics Reveals Classifiers of COVID-19 Infection.

Cell Syst 2020 Jun 2. Epub 2020 Jun 2.

The Francis Crick Institute, Molecular Biology of Metabolism Laboratory, London NW11AT, UK; Charité Universitätsmedizin, Department of Biochemistry, 10117 Berlin, Germany. Electronic address:

The COVID-19 pandemic is an unprecedented global challenge, and point-of-care diagnostic classifiers are urgently required. Here, we present a platform for ultra-high-throughput serum and plasma proteomics that builds on ISO13485 standardization to facilitate simple implementation in regulated clinical laboratories. Our low-cost workflow handles up to 180 samples per day, enables high precision quantification, and reduces batch effects for large-scale and longitudinal studies. Read More

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http://dx.doi.org/10.1016/j.cels.2020.05.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7264033PMC

Dissection of c-AMP Response Element Architecture by Using Genomic and Episomal Massively Parallel Reporter Assays.

Cell Syst 2020 Jun 26. Epub 2020 Jun 26.

Department of Chemistry and Biochemistry, UCLA-DOE Institute for Genomics and Proteomics, Molecular Biology Institute, Quantitative and Computational Biology Institute, Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, and Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address:

In eukaryotes, transcription factors (TFs) orchestrate gene expression by binding to TF-binding sites (TFBSs) and localizing transcriptional co-regulators and RNA polymerase II to cis-regulatory elements. However, we lack a basic understanding of the relationship between TFBS composition and their quantitative transcriptional responses. Here, we measured expression driven by 17,406 synthetic cis-regulatory elements with varied compositions of a model TFBS, the c-AMP response element (CRE) by using massively parallel reporter assays (MPRAs). Read More

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http://dx.doi.org/10.1016/j.cels.2020.05.011DOI Listing

Solo: Doublet Identification in Single-Cell RNA-Seq via Semi-Supervised Deep Learning.

Cell Syst 2020 Jun 19. Epub 2020 Jun 19.

Calico Life Sciences LLC, South San Francisco, CA, USA. Electronic address:

Single-cell RNA sequencing (scRNA-seq) measurements of gene expression enable an unprecedented high-resolution view into cellular state. However, current methods often result in two or more cells that share the same cell-identifying barcode; these "doublets" violate the fundamental premise of single-cell technology and can lead to incorrect inferences. Here, we describe Solo, a semi-supervised deep learning approach that identifies doublets with greater accuracy than existing methods. Read More

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http://dx.doi.org/10.1016/j.cels.2020.05.010DOI Listing

What is the Key Conceptual or Methodological Bottleneck to Controlling Neural Biology?

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Cell Syst 2020 Jun;10(6):461-462

Neurostimulation techniques allow us to manipulate the activity of nervous systems, and even that of single neurons. In this piece, researchers discuss what they see as the current key bottlenecks to controlling neural biology. Read More

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http://dx.doi.org/10.1016/j.cels.2020.06.001DOI Listing

Evaluation of Bunina et al.: Synthesizing Multi-omics Data to Delineate Neuronal Differentiation.

Cell Syst 2020 Jun;10(6):459-460

Institute for Cell Engineering, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA; Department of Biomedical Engineering, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA; Department of Molecular Biology and Genetics, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA. Electronic address:

One snapshot of the peer review process for "Genomic rewiring of SOX2 chromatin interaction network during differentiation of ESCs to postmitotic neurons" (Bunina et al., 2020). Read More

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http://dx.doi.org/10.1016/j.cels.2020.06.002DOI Listing

Being Black in the Ivory Tower.

Cell Syst 2020 Jun 18. Epub 2020 Jun 18.

Scientific Editor, Cell Systems.

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http://dx.doi.org/10.1016/j.cels.2020.06.007DOI Listing

Collective Dynamics of Focal Adhesions Regulate Direction of Cell Motion.

Cell Syst 2020 Jun 17;10(6):535-542.e4. Epub 2020 Jun 17.

Laboratory of Cell Physics ISIS/IGBMC, CNRS and University of Strasbourg, Strasbourg, France; Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France; Centre National de la Recherche Scientifique, UMR7104, Illkirch, France; Institut National de la Santé et de la Recherche Médicale, U964, Illkirch, France; Université de Strasbourg, Illkirch, France. Electronic address:

Directed cell motion is essential in physiological and pathological processes such as morphogenesis, wound healing, and cancer spreading. Chemotaxis has often been proposed as the driving mechanism, even though evidence of long-range gradients is often lacking in vivo. By patterning adhesive regions in space, we control cell shape and the potential to move along one direction in another migration mode coined ratchetaxis. Read More

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http://dx.doi.org/10.1016/j.cels.2020.05.005DOI Listing

The Scaffold Protein Axin Promotes Signaling Specificity within the Wnt Pathway by Suppressing Competing Kinase Reactions.

Cell Syst 2020 Jun 17;10(6):515-525.e5. Epub 2020 Jun 17.

Department of Chemistry, University of Washington, Seattle, WA 98195, USA. Electronic address:

Scaffold proteins are thought to promote signaling specificity by accelerating reactions between bound kinase and substrate proteins. To test the long-standing hypothesis that the scaffold protein Axin accelerates glycogen synthase kinase 3β (GSK3β)-mediated phosphorylation of β-catenin in the Wnt signaling network, we measured GSK3β reaction rates with multiple substrates in a minimal, biochemically reconstituted system. We observed an unexpectedly small, ∼2-fold Axin-mediated rate increase for the β-catenin reaction when measured in isolation. Read More

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http://dx.doi.org/10.1016/j.cels.2020.05.002DOI Listing

Predicting Evolutionary Constraints by Identifying Conflicting Demands in Regulatory Networks.

Cell Syst 2020 Jun 17;10(6):526-534.e3. Epub 2020 Jun 17.

AMOLF, Science Park 104, Amsterdam 1098 XG, the Netherlands; Department of Bionanoscience, Kavli Institute of Nanoscience Delft, Delft University of Technology, Van der Maasweg 9, Delft 2629, the Netherlands. Electronic address:

Gene regulation networks allow organisms to adapt to diverse environmental niches. However, the constraints underlying the evolution of gene regulation remain ill defined. Here, we show that partial order-a concept that ranks network output levels as a function of different input signals-identifies such constraints. Read More

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http://dx.doi.org/10.1016/j.cels.2020.05.004DOI Listing

Genomic Rewiring of SOX2 Chromatin Interaction Network during Differentiation of ESCs to Postmitotic Neurons.

Cell Syst 2020 Jun 17;10(6):480-494.e8. Epub 2020 Jun 17.

Structural and Computational Biology Unit, European Molecular Biology Laboratory, EMBL, Meyerhofstrasse 1 Heidelberg 69117, Germany. Electronic address:

Cellular differentiation requires dramatic changes in chromatin organization, transcriptional regulation, and protein production. To understand the regulatory connections between these processes, we generated proteomic, transcriptomic, and chromatin accessibility data during differentiation of mouse embryonic stem cells (ESCs) into postmitotic neurons and found extensive associations between different molecular layers within and across differentiation time points. We observed that SOX2, as a regulator of pluripotency and neuronal genes, redistributes from pluripotency enhancers to neuronal promoters during differentiation, likely driven by changes in its protein interaction network. Read More

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http://dx.doi.org/10.1016/j.cels.2020.05.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7322528PMC

MATCHA: Probing multi-way chromatin interaction with hypergraph representation learning.

Cell Syst 2020 May;10(5):397-407.e5

Computational Biology Department, School of Computer Science, Carnegie Mellon University, Pittsburgh, PA 15213, USA.

Recent advances in ligation-free, genome-wide chromatin interaction mapping such as SPRITE and ChIA-Drop have enabled the identification of simultaneous interactions involving multiple genomic loci within the same nuclei, which are informative to delineate higher-order genome organization and gene regulation mechanisms at single-nucleus resolution. Unfortunately, computational methods for analyzing multi-way chromatin interaction data are significantly underexplored. Here we develop an algorithm, called MATCHA, based on hypergraph representation learning where multi-way chromatin interactions are represented as hyperedges. Read More

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http://dx.doi.org/10.1016/j.cels.2020.04.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7299183PMC

Quantifying the Central Dogma in the p53 Pathway in Live Single Cells.

Cell Syst 2020 Jun 12;10(6):495-505.e4. Epub 2020 Jun 12.

Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA. Electronic address:

Transcription factors (TFs) integrate signals to regulate target gene expression, but we generally lack a quantitative understanding of how changes in TF levels regulate mRNA and protein production. Here, we established a system to simultaneously monitor the levels of p53, a TF that shows oscillations following DNA damage, and the transcription and protein levels of its target p21 in individual cells. p21 transcription tracked p53 dynamics, while p21 protein steadily accumulated. Read More

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http://dx.doi.org/10.1016/j.cels.2020.05.001DOI Listing

SCOPE: A Normalization and Copy-Number Estimation Method for Single-Cell DNA Sequencing.

Cell Syst 2020 May;10(5):445-452.e6

Department of Biostatistics, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA; Department of Genetics, School of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA. Electronic address:

Whole-genome single-cell DNA sequencing (scDNA-seq) enables characterization of copy-number profiles at the cellular level. We propose SCOPE, a normalization and copy-number estimation method for the noisy scDNA-seq data. SCOPE's main features include the following: (1) a Poisson latent factor model for normalization, which borrows information across cells and regions to estimate bias, using in silico identified negative control cells; (2) an expectation-maximization algorithm embedded in the normalization step, which accounts for the aberrant copy-number changes and allows direct ploidy estimation without the need for post hoc adjustment; and (3) a cross-sample segmentation procedure to identify breakpoints that are shared across cells with the same genetic background. Read More

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http://dx.doi.org/10.1016/j.cels.2020.03.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7250054PMC

Lattice Light-Sheet Microscopy Multi-dimensional Analyses (LaMDA) of T-Cell Receptor Dynamics Predict T-Cell Signaling States.

Cell Syst 2020 May;10(5):433-444.e5

Committee on Cancer Biology, University of Chicago, Chicago, IL 60637, USA; Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL 60637, USA. Electronic address:

Lattice light-sheet microscopy provides large amounts of high-dimensional, high-spatiotemporal resolution imaging data of cell surface receptors across the 3D surface of live cells, but user-friendly analysis pipelines are lacking. Here, we introduce lattice light-sheet microscopy multi-dimensional analyses (LaMDA), an end-to-end pipeline comprised of publicly available software packages that combines machine learning, dimensionality reduction, and diffusion maps to analyze surface receptor dynamics and classify cellular signaling states without the need for complex biochemical measurements or other prior information. We use LaMDA to analyze images of T-cell receptor (TCR) microclusters on the surface of live primary T cells under resting and stimulated conditions. Read More

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http://dx.doi.org/10.1016/j.cels.2020.04.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7250142PMC

CELLector: Genomics-Guided Selection of Cancer In Vitro Models.

Cell Syst 2020 May;10(5):424-432.e6

Open Targets, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SD, UK; Wellcome Trust Sanger Institute, Wellcome Genome Campus, Cambridge CB10 1SA, UK; Human Technopole, 20157, Milano, Italy. Electronic address:

Selecting appropriate cancer models is a key prerequisite for maximizing translational potential and clinical relevance of in vitro oncology studies. We developed CELLector: an R package and R Shiny application allowing researchers to select the most relevant cancer cell lines in a patient-genomic-guided fashion. CELLector leverages tumor genomics to identify recurrent subtypes with associated genomic signatures. Read More

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http://dx.doi.org/10.1016/j.cels.2020.04.007DOI Listing

Prediction of Signed Protein Kinase Regulatory Circuits.

Cell Syst 2020 May;10(5):384-396.e9

European Molecular Biology Laboratory-European Bioinformatics Institute, Hinxton CB10 1SD, UK. Electronic address:

Complex networks of regulatory relationships between protein kinases comprise a major component of intracellular signaling. Although many kinase-kinase regulatory relationships have been described in detail, these tend to be limited to well-studied kinases whereas the majority of possible relationships remains unexplored. Here, we implement a data-driven, supervised machine learning method to predict human kinase-kinase regulatory relationships and whether they have activating or inhibiting effects. Read More

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http://dx.doi.org/10.1016/j.cels.2020.04.005DOI Listing

Neural Polyamory: One Cell Forms Meaningful Connections with Hundreds of Partners.

Cell Syst 2020 May;10(5):381-383

Center for Neurobiology Research, Fralin Biomedical Research Institute at Virginia Tech Carilion, Virginia Tech, Roanoke, VA, USA. Electronic address:

Reconstruction of one thalamic neuron, mapping hundreds of presynaptic inputs and postsynaptic outputs, reveals diverse types of interaction in a neural microcircuit. Read More

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http://dx.doi.org/10.1016/j.cels.2020.04.009DOI Listing

What Is the Role for Algorithmics and Computational Biology in Responding to the COVID-19 Pandemic?

Authors:

Cell Syst 2020 05;10(5):379-380

We asked speakers from the Annual International Conference on Research in Computational Molecular Biology (RECOMB) about how computational biology as a discipline is being affected by COVID-19 and how the expertise of their community can help in the global response to the pandemic. Read More

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http://dx.doi.org/10.1016/j.cels.2020.04.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7238978PMC

Privacy-Preserving Biomedical Database Queries with Optimal Privacy-Utility Trade-Offs.

Cell Syst 2020 May 30;10(5):408-416.e9. Epub 2020 Apr 30.

Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Computer Science and AI Laboratory, MIT, Cambridge, MA 02139, USA; Department of Mathematics, MIT, Cambridge, MA 02139, USA. Electronic address:

Sharing data across research groups is an essential driver of biomedical research. While interactive query-answering systems for biomedical databases aim to facilitate the sharing of aggregate insights without divulging sensitive individual-level data, query answers can still leak private information about the individuals in the database. Here, we draw upon recent advances in differential privacy to introduce query-answering mechanisms that provably maximize the utility (e. Read More

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http://dx.doi.org/10.1016/j.cels.2020.03.006DOI Listing

Encoding Membrane-Potential-Based Memory within a Microbial Community.

Cell Syst 2020 May 27;10(5):417-423.e3. Epub 2020 Apr 27.

Division of Biological Sciences, University of California, San Diego, Pacific Hall Room 2225B, Mail Code 0347, 9500 Gilman Drive, La Jolla, CA 92093, USA; San Diego Center for Systems Biology, University of California, San Diego, La Jolla, CA 92093, USA; Center for Microbiome Innovation, University of California, San Diego, La Jolla, CA 92093-0380, USA. Electronic address:

Cellular membrane potential plays a key role in the formation and retrieval of memories in the metazoan brain, but it remains unclear whether such memory can also be encoded in simpler organisms like bacteria. Here, we show that single-cell-level memory patterns can be imprinted in bacterial biofilms by light-induced changes in the membrane potential. We demonstrate that transient optical perturbations generate a persistent and robust potassium-channel-mediated change in the membrane potential of bacteria within the biofilm. Read More

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http://dx.doi.org/10.1016/j.cels.2020.04.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7286314PMC

Gene Networks with Transcriptional Bursting Recapitulate Rare Transient Coordinated High Expression States in Cancer.

Cell Syst 2020 Apr;10(4):363-378.e12

Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA. Electronic address:

Non-genetic transcriptional variability is a potential mechanism for therapy resistance in melanoma. Specifically, rare subpopulations of cells occupy a transient pre-resistant state characterized by coordinated high expression of several genes and survive therapy. How might these rare states arise and disappear within the population? It is unclear whether the canonical models of probabilistic transcriptional pulsing can explain this behavior, or if it requires special, hitherto unidentified mechanisms. Read More

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http://dx.doi.org/10.1016/j.cels.2020.03.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7293108PMC

BraInMap Elucidates the Macromolecular Connectivity Landscape of Mammalian Brain.

Cell Syst 2020 Apr;10(4):333-350.e14

Donnelly Center for Cellular and Biomolecular Research, University of Toronto, Toronto, ON, Canada; Program in Bioinformatics, Boston University, Boston, MA, USA; Center for Network Systems Biology, Boston University, Boston, MA, USA; Department of Biochemistry, Boston University School of Medicine, Boston University, Boston, MA, USA; Departments of Biochemistry and Biology, Boston University, Boston, MA, USA. Electronic address:

Connectivity webs mediate the unique biology of the mammalian brain. Yet, while cell circuit maps are increasingly available, knowledge of their underlying molecular networks remains limited. Here, we applied multi-dimensional biochemical fractionation with mass spectrometry and machine learning to survey endogenous macromolecules across the adult mouse brain. Read More

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http://dx.doi.org/10.1016/j.cels.2020.03.003DOI Listing

Codon Usage and Splicing Jointly Influence mRNA Localization.

Cell Syst 2020 Apr 9;10(4):351-362.e8. Epub 2020 Apr 9.

MRC Human Genetics Unit, Institute for Genetics and Molecular Medicine, The University of Edinburgh, Edinburgh, UK. Electronic address:

In the human genome, most genes undergo splicing, and patterns of codon usage are splicing dependent: guanine and cytosine (GC) content is the highest within single-exon genes and within first exons of multi-exon genes. However, the effects of codon usage on gene expression are typically characterized in unspliced model genes. Here, we measured the effects of splicing on expression in a panel of synonymous reporter genes that varied in nucleotide composition. Read More

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http://dx.doi.org/10.1016/j.cels.2020.03.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7181179PMC

Quantification, Dynamic Visualization, and Validation of Bias in ATAC-Seq Data with ataqv.

Cell Syst 2020 Mar;10(3):298-306.e4

Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA; Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address:

The assay for transposase-accessible chromatin using sequencing (ATAC-seq) has become the preferred method for mapping chromatin accessibility due to its time and input material efficiency. However, it can be difficult to evaluate data quality and identify sources of technical bias across samples. Here, we present ataqv, a computational toolkit for efficiently measuring, visualizing, and comparing quality control (QC) results across samples and experiments. Read More

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http://dx.doi.org/10.1016/j.cels.2020.02.009DOI Listing

Comparing Technological Development and Biological Evolution from a Network Perspective.

Cell Syst 2020 Mar;10(3):219-222

Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520, USA; Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT 06520, USA; Department of Computer Science, Yale University, New Haven, CT 06520, USA; Department of Statistics and Data Science, Yale University, New Haven, CT 06520, USA. Electronic address:

We compare the "patterns of mutation" in biological and technological networks. Negative selection at central nodes in biological networks has been widely reported; however, we show technological networks have an opposite trend. This suggests a potential contrast: biological evolution involves random tinkering, whereas man-made systems change according to rational planning. Read More

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http://dx.doi.org/10.1016/j.cels.2020.02.004DOI Listing

Phenomics-Based Quantification of CRISPR-Induced Mosaicism in Zebrafish.

Cell Syst 2020 Mar 18;10(3):275-286.e5. Epub 2020 Mar 18.

Department of Orthopaedics and Sports Medicine, University of Washington, Seattle, WA, USA; Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA, USA; Department of Mechanical Engineering, University of Washington, Seattle, WA, USA.

Genetic mosaicism can manifest as spatially variable phenotypes that vary from site to site within an organism. Here, we use imaging-based phenomics to quantitate phenotypes at many sites within the axial skeleton of CRISPR-edited G0 zebrafish. Through characterization of loss-of-function cell clusters in the developing skeleton, we identify a distinctive size distribution shown to arise from clonal fragmentation and merger events. Read More

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http://dx.doi.org/10.1016/j.cels.2020.02.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7213258PMC

Engineered Fluorescent E. coli Lysogens Allow Live-Cell Imaging of Functional Prophage Induction Triggered inside Macrophages.

Cell Syst 2020 Mar 18;10(3):254-264.e9. Epub 2020 Mar 18.

Department of Bioengineering, Stanford University, Stanford, CA 94305, USA; Allen Discovery Center for Systems Modeling of Infection, Stanford University, Stanford, CA 94305, USA. Electronic address:

Half of the bacteria in the human gut microbiome are lysogens containing integrated prophages, which may activate in stressful immune environments. Although lysogens are likely to be phagocytosed by macrophages, whether prophage activation occurs or influences the outcome of bacterial infection remains unexplored. To study the dynamics of bacteria-phage interactions in living cells-in particular, the macrophage-triggered induction and lysis of dormant prophages in the phagosome-we adopted a tripartite system where murine macrophages engulf E. Read More

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http://dx.doi.org/10.1016/j.cels.2020.02.006DOI Listing

A Live-Cell Screen for Altered Erk Dynamics Reveals Principles of Proliferative Control.

Cell Syst 2020 Mar 18;10(3):240-253.e6. Epub 2020 Mar 18.

Department of Molecular Biology, Princeton University, Princeton, NJ 08544. Electronic address:

Complex, time-varying responses have been observed widely in cell signaling, but how specific dynamics are generated or regulated is largely unknown. One major obstacle has been that high-throughput screens are typically incompatible with the live-cell assays used to monitor dynamics. Here, we address this challenge by screening a library of 429 kinase inhibitors and monitoring extracellular-regulated kinase (Erk) activity over 5 h in more than 80,000 single primary mouse keratinocytes. Read More

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http://dx.doi.org/10.1016/j.cels.2020.02.005DOI Listing

Gut-Liver Physiomimetics Reveal Paradoxical Modulation of IBD-Related Inflammation by Short-Chain Fatty Acids.

Cell Syst 2020 Mar 18;10(3):223-239.e9. Epub 2020 Mar 18.

Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA; Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA; Center for Gynepathology Research, Massachusetts Institute of Technology, Cambridge, MA, USA. Electronic address:

Although the association between the microbiome and IBD and liver diseases is known, the cause and effect remain elusive. By connecting human microphysiological systems of the gut, liver, and circulating Treg and Th17 cells, we created a multi-organ model of ulcerative colitis (UC) ex vivo. The approach shows microbiome-derived short-chain fatty acids (SCFAs) to either improve or worsen UC severity, depending on the involvement of effector CD4 T cells. Read More

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http://dx.doi.org/10.1016/j.cels.2020.02.008DOI Listing

Inferring Causal Gene Regulatory Networks from Coupled Single-Cell Expression Dynamics Using Scribe.

Cell Syst 2020 Mar 4;10(3):265-274.e11. Epub 2020 Mar 4.

Department of Electrical Engineering, University of Washington, Seattle, WA, USA. Electronic address:

Here, we present Scribe (https://github.com/aristoteleo/Scribe-py), a toolkit for detecting and visualizing causal regulatory interactions between genes and explore the potential for single-cell experiments to power network reconstruction. Scribe employs restricted directed information to determine causality by estimating the strength of information transferred from a potential regulator to its downstream target. Read More

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http://dx.doi.org/10.1016/j.cels.2020.02.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7223477PMC

Keeping the Proportions of Protein Complex Components in Check.

Cell Syst 2020 Feb;10(2):125-132

Department of Genetics, Harvard Medical School, Boston, MA 02115, USA. Electronic address:

How do cells maintain relative proportions of protein complex components? Advances in quantitative, genome-wide measurements have begun to shed light onto the roles of protein synthesis and degradation in establishing the precise proportions in living cells: on the one hand, ribosome profiling studies indicate that proteins are already produced in the correct relative proportions. On the other hand, proteomic studies found that many complexes contain subunits that are made in excess and subsequently degraded. Here, we discuss these seemingly contradictory findings, emerging principles, and remaining open questions. Read More

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http://dx.doi.org/10.1016/j.cels.2020.01.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7195860PMC
February 2020

Evaluation of Kuroda et al.: Insight into Yeast Isobutanol Tolerance with Advances Still Needed.

Cell Syst 2020 Feb;10(2):124

Laboratory of Genetics, DOE Great Lakes Bioenergy Research Center, Wisconsin Energy Institute, J. F. Crow Institute for the Study of Evolution, Genome Center of Wisconsin, University of Wisconsin-Madison, Madison, WI 53726-4084, USA. Electronic address:

One snapshot of the peer review process for "Critical Roles of the Pentose Phosphate Pathway and GLN3 in Isobutanol-Specific Tolerance in Yeast" (Kuroda et al., 2019). Read More

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http://dx.doi.org/10.1016/j.cels.2020.01.005DOI Listing
February 2020

Science that Inspires.

Authors:

Cell Syst 2020 Feb;10(2):122-123

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http://dx.doi.org/10.1016/j.cels.2020.02.001DOI Listing
February 2020

"How Do You Know?" The Answer Lies in Methods.

Authors:
Quincey Justman

Cell Syst 2020 Feb;10(2):121

Editor-in-Chief, Cell Systems.

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http://dx.doi.org/10.1016/j.cels.2020.01.006DOI Listing
February 2020

Mitochondrial Fission and Fusion Dynamics Generate Efficient, Robust, and Evenly Distributed Network Topologies in Budding Yeast Cells.

Cell Syst 2020 Mar 26;10(3):287-297.e5. Epub 2020 Feb 26.

Developmental & Cell Biology and Center for Complex Biological Systems, UC Irvine, Irvine, CA 92697, USA; Biomedical Engineering, UC Irvine, Irvine, CA 92697, USA. Electronic address:

The simplest configuration of mitochondria in a cell is as small separate organellar units. Instead, mitochondria often form a dynamic, intricately connected network. A basic understanding of the topological properties of mitochondrial networks, and their influence on cell function is lacking. Read More

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http://dx.doi.org/10.1016/j.cels.2020.02.002DOI Listing

FLASHDeconv: Ultrafast, High-Quality Feature Deconvolution for Top-Down Proteomics.

Cell Syst 2020 Feb 19;10(2):213-218.e6. Epub 2020 Feb 19.

Applied Bioinformatics, Department for Computer Science, University of Tübingen, Sand 14, 72076 Tübingen, Germany; Institute for Bioinformatics and Medical Informatics, University of Tübingen, Sand 14, 72076 Tübingen, Germany; Center for Quantitative Biology, University of Tübingen, Sand 14, 72076 Tübingen, Germany; Biomolecular Interactions, Max Planck Institute for Developmental Biology, Max-Planck-Ring 4, 72076 Tübingen, Germany; Translational Bioinformatics, University Hospital Tübingen, Hoppe-Seyler-Str. 9, 72076 Tübingen, Germany.

Top-down mass spectrometry (TD-MS)-based proteomics analyzes intact proteoforms and thus preserves information about individual protein species. The MS signal of these high-mass analytes is complex and challenges the accurate determination of proteoform masses. Fast and accurate feature deconvolution (i. Read More

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http://dx.doi.org/10.1016/j.cels.2020.01.003DOI Listing
February 2020

Differential Allele-Specific Expression Uncovers Breast Cancer Genes Dysregulated by Cis Noncoding Mutations.

Cell Syst 2020 Feb 19;10(2):193-203.e4. Epub 2020 Feb 19.

Department of Computer Science, Princeton University, Princeton, NJ 08544, USA; Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA. Electronic address:

Identifying cancer-relevant mutations in noncoding regions is challenging due to the large numbers of such mutations, their low levels of recurrence, and difficulties in interpreting their functional impact. To uncover genes that are dysregulated due to somatic mutations in cis, we build upon the concept of differential allele-specific expression (ASE) and introduce methods to identify genes within an individual's cancer whose ASE differs from what is found in matched normal tissue. When applied to breast cancer tumor samples, our methods detect the known allele-specific effects of copy number variation and nonsense-mediated decay. Read More

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http://dx.doi.org/10.1016/j.cels.2020.01.002DOI Listing
February 2020

A Global Screen for Assembly State Changes of the Mitotic Proteome by SEC-SWATH-MS.

Cell Syst 2020 Feb 5;10(2):133-155.e6. Epub 2020 Feb 5.

Institute of Molecular Systems Biology, Department of Biology, ETH Zurich, Zurich, Switzerland; Faculty of Science, University of Zurich, Zurich, Switzerland. Electronic address:

Living systems integrate biochemical reactions that determine the functional state of each cell. Reactions are primarily mediated by proteins. In proteomic studies, these have been treated as independent entities, disregarding their higher-level organization into complexes that affects their activity and/or function and is thus of great interest for biological research. Read More

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http://dx.doi.org/10.1016/j.cels.2020.01.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7042714PMC
February 2020

Molecular and Functional Networks Linked to Sarcopenia Prevention by Caloric Restriction in Rhesus Monkeys.

Cell Syst 2020 Feb 22;10(2):156-168.e5. Epub 2020 Jan 22.

Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA; Geriatric Research Education and Clinical Center, William S. Middleton Memorial Veterans Hospital, Madison, WI 53705, USA. Electronic address:

Caloric restriction (CR) improves survival in nonhuman primates and delays the onset of age-related morbidities including sarcopenia, which is characterized by the age-related loss of muscle mass and function. A shift in metabolism anticipates the onset of muscle-aging phenotypes in nonhuman primates, suggesting a potential role for metabolism in the protective effects of CR. Here, we show that CR induced profound changes in muscle composition and the cellular metabolic environment. Read More

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http://dx.doi.org/10.1016/j.cels.2019.12.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7047532PMC
February 2020

CRISPR-Based Synthetic Transcription Factors In Vivo: The Future of Therapeutic Cellular Programming.

Cell Syst 2020 Jan;10(1):1-14

School of Biological and Health Systems Engineering, Ira A. Fulton Schools of Engineering, Arizona State University, Tempe, AZ, USA; Department of Pathology, Division of Experimental Pathology, University of Pittsburgh, Pittsburgh, PA, USA; Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA, USA. Electronic address:

Pinpoint control over endogenous gene expression in vivo has long been a fevered dream for clinicians and researchers alike. With the recent repurposing of programmable, RNA-guided DNA endonucleases from the CRISPR bacterial immune system, this dream is becoming a powerful reality. Engineered CRISPR/Cas9-based transcriptional regulators and epigenome editors have enabled researchers to perturb endogenous gene expression in vivo, allowing for the therapeutic reprogramming of cell and tissue behavior. Read More

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http://dx.doi.org/10.1016/j.cels.2019.10.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7175797PMC
January 2020

Gene Regulatory Strategies that Decode the Duration of NFκB Dynamics Contribute to LPS- versus TNF-Specific Gene Expression.

Cell Syst 2020 Feb 22;10(2):169-182.e5. Epub 2020 Jan 22.

Department of Microbiology, Immunology, and Molecular Genetics (MIMG), University of California, Los Angeles, Los Angeles, CA 90095, USA; Institute for Quantitative and Computational Biosciences (QCB), University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address:

Pathogen-derived lipopolysaccharide (LPS) and cytokine tumor necrosis factor (TNF) activate NFκB with distinct duration dynamics, but how immune response genes decode NFκB duration to produce stimulus-specific expression remains unclear. Here, detailed transcriptomic profiling of combinatorial and temporal control mutants identified 81 genes that depend on stimulus-specific NFκB duration for their stimulus-specificity. Combining quantitative experimentation with mathematical modeling, we found that for some genes a long mRNA half-life allowed effective decoding, but for many genes this was insufficient to account for the data; instead, we found that chromatin mechanisms, such as a slow transition rate between inactive and RelA-bound enhancer states, could also decode NFκB dynamics. Read More

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http://dx.doi.org/10.1016/j.cels.2019.12.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7047529PMC
February 2020

The Key Parameters that Govern Translation Efficiency.

Cell Syst 2020 Feb 15;10(2):183-192.e6. Epub 2020 Jan 15.

Computer Science Division, University of California, Berkeley, Berkeley, CA 94720, USA; Department of Statistics, University of California, Berkeley, Berkeley, CA 94720, USA; Chan Zuckerberg Biohub, San Francisco, CA 94158, USA. Electronic address:

Translation of mRNA into protein is a fundamental yet complex biological process with multiple factors that can potentially affect its efficiency. Here, we study a stochastic model describing the traffic flow of ribosomes along the mRNA and identify the key parameters that govern the overall rate of protein synthesis, sensitivity to initiation rate changes, and efficiency of ribosome usage. By analyzing a continuum limit of the model, we obtain closed-form expressions for stationary currents and ribosomal densities, which agree well with Monte Carlo simulations. Read More

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http://dx.doi.org/10.1016/j.cels.2019.12.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7047610PMC
February 2020

Cellular Dialogues: Cell-Cell Communication through Diffusible Molecules Yields Dynamic Spatial Patterns.

Cell Syst 2020 Jan 15;10(1):82-98.e7. Epub 2020 Jan 15.

Kavli Institute of Nanoscience, Delft University of Technology, Delft 2629HZ, the Netherlands; Department of Bionanoscience, Delft University of Technology, Delft 2629HZ, the Netherlands; CIFAR, CIFAR Azrieli Global Scholars Program, Toronto, ON M5G 1M1, Canada. Electronic address:

Cells form spatial patterns by coordinating their gene expressions. How a group of mesoscopic numbers (hundreds to thousands) of cells, without pre-existing morphogen gradients and spatial organization, self-organizes spatial patterns remains poorly understood. Of particular importance are dynamic spatial patterns such as spiral waves that perpetually move and transmit information. Read More

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http://dx.doi.org/10.1016/j.cels.2019.12.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6975168PMC
January 2020

Defining Higher-Order Interactions in Synthetic Ecology: Lessons from Physics and Quantitative Genetics.

Authors:
Alvaro Sanchez

Cell Syst 2019 12 18;9(6):519-520. Epub 2019 Dec 18.

Department of Ecology & Evolutionary Biology and Microbial Sciences Institute, Yale University, New Haven, CT, USA. Electronic address:

A new paper from Mickalide and Kuehn studies a well-controlled microbial trophic chain and identifies a high-order interaction between its species. Read More

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http://dx.doi.org/10.1016/j.cels.2019.11.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7194221PMC
December 2019

Guiding the Refinement of Biochemical Knowledgebases with Ensembles of Metabolic Networks and Machine Learning.

Cell Syst 2020 Jan 8;10(1):109-119.e3. Epub 2020 Jan 8.

Department of Biomedical Engineering, University of Virginia, Charlottesville, VA, USA; Department of Medicine, Division of Infectious Diseases & International Health, University of Virginia, Charlottesville, VA, USA; Department of Biochemistry & Molecular Genetics, University of Virginia, Charlottesville, VA, USA. Electronic address:

Mechanistic models explicitly represent hypothesized biological knowledge. As such, they offer more generalizability than data-driven models. However, identifying model curation efforts that improve performance for mechanistic models is nontrivial. Read More

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http://dx.doi.org/10.1016/j.cels.2019.11.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6975163PMC
January 2020

De Novo Peptide Sequencing Reveals Many Cyclopeptides in the Human Gut and Other Environments.

Cell Syst 2020 Jan 18;10(1):99-108.e5. Epub 2019 Dec 18.

Department of Computer Science and Engineering, University of California, San Diego, La Jolla, CA, USA; Center for Algorithmic Biotechnology, Institute of Translational Biomedicine, St. Petersburg State University, St. Petersburg, Russia; Center for Microbiome Innovation, University of California, San Diego, La Jolla, CA, USA.

Cyclic and branch cyclic peptides (cyclopeptides) represent a class of bioactive natural products that include many antibiotics and anti-tumor compounds. Despite the recent advances in metabolomics analysis, still little is known about the cyclopeptides in the human gut and their possible interactions due to a lack of computational analysis pipelines that are applicable to such compounds. Here, we introduce CycloNovo, an algorithm for automated de novo cyclopeptide analysis and sequencing that employs de Bruijn graphs, the workhorse of DNA sequencing algorithms, to identify cyclopeptides in spectral datasets. Read More

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http://dx.doi.org/10.1016/j.cels.2019.11.007DOI Listing
January 2020