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Cell Systems

Kristin L Patrick, Jason A Wojcechowskyj, Samantha L Bell, Morgan N Riba, Tao Jing, Sara Talmage, Pengbiao Xu, Ana L Cabello, Jiewei Xu, Michael Shales, David Jimenez-Morales, Thomas A Ficht, Paul de Figueiredo, James E Samuel, Pingwei Li, Nevan J Krogan, Robert O Watson
Intracellular bacterial pathogens secrete a repertoire of effector proteins into host cells that are required to hijack cellular pathways and cause disease. Despite decades of research, the molecular functions of most bacterial effectors remain unclear. To address this gap, we generated quantitative genetic interaction profiles between 36 validated and putative effectors from three evolutionarily divergent human bacterial pathogens and 4,190 yeast deletion strains. Correlating effector-generated profiles with those of yeast mutants, we recapitulated known biology for several effectors with remarkable specificity and predicted previously unknown functions for others...
July 26, 2018: Cell Systems
David Borland, Hong Yi, Gavin D Grant, Katarzyna M Kedziora, Hui Xiao Chao, Rachel A Haggerty, Jayashree Kumar, Samuel C Wolff, Jeanette G Cook, Jeremy E Purvis
The cell cycle is driven by precise temporal coordination among many molecular activities. To understand and explore this process, we developed the Cell Cycle Browser (CCB), an interactive web interface based on real-time reporter data collected in proliferating human cells. This tool facilitates visualizing, organizing, simulating, and predicting the outcomes of perturbing cell-cycle parameters. Time-series traces from individual cells can be combined to build a multi-layered timeline of molecular activities...
July 23, 2018: Cell Systems
Anton Bankevich, Pavel A Pevzner
Reduced microbiome diversity has been linked to several diseases. However, estimating the diversity of bacterial communities-the number and the total length of distinct genomes within a metagenome-remains an open problem in microbial ecology. Here, we describe an algorithm for estimating the microbial diversity in a metagenomic sample based on a joint analysis of short and long reads. Unlike previous approaches, the algorithm does not make any assumptions on the distribution of the frequencies of genomes within a metagenome (as in parametric methods) and does not require a large database that covers the total diversity (as in non-parametric methods)...
July 19, 2018: Cell Systems
Joseph W Larkin, Xiaoling Zhai, Kaito Kikuchi, Samuel E Redford, Arthur Prindle, Jintao Liu, Sacha Greenfield, Aleksandra M Walczak, Jordi Garcia-Ojalvo, Andrew Mugler, Gürol M Süel
Signal transmission among cells enables long-range coordination in biological systems. However, the scarcity of quantitative measurements hinders the development of theories that relate signal propagation to cellular heterogeneity and spatial organization. We address this problem in a bacterial community that employs electrochemical cell-to-cell communication. We developed a model based on percolation theory, which describes how signals propagate through a heterogeneous medium. Our model predicts that signal transmission becomes possible when the community is organized near a critical phase transition between a disconnected and a fully connected conduit of signaling cells...
July 14, 2018: Cell Systems
Anthony M D'Ippolito, Ian C McDowell, Alejandro Barrera, Linda K Hong, Sarah M Leichter, Luke C Bartelt, Christopher M Vockley, William H Majoros, Alexias Safi, Lingyun Song, Charles A Gersbach, Gregory E Crawford, Timothy E Reddy
The glucocorticoid receptor (GR) is a hormone-inducible transcription factor involved in metabolic and anti-inflammatory gene expression responses. To investigate what controls interactions between GR binding sites and their target genes, we used in situ Hi-C to generate high-resolution, genome-wide maps of chromatin interactions before and after glucocorticoid treatment. We found that GR binding to the genome typically does not cause new chromatin interactions to target genes but instead acts through chromatin interactions that already exist prior to hormone treatment...
July 10, 2018: Cell Systems
Oleksii S Rukhlenko, Fahimeh Khorsand, Aleksandar Krstic, Jan Rozanc, Leonidas G Alexopoulos, Nora Rauch, Keesha E Erickson, William S Hlavacek, Richard G Posner, Silvia Gómez-Coca, Edina Rosta, Cheree Fitzgibbon, David Matallanas, Jens Rauch, Walter Kolch, Boris N Kholodenko
Clinically used RAF inhibitors are ineffective in RAS mutant tumors because they enhance homo- and heterodimerization of RAF kinases, leading to paradoxical activation of ERK signaling. Overcoming enhanced RAF dimerization and the resulting resistance is a challenge for drug design. Combining multiple inhibitors could be more effective, but it is unclear how the best combinations can be chosen. We built a next-generation mechanistic dynamic model to analyze combinations of structurally different RAF inhibitors, which can efficiently suppress MEK/ERK signaling...
July 3, 2018: Cell Systems
Hyunghoon Cho, Bonnie Berger, Jian Peng
Visualization algorithms are fundamental tools for interpreting single-cell data. However, standard methods, such as t-stochastic neighbor embedding (t-SNE), are not scalable to datasets with millions of cells and the resulting visualizations cannot be generalized to analyze new datasets. Here we introduce net-SNE, a generalizable visualization approach that trains a neural network to learn a mapping function from high-dimensional single-cell gene-expression profiles to a low-dimensional visualization. We benchmark net-SNE on 13 different datasets, and show that it achieves visualization quality and clustering accuracy comparable with t-SNE...
June 19, 2018: Cell Systems
Yang Yang, Quanquan Gu, Yang Zhang, Takayo Sasaki, Julianna Crivello, Rachel J O'Neill, David M Gilbert, Jian Ma
A large amount of multi-species functional genomic data from high-throughput assays are becoming available to help understand the molecular mechanisms for phenotypic diversity across species. However, continuous-trait probabilistic models, which are key to such comparative analysis, remain under-explored. Here we develop a new model, called phylogenetic hidden Markov Gaussian processes (Phylo-HMGP), to simultaneously infer heterogeneous evolutionary states of functional genomic features in a genome-wide manner...
June 18, 2018: Cell Systems
Prashant Pandey, Fatemeh Almodaresi, Michael A Bender, Michael Ferdman, Rob Johnson, Rob Patro
Sequence-level searches on large collections of RNA sequencing experiments, such as the NCBI Sequence Read Archive (SRA), would enable one to ask many questions about the expression or variation of a given transcript in a population. Existing approaches, such as the sequence Bloom tree, suffer from fundamental limitations of the Bloom filter, resulting in slow build and query times, less-than-optimal space usage, and potentially large numbers of false-positives. This paper introduces Mantis, a space-efficient system that uses new data structures to index thousands of raw-read experiments and facilitates large-scale sequence searches...
June 18, 2018: Cell Systems
Ismael Al-Ramahi, Boxun Lu, Simone Di Paola, Kaifang Pang, Maria de Haro, Ivana Peluso, Tatiana Gallego-Flores, Nazish T Malik, Kelly Erikson, Benjamin A Bleiberg, Matthew Avalos, George Fan, Laura Elizabeth Rivers, Andrew M Laitman, Javier R Diaz-García, Marc Hild, James Palacino, Zhandong Liu, Diego L Medina, Juan Botas
Discriminating transcriptional changes that drive disease pathogenesis from nonpathogenic and compensatory responses is a daunting challenge. This is particularly true for neurodegenerative diseases, which affect the expression of thousands of genes in different brain regions at different disease stages. Here we integrate functional testing and network approaches to analyze previously reported transcriptional alterations in the brains of Huntington disease (HD) patients. We selected 312 genes whose expression is dysregulated both in HD patients and in HD mice and then replicated and/or antagonized each alteration in a Drosophila HD model...
June 6, 2018: Cell Systems
Leighton H Daigh, Chad Liu, Mingyu Chung, Karlene A Cimprich, Tobias Meyer
Faithful DNA replication is challenged by stalling of replication forks during S phase. Replication stress is further increased in cancer cells or in response to genotoxic insults. Using live single-cell image analysis, we found that CDK2 activity fluctuates throughout an unperturbed S phase. We show that CDK2 fluctuations result from transient ATR signals triggered by stochastic replication stress events. In turn, fluctuating endogenous CDK2 activity causes corresponding decreases and increases in DNA synthesis rates, linking changes in stochastic replication stress to fluctuating global DNA replication rates throughout S phase...
June 4, 2018: Cell Systems
Tanel Ozdemir, Alex J H Fedorec, Tal Danino, Chris P Barnes
Recent advances in synthetic biology and biological system engineering have allowed the design and construction of engineered live biotherapeutics targeting a range of human clinical applications. In this review, we outline how systems approaches have been used to move from simple constitutive systems, where a single therapeutic molecule is expressed, to systems that incorporate sensing of the in vivo environment, feedback, computation, and biocontainment. We outline examples where each of these capabilities are achieved in different human disorders, including cancer, inflammation, and metabolic disease, in a number of environments, including the gastrointestinal tract, the liver, and the oral cavity...
July 25, 2018: Cell Systems
Davide Cora', Michele Caselle
A new study coupling bioinformatic and experimental investigations highlights the importance of combinatorial microRNA targeting in human EMT, a phenotypic program underlying normal and pathological processes.
July 25, 2018: Cell Systems
Hernan G Garcia, Dirk Benzinger, Marc Rullan, Andreas Milias-Argeitis, Mustafa Khammash, Adam M Deutschbauer, Erin M Langdon, Amy S Gladfelter
This month: two examples of door-opening, innovative microscopy (Garcia and also Benzinger et al.), expanding our functional knowledge of bacteria by over 10,000 genes (Deutschbauer), and probing how RNA structure dictates inclusion in liquid-like droplets in vivo (Langdon and Gladfelter).
July 25, 2018: Cell Systems
Steffen Rulands, Heather J Lee, Stephen J Clark, Christof Angermueller, Sébastien A Smallwood, Felix Krueger, Hisham Mohammed, Wendy Dean, Jennifer Nichols, Peter Rugg-Gunn, Gavin Kelsey, Oliver Stegle, Benjamin D Simons, Wolf Reik
Pluripotency is accompanied by the erasure of parental epigenetic memory, with naïve pluripotent cells exhibiting global DNA hypomethylation both in vitro and in vivo. Exit from pluripotency and priming for differentiation into somatic lineages is associated with genome-wide de novo DNA methylation. We show that during this phase, co-expression of enzymes required for DNA methylation turnover, DNMT3s and TETs, promotes cell-to-cell variability in this epigenetic mark. Using a combination of single-cell sequencing and quantitative biophysical modeling, we show that this variability is associated with coherent, genome-scale oscillations in DNA methylation with an amplitude dependent on CpG density...
July 25, 2018: Cell Systems
Joseph Cursons, Katherine A Pillman, Kaitlin G Scheer, Philip A Gregory, Momeneh Foroutan, Soroor Hediyeh-Zadeh, John Toubia, Edmund J Crampin, Gregory J Goodall, Cameron P Bracken, Melissa J Davis
MicroRNAs (miRNAs) are important post-transcriptional regulators of gene expression, functioning in part by facilitating the degradation of target mRNAs. They have an established role in controlling epithelial-mesenchymal transition (EMT), a reversible phenotypic program underlying normal and pathological processes. Many studies demonstrate the role of individual miRNAs using overexpression at levels greatly exceeding physiological abundance. This can influence transcripts with relatively poor targeting and may in part explain why over 130 different miRNAs are directly implicated as EMT regulators...
July 25, 2018: Cell Systems
Ryan A Robinett, Ning Guan, Anja Lux, Markus Biburger, Falk Nimmerjahn, Aaron S Meyer
Many immune receptors transduce activation across the plasma membrane through their clustering. With Fcγ receptors (FcγRs), this clustering is driven by binding to antibodies of differing affinities that are in turn bound to multivalent antigen. As a consequence of this activation mechanism, accounting for and rationally manipulating immunoglobulin (Ig)G effector function is complicated by, among other factors, differing affinities between FcγR species and changes in the valency of antigen binding. In this study, we show that a model of multivalent receptor-ligand binding can effectively account for the contribution of IgG-FcγR affinity and immune complex valency...
July 25, 2018: Cell Systems
James C Chen, Rolando Perez-Lorenzo, Yvonne M Saenger, Charles G Drake, Angela M Christiano
Immunotherapies are some of the most promising emergent treatments for several cancers, yet there remains a majority of patients who do not benefit from them due to immune-resistant tumors. One avenue for enhancing treatment for these patients is by converting these tumors to an immunoreactive state, thereby restoring treatment efficacy. By leveraging regulatory networks we previously characterized in autoimmunity, here we show that overexpression of the master regulator IKZF1 leads to enhanced immune infiltrate recruitment and tumor sensitivity to PD1 and CTLA4 inhibitors in several tumors that normally lack IKZF1 expression...
July 25, 2018: Cell Systems
Lukas Bahati Tanner, Alexander G Goglia, Monica H Wei, Talen Sehgal, Lance R Parsons, Junyoung O Park, Eileen White, Jared E Toettcher, Joshua D Rabinowitz
Altered glycolysis is a hallmark of diseases including diabetes and cancer. Despite intensive study of the contributions of individual glycolytic enzymes, systems-level analyses of flux control through glycolysis remain limited. Here, we overexpress in two mammalian cell lines the individual enzymes catalyzing each of the 12 steps linking extracellular glucose to excreted lactate, and find substantial flux control at four steps: glucose import, hexokinase, phosphofructokinase, and lactate export (and not at any steps of lower glycolysis)...
July 25, 2018: Cell Systems
Timothy J O'Donnell, Alex Rubinsteyn, Maria Bonsack, Angelika B Riemer, Uri Laserson, Jeff Hammerbacher
Predicting the binding affinity of major histocompatibility complex I (MHC I) proteins and their peptide ligands is important for vaccine design. We introduce an open-source package for MHC I binding prediction, MHCflurry. The software implements allele-specific neural networks that use a novel architecture and peptide encoding scheme. When trained on affinity measurements, MHCflurry outperformed the standard predictors NetMHC 4.0 and NetMHCpan 3.0 overall and particularly on non-9-mer peptides in a benchmark of ligands identified by mass spectrometry...
July 25, 2018: Cell Systems
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