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Cell Systems

Michael Ku Yu, Jianzhu Ma, Keiichiro Ono, Fan Zheng, Samson H Fong, Aaron Gary, Jing Chen, Barry Demchak, Dexter Pratt, Trey Ideker
Systems biology requires not only genome-scale data but also methods to integrate these data into interpretable models. Previously, we developed approaches that organize omics data into a structured hierarchy of cellular components and pathways, called a "data-driven ontology." Such hierarchies recapitulate known cellular subsystems and discover new ones. To broadly facilitate this type of modeling, we report the development of a software library called the Data-Driven Ontology Toolkit (DDOT), consisting of a Python package (https://github...
March 11, 2019: Cell Systems
Adam Freund
Research on aging requires the ability to measure aging, and therein lies a challenge: it is impossible to measure every molecular, cellular, and physiological change that develops over time, but it is difficult to prioritize phenotypes for measurement because it is unclear which biological changes should be considered aspects of aging and, further, which species and environments exhibit "real aging." Here, I propose a strategy to address this challenge: rather than classify phenotypes as "real aging" or not, conceptualize aging as the set of all age-dependent phenotypes and appreciate that this set and its underlying mechanisms may vary by population...
March 7, 2019: Cell Systems
Meng Jin, Yang Li, Richard O'Laughlin, Philip Bittihn, Lorraine Pillus, Lev S Tsimring, Jeff Hasty, Nan Hao
Although genetic mutations that alter organisms' average lifespans have been identified in aging research, our understanding of the dynamic changes during aging remains limited. Here, we integrate single-cell imaging, microfluidics, and computational modeling to investigate phenotypic divergence and cellular heterogeneity during replicative aging of single S. cerevisiae cells. Specifically, we find that isogenic cells diverge early in life toward one of two aging paths, which are characterized by distinct age-associated phenotypes...
February 27, 2019: Cell Systems
Yutaka Hashimoto, Noriyuki Kinoshita, Todd M Greco, Joel D Federspiel, Pierre M Jean Beltran, Naoto Ueno, Ileana M Cristea
Mechanical forces are essential drivers of numerous biological processes, notably during development. Although it is well recognized that cells sense and adapt to mechanical forces, the signal transduction pathways that underlie mechanosensing have remained elusive. Here, we investigate the impact of mechanical centrifugation force on phosphorylation-mediated signaling in Xenopus embryos. By monitoring temporal phosphoproteome and proteome alterations in response to force, we discover and validate elevated phosphorylation on focal adhesion and tight junction components, leading to several mechanistic insights into mechanosensing and tissue restoration...
February 18, 2019: Cell Systems
Christian T Meyer, David J Wooten, B Bishal Paudel, Joshua Bauer, Keisha N Hardeman, David Westover, Christine M Lovly, Leonard A Harris, Darren R Tyson, Vito Quaranta
Two goals motivate treating diseases with drug combinations: reduce off-target toxicity by minimizing doses (synergistic potency) and improve outcomes by escalating effect (synergistic efficacy). Established drug synergy frameworks obscure such distinction, failing to harness the potential of modern chemical libraries. We therefore developed multi-dimensional synergy of combinations (MuSyC), a formalism based on a generalized, multi-dimensional Hill equation, which decouples synergistic potency and efficacy...
February 14, 2019: Cell Systems
Adan Codina, Paul A Renauer, Guangchuan Wang, Ryan D Chow, Jonathan J Park, Hanghui Ye, Kerou Zhang, Matthew B Dong, Brandon Gassaway, Lupeng Ye, Youssef Errami, Li Shen, Alan Chang, Dhanpat Jain, Roy S Herbst, Marcus Bosenberg, Jesse Rinehart, Rong Fan, Sidi Chen
The genetic makeup of cancer cells directs oncogenesis and influences the tumor microenvironment. In this study, we massively profiled genes that functionally drive tumorigenesis using genome-scale in vivo CRISPR screens in hosts with different levels of immunocompetence. As a convergent hit from these screens, Prkar1a mutant cells are able to robustly outgrow as tumors in fully immunocompetent hosts. Functional interrogation showed that Prkar1a loss greatly altered the transcriptome and proteome involved in inflammatory and immune responses as well as extracellular protein production...
February 11, 2019: Cell Systems
Jesse C Patterson, Brian A Joughin, Bert van de Kooij, Daniel C Lim, Douglas A Lauffenburger, Michael B Yaffe
Although elevated levels of reactive oxygen species (ROS) have been observed in cancer cells and cancer cells aberrantly proliferate, it is not known whether the level of reactive oxygen species and the accumulation of oxidative damage to macromolecules vary across the cell cycle. Here, we measure the prevalence of reactive oxygen species and of biomolecule oxidation across the cell cycle in freely cycling cancer cells. We report that reactive oxygen species vary during the cell cycle and peak in mitosis, resulting in mitotic accumulation of oxidized protein cysteine residues...
February 6, 2019: Cell Systems
Ronnie Blecher-Gonen, Pierre Bost, Kerry L Hilligan, Eyal David, Tomer Meir Salame, Elsa Roussel, Lisa M Connor, Johannes U Mayer, Keren Bahar Halpern, Beáta Tóth, Shalev Itzkovitz, Benno Schwikowski, Franca Ronchese, Ido Amit
The immune system generates pathogen-tailored responses. The precise innate immune cell types and pathways that direct robust adaptive immune responses have not been fully characterized. By using fluorescent pathogens combined with massively parallel single-cell RNA-seq, we comprehensively characterized the initial 48 h of the innate immune response to diverse pathogens. We found that across all pathogens tested, most of the lymph node cell types and states showed little pathogen specificity. In contrast, the rare antigen-positive cells displayed pathogen-specific transcriptional programs as early as 24 h after immunization...
February 1, 2019: Cell Systems
Jocelynn R Pearl, Carlo Colantuoni, Dani E Bergey, Cory C Funk, Paul Shannon, Bijoya Basu, Alex M Casella, Rediet T Oshone, Leroy Hood, Nathan D Price, Seth A Ament
Transcriptional regulatory changes in the developing and adult brain are prominent features of brain diseases, but the involvement of specific transcription factors (TFs) remains poorly understood. We integrated brain-specific DNase footprinting and TF-gene co-expression to reconstruct a transcriptional regulatory network (TRN) model for the human brain. We identified key regulator TFs whose predicted target genes were enriched for differentially expressed genes in the prefrontal cortex of individuals with psychiatric and neurodegenerative diseases...
January 31, 2019: Cell Systems
Young-Suk Lee, Arjun Krishnan, Rose Oughtred, Jennifer Rust, Christie S Chang, Joseph Ryu, Vessela N Kristensen, Kara Dolinski, Chandra L Theesfeld, Olga G Troyanskaya
A key challenge for the diagnosis and treatment of complex human diseases is identifying their molecular basis. Here, we developed a unified computational framework, URSAHD (Unveiling RNA Sample Annotation for Human Diseases), that leverages machine learning and the hierarchy of anatomical relationships present among diseases to integrate thousands of clinical gene expression profiles and identify molecular characteristics specific to each of the hundreds of complex diseases. URSAHD can distinguish between closely related diseases more accurately than literature-validated genes or traditional differential-expression-based computational approaches and is applicable to any disease, including rare and understudied ones...
January 14, 2019: Cell Systems
Michał Komorowski, Dan S Tawfik
Signaling systems expand by duplications of various components, be it receptors or downstream effectors. However, whether and how duplicated components contribute to higher signaling capacity is unclear, especially because in most cases, their specificities overlap. Using information theory, we found that augmentation of capacity by an increase in the copy number is strongly limited by logarithmic diminishing returns. Moreover, counter to conventional biochemical wisdom, refinements of the response mechanism, e...
January 9, 2019: Cell Systems
Md Abul Hassan Samee, Benoit G Bruneau, Katherine S Pollard
DNA shape adds specificity to sequence motifs but has not been explored systematically outside this context. We hypothesized that DNA-binding proteins (DBPs) preferentially occupy DNA with specific structures ("shape motifs") regardless of whether or not these correspond to high information content sequence motifs. We present ShapeMF, a Gibbs sampling algorithm that identifies de novo shape motifs. Using binding data from hundreds of in vivo and in vitro experiments, we show that most DBPs have shape motifs and can occupy these in the absence of sequence motifs...
January 4, 2019: Cell Systems
Lekshmi Dharmarajan, Hans-Michael Kaltenbach, Fabian Rudolf, Joerg Stelling
Single-cell time-lapse data provide the means for disentangling sources of cell-to-cell and intra-cellular variability, a key step for understanding heterogeneity in cell populations. However, single-cell analysis with dynamic models is a challenging open problem: current inference methods address only single-gene expression or neglect parameter correlations. We report on a simple, flexible, and scalable method for estimating cell-specific and population-average parameters of non-linear mixed-effects models of cellular networks, demonstrating its accuracy with a published model and dataset...
January 4, 2019: Cell Systems
Timur Sander, Niklas Farke, Christoph Diehl, Michelle Kuntz, Timo Glatter, Hannes Link
Microbes must ensure robust amino acid metabolism in the face of external and internal perturbations. This robustness is thought to emerge from regulatory interactions in metabolic and genetic networks. Here, we explored the consequences of removing allosteric feedback inhibition in seven amino acid biosynthesis pathways in Escherichia coli (arginine, histidine, tryptophan, leucine, isoleucine, threonine, and proline). Proteome data revealed that enzyme levels decreased in five of the seven dysregulated pathways...
January 4, 2019: Cell Systems
Miri Adler, Yael Korem Kohanim, Avichai Tendler, Avi Mayo, Uri Alon
Single-cell gene expression reveals the diversity within a differentiated cell type. Often, cells of the same type show a continuum of gene-expression patterns. The origin of such continuum gene-expression patterns is unclear. To address this, we develop a theory to understand how a continuum provides division of labor in a tissue in which cells collectively contribute to several tasks. We find that a continuum is optimal when there are spatial gradients in the tissue that affect the performance in each task...
January 4, 2019: Cell Systems
Laura J Dunphy, Phillip Yen, Jason A Papin
Metabolic adaptations accompanying the development of antibiotic resistance in bacteria remain poorly understood. To study this relationship, we profiled the growth of lab-evolved antibiotic-resistant lineages of the opportunistic pathogen Pseudomonas aeruginosa across 190 unique carbon sources. Our data revealed that the evolution of antibiotic resistance resulted in systems-level changes to growth dynamics and metabolic phenotype. A genome-scale metabolic network reconstruction of P. aeruginosa was paired with whole-genome sequencing data to predict genes contributing to observed changes in metabolism...
December 28, 2018: Cell Systems
Rhys M Adams, Justin B Kinney, Aleksandra M Walczak, Thierry Mora
Epistasis is the phenomenon by which the effect of a mutation depends on its genetic background. While it is usually defined in terms of organismal fitness, for single proteins, it must reflect physical interactions among residues. Here, we systematically extract the specific contribution pairwise epistasis makes to the physical affinity of antibody-antigen binding relevant to affinity maturation, a process of accelerated Darwinian evolution. We find that, among competing definitions of affinity, the binding free energy is the most appropriate to describe epistasis...
December 27, 2018: Cell Systems
Quincey Justman
No abstract text is available yet for this article.
February 27, 2019: Cell Systems
Michael Springer
One snapshot of the peer review process for "Integrated Experimental and Computational Analyses Reveal Differential Metabolic Functionality in Antibiotic-Resistant Pseudomonas aeruginosa" (Dunphy et al., 2019).
January 23, 2019: Cell Systems
Matthew D B Jackson, Salva Duran-Nebreda, Daniel Kierzkowski, Soeren Strauss, Hao Xu, Benoit Landrein, Olivier Hamant, Richard S Smith, Iain G Johnston, George W Bassel
The control of cell position and division act in concert to dictate multicellular organization in tissues and organs. How these processes shape global order and molecular movement across organs is an outstanding problem in biology. Using live 3D imaging and computational analyses, we extracted networks capturing cellular connectivity dynamics across the Arabidopsis shoot apical meristem (SAM) and topologically analyzed the local and global properties of cellular architecture. Locally generated cell division rules lead to the emergence of global tissue-scale organization of the SAM, facilitating robust global communication...
January 23, 2019: Cell Systems
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