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Molecular Systems Biology

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https://www.readbyqxmd.com/read/28320772/mechanism-for-microbial-population-collapse-in-a-fluctuating-resource-environment
#1
Serdar Turkarslan, Arjun V Raman, Anne W Thompson, Christina E Arens, Mark A Gillespie, Frederick von Netzer, Kristina L Hillesland, Sergey Stolyar, Adrian López García de Lomana, David J Reiss, Drew Gorman-Lewis, Grant M Zane, Jeffrey A Ranish, Judy D Wall, David A Stahl, Nitin S Baliga
Managing trade-offs through gene regulation is believed to confer resilience to a microbial community in a fluctuating resource environment. To investigate this hypothesis, we imposed a fluctuating environment that required the sulfate-reducer Desulfovibrio vulgaris to undergo repeated ecologically relevant shifts between retaining metabolic independence (active capacity for sulfate respiration) and becoming metabolically specialized to a mutualistic association with the hydrogen-consuming Methanococcus maripaludis Strikingly, the microbial community became progressively less proficient at restoring the environmentally relevant physiological state after each perturbation and most cultures collapsed within 3-7 shifts...
March 20, 2017: Molecular Systems Biology
https://www.readbyqxmd.com/read/28302863/transfer-of-dysbiotic-gut-microbiota-has-beneficial-effects-on-host-liver-metabolism
#2
Simon Nicolas, Vincent Blasco-Baque, Audren Fournel, Jerome Gilleron, Pascale Klopp, Aurelie Waget, Franck Ceppo, Alysson Marlin, Roshan Padmanabhan, Jason S Iacovoni, François Tercé, Patrice D Cani, Jean-François Tanti, Remy Burcelin, Claude Knauf, Mireille Cormont, Matteo Serino
Gut microbiota dysbiosis has been implicated in a variety of systemic disorders, notably metabolic diseases including obesity and impaired liver function, but the underlying mechanisms are uncertain. To investigate this question, we transferred caecal microbiota from either obese or lean mice to antibiotic-free, conventional wild-type mice. We found that transferring obese-mouse gut microbiota to mice on normal chow (NC) acutely reduces markers of hepatic gluconeogenesis with decreased hepatic PEPCK activity, compared to non-inoculated mice, a phenotypic trait blunted in conventional NOD2 KO mice...
March 16, 2017: Molecular Systems Biology
https://www.readbyqxmd.com/read/28298427/systematic-protein-protein-interaction-mapping-for-clinically-relevant-human-gpcrs
#3
Kate Sokolina, Saranya Kittanakom, Jamie Snider, Max Kotlyar, Pascal Maurice, Jorge Gandía, Abla Benleulmi-Chaachoua, Kenjiro Tadagaki, Atsuro Oishi, Victoria Wong, Ramy H Malty, Viktor Deineko, Hiroyuki Aoki, Shahreen Amin, Zhong Yao, Xavier Morató, David Otasek, Hiroyuki Kobayashi, Javier Menendez, Daniel Auerbach, Stephane Angers, Natasa Pržulj, Michel Bouvier, Mohan Babu, Francisco Ciruela, Ralf Jockers, Igor Jurisica, Igor Stagljar
G-protein-coupled receptors (GPCRs) are the largest family of integral membrane receptors with key roles in regulating signaling pathways targeted by therapeutics, but are difficult to study using existing proteomics technologies due to their complex biochemical features. To obtain a global view of GPCR-mediated signaling and to identify novel components of their pathways, we used a modified membrane yeast two-hybrid (MYTH) approach and identified interacting partners for 48 selected full-length human ligand-unoccupied GPCRs in their native membrane environment...
March 15, 2017: Molecular Systems Biology
https://www.readbyqxmd.com/read/28270558/tt-seq-captures-enhancer-landscapes-immediately-after-t-cell-stimulation
#4
Margaux Michel, Carina Demel, Benedikt Zacher, Björn Schwalb, Stefan Krebs, Helmut Blum, Julien Gagneur, Patrick Cramer
To monitor transcriptional regulation in human cells, rapid changes in enhancer and promoter activity must be captured with high sensitivity and temporal resolution. Here, we show that the recently established protocol TT-seq ("transient transcriptome sequencing") can monitor rapid changes in transcription from enhancers and promoters during the immediate response of T cells to ionomycin and phorbol 12-myristate 13-acetate (PMA). TT-seq maps eRNAs and mRNAs every 5 min after T-cell stimulation with high sensitivity and identifies many new primary response genes...
March 7, 2017: Molecular Systems Biology
https://www.readbyqxmd.com/read/28265005/metabolic-constraints-on-the-evolution-of-antibiotic-resistance
#5
Mattia Zampieri, Tim Enke, Victor Chubukov, Vito Ricci, Laura Piddock, Uwe Sauer
Despite our continuous improvement in understanding antibiotic resistance, the interplay between natural selection of resistance mutations and the environment remains unclear. To investigate the role of bacterial metabolism in constraining the evolution of antibiotic resistance, we evolved Escherichia coli growing on glycolytic or gluconeogenic carbon sources to the selective pressure of three different antibiotics. Profiling more than 500 intracellular and extracellular putative metabolites in 190 evolved populations revealed that carbon and energy metabolism strongly constrained the evolutionary trajectories, both in terms of speed and mode of resistance acquisition...
March 6, 2017: Molecular Systems Biology
https://www.readbyqxmd.com/read/28254760/personal-model-assisted-identification-of-nad-and%C3%A2-glutathione-metabolism-as-intervention-target-in-nafld
#6
Adil Mardinoglu, Elias Bjornson, Cheng Zhang, Martina Klevstig, Sanni Söderlund, Marcus Ståhlman, Martin Adiels, Antti Hakkarainen, Nina Lundbom, Murat Kilicarslan, Björn M Hallström, Jesper Lundbom, Bruno Vergès, Peter Hugh R Barrett, Gerald F Watts, Mireille J Serlie, Jens Nielsen, Mathias Uhlén, Ulf Smith, Hanns-Ulrich Marschall, Marja-Riitta Taskinen, Jan Boren
To elucidate the molecular mechanisms underlying non-alcoholic fatty liver disease (NAFLD), we recruited 86 subjects with varying degrees of hepatic steatosis (HS). We obtained experimental data on lipoprotein fluxes and used these individual measurements as personalized constraints of a hepatocyte genome-scale metabolic model to investigate metabolic differences in liver, taking into account its interactions with other tissues. Our systems level analysis predicted an altered demand for NAD(+) and glutathione (GSH) in subjects with high HS Our analysis and metabolomic measurements showed that plasma levels of glycine, serine, and associated metabolites are negatively correlated with HS, suggesting that these GSH metabolism precursors might be limiting...
March 2, 2017: Molecular Systems Biology
https://www.readbyqxmd.com/read/28202506/recurrent-patterns-of-dna-copy-number-alterations-in-tumors-reflect-metabolic-selection-pressures
#7
Nicholas A Graham, Aspram Minasyan, Anastasia Lomova, Ashley Cass, Nikolas G Balanis, Michael Friedman, Shawna Chan, Sophie Zhao, Adrian Delgado, James Go, Lillie Beck, Christian Hurtz, Carina Ng, Rong Qiao, Johanna Ten Hoeve, Nicolaos Palaskas, Hong Wu, Markus Müschen, Asha S Multani, Elisa Port, Steven M Larson, Nikolaus Schultz, Daniel Braas, Heather R Christofk, Ingo K Mellinghoff, Thomas G Graeber
Copy number alteration (CNA) profiling of human tumors has revealed recurrent patterns of DNA amplifications and deletions across diverse cancer types. These patterns are suggestive of conserved selection pressures during tumor evolution but cannot be fully explained by known oncogenes and tumor suppressor genes. Using a pan-cancer analysis of CNA data from patient tumors and experimental systems, here we show that principal component analysis-defined CNA signatures are predictive of glycolytic phenotypes, including (18)F-fluorodeoxy-glucose (FDG) avidity of patient tumors, and increased proliferation...
February 15, 2017: Molecular Systems Biology
https://www.readbyqxmd.com/read/28193641/a-method-for-high-throughput-production-of-sequence-verified-dna-libraries-and-strain-collections
#8
Justin D Smith, Ulrich Schlecht, Weihong Xu, Sundari Suresh, Joe Horecka, Michael J Proctor, Raeka S Aiyar, Richard A O Bennett, Angela Chu, Yong Fuga Li, Kevin Roy, Ronald W Davis, Lars M Steinmetz, Richard W Hyman, Sasha F Levy, Robert P St Onge
The low costs of array-synthesized oligonucleotide libraries are empowering rapid advances in quantitative and synthetic biology. However, high synthesis error rates, uneven representation, and lack of access to individual oligonucleotides limit the true potential of these libraries. We have developed a cost-effective method called Recombinase Directed Indexing (REDI), which involves integration of a complex library into yeast, site-specific recombination to index library DNA, and next-generation sequencing to identify desired clones...
February 13, 2017: Molecular Systems Biology
https://www.readbyqxmd.com/read/28183842/metabolic-pattern-formation-in-the-tumor%C3%A2-microenvironment
#9
Ziwei Dai, Jason W Locasale
No abstract text is available yet for this article.
February 9, 2017: Molecular Systems Biology
https://www.readbyqxmd.com/read/28183841/mathematical-modeling-links-wnt-signaling-to-emergent-patterns-of-metabolism-in-colon-cancer
#10
Mary Lee, George T Chen, Eric Puttock, Kehui Wang, Robert A Edwards, Marian L Waterman, John Lowengrub
Cell-intrinsic metabolic reprogramming is a hallmark of cancer that provides anabolic support to cell proliferation. How reprogramming influences tumor heterogeneity or drug sensitivities is not well understood. Here, we report a self-organizing spatial pattern of glycolysis in xenograft colon tumors where pyruvate dehydrogenase kinase (PDK1), a negative regulator of oxidative phosphorylation, is highly active in clusters of cells arranged in a spotted array. To understand this pattern, we developed a reaction-diffusion model that incorporates Wnt signaling, a pathway known to upregulate PDK1 and Warburg metabolism...
February 9, 2017: Molecular Systems Biology
https://www.readbyqxmd.com/read/28167566/transcription-factor-family-specific-dna-shape-readout-revealed-by-quantitative-specificity-models
#11
Lin Yang, Yaron Orenstein, Arttu Jolma, Yimeng Yin, Jussi Taipale, Ron Shamir, Remo Rohs
Transcription factors (TFs) achieve DNA-binding specificity through contacts with functional groups of bases (base readout) and readout of structural properties of the double helix (shape readout). Currently, it remains unclear whether DNA shape readout is utilized by only a few selected TF families, or whether this mechanism is used extensively by most TF families. We resequenced data from previously published HT-SELEX experiments, the most extensive mammalian TF-DNA binding data available to date. Using these data, we demonstrated the contributions of DNA shape readout across diverse TF families and its importance in core motif-flanking regions...
February 6, 2017: Molecular Systems Biology
https://www.readbyqxmd.com/read/28137776/combinatorial-actions-of-bacterial-effectors-revealed-by-exploiting-genetic-tools-in-yeast
#12
Alan Huett
No abstract text is available yet for this article.
January 30, 2017: Molecular Systems Biology
https://www.readbyqxmd.com/read/28137775/a-living-vector-field-reveals-constraints-on-galactose-network-induction-in-yeast
#13
Sarah R Stockwell, Scott A Rifkin
When a cell encounters a new environment, its transcriptional response can be constrained by its history. For example, yeast cells in galactose induce GAL genes with a speed and unanimity that depends on previous nutrient conditions. Cellular memory of long-term glucose exposure delays GAL induction and makes it highly variable with in a cell population, while other nutrient histories lead to rapid, uniform responses. To investigate how cell-level gene expression dynamics produce population-level phenotypes, we built living vector fields from thousands of single-cell time courses of the proteins Gal3p and Gal1p as cells switched to galactose from various nutrient histories...
January 30, 2017: Molecular Systems Biology
https://www.readbyqxmd.com/read/28123004/protein-abundance-of-akt-and-erk-pathway-components-governs-cell-type-specific-regulation-of%C3%A2-proliferation
#14
Lorenz Adlung, Sandip Kar, Marie-Christine Wagner, Bin She, Sajib Chakraborty, Jie Bao, Susen Lattermann, Melanie Boerries, Hauke Busch, Patrick Wuchter, Anthony D Ho, Jens Timmer, Marcel Schilling, Thomas Höfer, Ursula Klingmüller
Signaling through the AKT and ERK pathways controls cell proliferation. However, the integrated regulation of this multistep process, involving signal processing, cell growth and cell cycle progression, is poorly understood. Here, we study different hematopoietic cell types, in which AKT and ERK signaling is triggered by erythropoietin (Epo). Although these cell types share the molecular network topology for pro-proliferative Epo signaling, they exhibit distinct proliferative responses. Iterating quantitative experiments and mathematical modeling, we identify two molecular sources for cell type-specific proliferation...
January 24, 2017: Molecular Systems Biology
https://www.readbyqxmd.com/read/28115550/stochastic-gene-expression-bacterial-elites-in-chemotaxis
#15
Simon van Vliet, Martin Ackermann
No abstract text is available yet for this article.
January 23, 2017: Molecular Systems Biology
https://www.readbyqxmd.com/read/28093455/genomewide-landscape-of-gene-metabolome-associations-in-escherichia-coli
#16
Tobias Fuhrer, Mattia Zampieri, Daniel C Sévin, Uwe Sauer, Nicola Zamboni
Metabolism is one of the best-understood cellular processes whose network topology of enzymatic reactions is determined by an organism's genome. The influence of genes on metabolite levels, however, remains largely unknown, particularly for the many genes encoding non-enzymatic proteins. Serendipitously, genomewide association studies explore the relationship between genetic variants and metabolite levels, but a comprehensive interaction network has remained elusive even for the simplest single-celled organisms...
January 16, 2017: Molecular Systems Biology
https://www.readbyqxmd.com/read/28082348/interactome-disassembly-during-apoptosis-occurs-independent-of-caspase-cleavage
#17
Nichollas E Scott, Lindsay D Rogers, Anna Prudova, Nat F Brown, Nikolaus Fortelny, Christopher M Overall, Leonard J Foster
Protein-protein interaction networks (interactomes) define the functionality of all biological systems. In apoptosis, proteolysis by caspases is thought to initiate disassembly of protein complexes and cell death. Here we used a quantitative proteomics approach, protein correlation profiling (PCP), to explore changes in cytoplasmic and mitochondrial interactomes in response to apoptosis initiation as a function of caspase activity. We measured the response to initiation of Fas-mediated apoptosis in 17,991 interactions among 2,779 proteins, comprising the largest dynamic interactome to date...
January 12, 2017: Molecular Systems Biology
https://www.readbyqxmd.com/read/28069687/adaptive-resistance-of-melanoma-cells-to-raf-inhibition-via-reversible-induction-of-a-slowly-dividing-de-differentiated-state
#18
Mohammad Fallahi-Sichani, Verena Becker, Benjamin Izar, Gregory J Baker, Jia-Ren Lin, Sarah A Boswell, Parin Shah, Asaf Rotem, Levi A Garraway, Peter K Sorger
Treatment of BRAF-mutant melanomas with MAP kinase pathway inhibitors is paradigmatic of the promise of precision cancer therapy but also highlights problems with drug resistance that limit patient benefit. We use live-cell imaging, single-cell analysis, and molecular profiling to show that exposure of tumor cells to RAF/MEK inhibitors elicits a heterogeneous response in which some cells die, some arrest, and the remainder adapt to drug. Drug-adapted cells up-regulate markers of the neural crest (e.g., NGFR), a melanocyte precursor, and grow slowly...
January 9, 2017: Molecular Systems Biology
https://www.readbyqxmd.com/read/28049137/few-regulatory-metabolites-coordinate-expression-of-central-metabolic-genes-in-escherichia-coli
#19
Karl Kochanowski, Luca Gerosa, Simon F Brunner, Dimitris Christodoulou, Yaroslav V Nikolaev, Uwe Sauer
Transcription networks consist of hundreds of transcription factors with thousands of often overlapping target genes. While we can reliably measure gene expression changes, we still understand relatively little why expression changes the way it does. How does a coordinated response emerge in such complex networks and how many input signals are necessary to achieve it? Here, we unravel the regulatory program of gene expression in Escherichia coli central carbon metabolism with more than 30 known transcription factors...
January 3, 2017: Molecular Systems Biology
https://www.readbyqxmd.com/read/28049136/early-commitment-and-robust-differentiation-in-colonic-crypts
#20
Beáta Tóth, Shani Ben-Moshe, Avishai Gavish, Naama Barkai, Shalev Itzkovitz
Tissue stem cells produce a constant flux of differentiated cells with distinct proportions. Here, we show that stem cells in colonic crypts differentiate early to form precisely 1:3 ratio of secretory to absorptive cells. This precision is surprising, as there are only eight stem cells making irreversible fate decisions, and so large stochastic effects of this small pool should have yielded much larger noise in cell proportions. We use single molecule FISH, lineage-tracing mice and simulations to identify the homeostatic mechanisms facilitating robust proportions...
January 3, 2017: Molecular Systems Biology
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