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Molecular Systems Biology

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https://www.readbyqxmd.com/read/28495919/alternative-tsss-are-co-regulated-in-single-cells-in-the-mouse-brain
#1
Kasper Karlsson, Peter Lönnerberg, Sten Linnarsson
Alternative transcription start sites (TSSs) have been extensively studied genome-wide for many cell types and have been shown to be important during development and to regulate transcript abundance between cell types. Likewise, single-cell gene expression has been extensively studied for many cell types. However, how single cells use TSSs has not yet been examined. In particular, it is unknown whether alternative TSSs are independently expressed, or whether they are co-activated or even mutually exclusive in single cells...
May 11, 2017: Molecular Systems Biology
https://www.readbyqxmd.com/read/28490437/high-throughput-crispri-phenotyping-identifies-new-essential-genes-in-streptococcus-pneumoniae
#2
Xue Liu, Clement Gallay, Morten Kjos, Arnau Domenech, Jelle Slager, Sebastiaan P van Kessel, Kèvin Knoops, Robin A Sorg, Jing-Ren Zhang, Jan-Willem Veening
Genome-wide screens have discovered a large set of essential genes in the opportunistic human pathogen Streptococcus pneumoniae However, the functions of many essential genes are still unknown, hampering vaccine development and drug discovery. Based on results from transposon sequencing (Tn-seq), we refined the list of essential genes in S. pneumoniae serotype 2 strain D39. Next, we created a knockdown library targeting 348 potentially essential genes by CRISPR interference (CRISPRi) and show a growth phenotype for 254 of them (73%)...
May 10, 2017: Molecular Systems Biology
https://www.readbyqxmd.com/read/28468958/an-immediate-late-gene-expression-module-decodes-erk-signal-duration
#3
Florian Uhlitz, Anja Sieber, Emanuel Wyler, Raphaela Fritsche-Guenther, Johannes Meisig, Markus Landthaler, Bertram Klinger, Nils Blüthgen
The RAF-MEK-ERK signalling pathway controls fundamental, often opposing cellular processes such as proliferation and apoptosis. Signal duration has been identified to play a decisive role in these cell fate decisions. However, it remains unclear how the different early and late responding gene expression modules can discriminate short and long signals. We obtained both protein phosphorylation and gene expression time course data from HEK293 cells carrying an inducible construct of the proto-oncogene RAF By mathematical modelling, we identified a new gene expression module of immediate-late genes (ILGs) distinct in gene expression dynamics and function...
May 3, 2017: Molecular Systems Biology
https://www.readbyqxmd.com/read/28455349/a-notch-positive-feedback-in-the-intestinal-stem-cell-niche-is-essential-for-stem-cell-self-renewal
#4
Kai-Yuan Chen, Tara Srinivasan, Kuei-Ling Tung, Julio M Belmonte, Lihua Wang, Preetish Kadur Lakshminarasimha Murthy, Jiahn Choi, Nikolai Rakhilin, Sarah King, Anastasia Kristine Varanko, Mavee Witherspoon, Nozomi Nishimura, James A Glazier, Steven M Lipkin, Pengcheng Bu, Xiling Shen
The intestinal epithelium is the fastest regenerative tissue in the body, fueled by fast-cycling stem cells. The number and identity of these dividing and migrating stem cells are maintained by a mosaic pattern at the base of the crypt. How the underlying regulatory scheme manages this dynamic stem cell niche is not entirely clear. We stimulated intestinal organoids with Notch ligands and inhibitors and discovered that intestinal stem cells employ a positive feedback mechanism via direct Notch binding to the second intron of the Notch1 gene...
April 28, 2017: Molecular Systems Biology
https://www.readbyqxmd.com/read/28455348/a-spectrum-of-modularity-in-multi-functional-gene-circuits
#5
Alba Jiménez, James Cotterell, Andreea Munteanu, James Sharpe
A major challenge in systems biology is to understand the relationship between a circuit's structure and its function, but how is this relationship affected if the circuit must perform multiple distinct functions within the same organism? In particular, to what extent do multi-functional circuits contain modules which reflect the different functions? Here, we computationally survey a range of bi-functional circuits which show no simple structural modularity: They can switch between two qualitatively distinct functions, while both functions depend on all genes of the circuit...
April 27, 2017: Molecular Systems Biology
https://www.readbyqxmd.com/read/28442489/integrative-genomics-of-gene-and-metabolic-regulation-by-estrogen-receptors-%C3%AE-and-%C3%AE-and-their-coregulators
#6
Zeynep Madak-Erdogan, Tze-Howe Charn, Yan Jiang, Edison T Liu, John A Katzenellenbogen, Benita S Katzenellenbogen
No abstract text is available yet for this article.
April 25, 2017: Molecular Systems Biology
https://www.readbyqxmd.com/read/28438832/a-photoconversion-model-for-full-spectral-programming-and-multiplexing-of-optogenetic%C3%A2-systems
#7
Evan J Olson, Constantine N Tzouanas, Jeffrey J Tabor
Optogenetics combines externally applied light signals and genetically engineered photoreceptors to control cellular processes with unmatched precision. Here, we develop a mathematical model of wavelength- and intensity-dependent photoconversion, signaling, and output gene expression for our two previously engineered light-sensing Escherichia coli two-component systems. To parameterize the model, we develop a simple set of spectral and dynamical calibration experiments using our recent open-source "Light Plate Apparatus" device...
April 24, 2017: Molecular Systems Biology
https://www.readbyqxmd.com/read/28420678/automated-analysis-of-high-content-microscopy-data-with-deep-learning
#8
Oren Z Kraus, Ben T Grys, Jimmy Ba, Yolanda Chong, Brendan J Frey, Charles Boone, Brenda J Andrews
Existing computational pipelines for quantitative analysis of high-content microscopy data rely on traditional machine learning approaches that fail to accurately classify more than a single dataset without substantial tuning and training, requiring extensive analysis. Here, we demonstrate that the application of deep learning to biological image data can overcome the pitfalls associated with conventional machine learning classifiers. Using a deep convolutional neural network (DeepLoc) to analyze yeast cell images, we show improved performance over traditional approaches in the automated classification of protein subcellular localization...
April 18, 2017: Molecular Systems Biology
https://www.readbyqxmd.com/read/28373240/engineering-bacterial-thiosulfate-and-tetrathionate-sensors-for-detecting-gut-inflammation
#9
Kristina N-M Daeffler, Jeffrey D Galley, Ravi U Sheth, Laura C Ortiz-Velez, Christopher O Bibb, Noah F Shroyer, Robert A Britton, Jeffrey J Tabor
There is a groundswell of interest in using genetically engineered sensor bacteria to study gut microbiota pathways, and diagnose or treat associated diseases. Here, we computationally identify the first biological thiosulfate sensor and an improved tetrathionate sensor, both two-component systems from marine Shewanella species, and validate them in laboratory Escherichia coli Then, we port these sensors into a gut-adapted probiotic E. coli strain, and develop a method based upon oral gavage and flow cytometry of colon and fecal samples to demonstrate that colon inflammation (colitis) activates the thiosulfate sensor in mice harboring native gut microbiota...
April 3, 2017: Molecular Systems Biology
https://www.readbyqxmd.com/read/28348067/proteomics-and-integrative-omic-approaches-for-understanding-host-pathogen-interactions-and-infectious-diseases
#10
REVIEW
Pierre M Jean Beltran, Joel D Federspiel, Xinlei Sheng, Ileana M Cristea
Organisms are constantly exposed to microbial pathogens in their environments. When a pathogen meets its host, a series of intricate intracellular interactions shape the outcome of the infection. The understanding of these host-pathogen interactions is crucial for the development of treatments and preventive measures against infectious diseases. Over the past decade, proteomic approaches have become prime contributors to the discovery and understanding of host-pathogen interactions that represent anti- and pro-pathogenic cellular responses...
March 27, 2017: Molecular Systems Biology
https://www.readbyqxmd.com/read/28320772/mechanism-for-microbial-population-collapse-in-a-fluctuating-resource-environment
#11
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
#12
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
#13
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
#14
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
#15
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
#16
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
#17
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
#18
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
#19
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
#20
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
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