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Publications about 'translation'
Articles in journal or book chapters
  1. V. H. Nagaraj, J. M. Greene, A. M. Sengupta, and and E.D. Sontag. Translation inhibition and resource balance in the TX-TL cell-free gene expression system. Synthetic Biology, 2017. Note: In press. Preprint in biorxiv 10.1101/142869 with same title, May 2017.Keyword(s): cell-free systems, in vitro synthetic biology.
    Abstract:
    Utilizing the synthetic transcription-translation (TX-TL) system, this paper studies the impact of nucleotide triphosphates (NTPs) and magnesium (Mg2+), on gene expression, in the context of the counterintuitive phenomenon of suppression of gene expression at high NTP concentration. Measuring translation rates for different Mg2+ and NTP concentrations, we observe a complex resource dependence. We demonstrate that translation is the rate-limiting process that is directly inhibited by high NTP concentrations. Additional Mg2+ can partially reverse this inhibition. In several experiments, we observe two maxima of the translation rate viewed as a function of both Mg2+ and NTP concentration, which can be explained in terms of an NTP-independent effect on the ribosome complex and an NTP- Mg2+ titration effect. The non-trivial compensatory effects of abundance of different vital resources signals the presence of complex regulatory mechanisms to achieve optimal gene expression.


  2. Y. Vodovotz, A. Xia, E. Read, J. Bassaganya-Riera, D.A. Hafler, E.D. Sontag, J. Wang, J.S. Tsang, J.D. Day, S. Kleinstein, A.J. Butte, M.C. Altman, R. Hammond, C. Benoist, and S.C. Sealfon. Solving Immunology?. Trends in Immunology, 38:116-127, 2017. [PDF] Keyword(s): Immunology.
    Abstract:
    Emergent responses of the immune system result from the integration of molecular and cellular networks over time and across multiple organs. High-content and high-throughput analysis technologies, concomitantly with data-driven and mechanistic modeling, hold promise for the systematic interrogation of these complex pathways. However, connecting genetic variation and molecular mechanisms to individual phenotypes and health outcomes has proven elusive. Gaps remain in data, and disagreements persist about the value of mechanistic modeling for immunology. This paper presents perspectives that emerged from the National Institute of Allergy and Infectious Disease (NIAID) workshop `Complex Systems Science, Modeling and Immunity' and subsequent discussions regarding the potential synergy of high-throughput data acquisition, data-driven modeling, and mechanistic modeling to define new mechanisms of immunological disease and to accelerate the translation of these insights into therapies.


  3. Y. Zarai, M. Margaliot, E.D. Sontag, and T. Tuller. Controllability analysis and control synthesis for the ribosome flow model. IEEE/ACM Transactions on Computational Biology and Bioinformatics, 2017. Note: To appear.[PDF] Keyword(s): systems biology, ribosomes, controllability.
    Abstract:
    The ribosomal density along the coding region of the mRNA molecule affects various fundamental intracellular phenomena including: protein production rates, organismal fitness, ribosomal drop off, and co-translational protein folding. Thus, regulating translation in order to obtain a desired ribosomal profile along the mRNA molecule is an important biological problem. This paper studies this problem formulated in the context of the ribosome flow model (RFM) in which one views the transition rates between site as controls.


  4. J.A. Ascensao, P. Datta, B. Hancioglu, E.D. Sontag, M.L. Gennaro, and O.A. Igoshin. Non-monotonic response dynamics of glyoxylate shunt genes in Mycobacterium tuberculosis. PLoS Computational Biology, 12:e1004741, 2016. [PDF]
    Abstract:
    Understanding how dynamical responses of biological networks are constrained by underlying network topology is one of the fundamental goals of systems biology. Here we employ monotone systems theory to formulate a theorem stating necessary conditions for non-monotonic time-response of a biochemical network to a monotonic stimulus. We apply this theorem to analyze the non-monotonic dynamics of the sigmaB-regulated glyoxylate shunt gene expression in Mycobacterium tuberculosis cells exposed to hypoxia. We first demonstrate that the known network structure is inconsistent with observed dynamics. To resolve this inconsistency we employ the formulated theorem, modeling simulations and optimization along with follow-up dynamic experimental measurements. We show a requirement for post-translational modulation of sigmaB activity in order to reconcile the network dynamics with its topology. The results of this analysis make testable experimental predictions and demonstrate wider applicability of the developed methodology to a wide class of biological systems.


  5. A. Raveh, M. Margaliot, E.D. Sontag, and T. Tuller. A model for competition for ribosomes in the cell. Proc. Royal Society Interface, 13:2015.1062, 2016. [PDF] Keyword(s): resource competition, ribosomes, entrainment, nonlinear systems, stability, contractions, contractive systems.
    Abstract:
    We develop and analyze a general model for large-scale simultaneous mRNA translation and competition for ribosomes. Such models are especially important when dealing with highly expressed genes, as these consume more resources. For our model, we prove that the compound system always converges to a steady-state and that it always entrains or phase locks to periodically time-varying transition rates in any of the mRNA molecules. We use this model to explore the interactions between the various mRNA molecules and ribosomes at steady-state. We show that increasing the length of an mRNA molecule decreases the production rate of all the mRNAs. Increasing any of the codon translation rates in a specific mRNA molecule yields a local effect: an increase in the translation rate of this mRNA, and also a global effect: the translation rates in the other mRNA molecules all increase or all decrease. These results suggest that the effect of codon decoding rates of endogenous and heterologous mRNAs on protein production might be more complicated than previously thought.


  6. M. Margaliot, E.D. Sontag, and T. Tuller. Entrainment to periodic initiation and transition rates in a computational model for gene translation. PLoS ONE, 9(5):e96039, 2014. [WWW] [PDF] [doi:10.1371/journal.pone.0096039] Keyword(s): ribosomes, entrainment, nonlinear systems, stability, contractions, contractive systems.
    Abstract:
    A recent biological study has demonstrated that the gene expression pattern entrains to a periodically varying abundance of tRNA molecules. This motivates developing mathematical tools for analyzing entrainment of translation elongation to intra-cellular signals such as tRNAs levels and other factors affecting translation. We consider a recent deterministic mathematical model for translation called the Ribosome Flow Model (RFM). We analyze this model under the assumption that the elongation rate of the tRNA genes and/or the initiation rate are periodic functions with a common period T. We show that the protein synthesis pattern indeed converges to a unique periodic trajectory with period T. The analysis is based on introducing a novel property of dynamical systems, called contraction after a short transient (CAST), that may be of independent interest. We provide a sufficient condition for CAST and use it to prove that the RFM is CAST, and that this implies entrainment. Our results support the conjecture that periodic oscillations in tRNA levels and other factors related to the translation process can induce periodic oscillations in protein levels, and suggest a new approach for engineering genes to obtain a desired, periodic, synthesis rate.


  7. D. Angeli and E.D. Sontag. Translation-invariant monotone systems, and a global convergence result for enzymatic futile cycles. Nonlinear Analysis Series B: Real World Applications, 9:128-140, 2008. [PDF] [doi:10.1016/j.nonrwa.2006.09.006] Keyword(s): systems biology, biochemical networks, nonlinear stability, dynamical systems, monotone systems.
    Abstract:
    Strongly monotone systems of ordinary differential equations which have a certain translation-invariance property are shown to have the property that all projected solutions converge to a unique equilibrium. This result may be seen as a dual of a well-known theorem of Mierczynski for systems that satisfy a conservation law. As an application, it is shown that enzymatic futile cycles have a global convergence property.


  8. M. Chaves, R. Albert, and E.D. Sontag. Robustness and fragility of Boolean models for genetic regulatory networks. J. Theoret. Biol., 235(3):431-449, 2005. [PDF] Keyword(s): systems biology, biochemical networks, boolean systems, gene and protein networks.
    Abstract:
    Interactions between genes and gene products give rise to complex circuits that enable cells to process information and respond to external signals. Theoretical studies often describe these interactions using continuous, stochastic, or logical approaches. Here we propose a framework for gene regulatory networks that combines the intuitive appeal of a qualitative description of gene states with a high flexibility in incorporating stochasticity in the duration of cellular processes. We apply our methods to the regulatory network of the segment polarity genes, thus gaining novel insights into the development of gene expression patterns. For example, we show that very short synthesis and decay times can perturb the wild type pattern. On the other hand, separation of timescales between pre- and post-translational processes and a minimal prepattern ensure convergence to the wild type expression pattern regardless of fluctuations.


Conference articles
  1. Y. Zarai, M. Margaliot, E.D. Sontag, and T. Tuller. Controlling the ribosomal density profile in mRNA translation. In Proc. IEEE Conf. Decision and Control, Dec. 2016, pages 4184-4189, 2016. Keyword(s): ribosomes, translation.


  2. D. Angeli and E.D. Sontag. A note on monotone systems with positive translation invariance. In Control and Automation, 2006. MED '06. 14th Mediterranean Conference on, 28-30 June 2006, pages 1-6, 2006. IEEE. Note: Available from ieeexplore.ieee.org. [PDF] [doi:10.1109/MED.2006.3287822B2B2B2B2B2B] Keyword(s): systems biology, biochemical networks, nonlinear stability, dynamical systems, monotone systems.
    Abstract:
    Strongly monotone systems of ordinary differential equations which have a certain translation-invariance property are shown to have the property that all projected solutions converge to a unique equilibrium. This result may be seen as a dual of a well-known theorem of Mierczynski for systems that satisfy a conservation law. As an application, it is shown that enzymatic futile cycles have a global convergence property.



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Last modified: Thu Nov 23 10:40:57 2017
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