Online ISSN
1751-8857
Print ISSN
1751-8849
IET Systems Biology
Volume 5, Issue 1, January 2011
Volumes & issues:
Volume 5, Issue 1
January 2011
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- Author(s): M.A. Henson
- Source: IET Systems Biology, Volume 5, Issue 1, page: 1 –1
- DOI: 10.1049/iet-syb.2011.9005
- Type: Article
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- Author(s): S. Nayak ; J.K. Siddiqui ; J.D. Varner
- Source: IET Systems Biology, Volume 5, Issue 1, p. 2 –14
- DOI: 10.1049/iet-syb.2009.0065
- Type: Article
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Programmed protein synthesis plays an important role in the cell cycle. Deregulated translation has been observed in several cancers. In this study, the authors constructed an ensemble of mathematical models describing the integration of growth factor signals with translation initiation. Using these models, the authors estimated critical structural features of the translation architecture. Sensitivity and robustness analysis with and without growth factors suggested that a balance between competing regulatory programmes governed translation initiation. Proteins such as Akt and mTor promoted initiation by integrating growth factor signals with the assembly of the 80S initiation complex. However, negative regulators such as PTEN and 4EBP1 restrained initiation in the absence of stimulation. Other proteins such as eIF4E were also found to be structurally critical as deletion of amplification of these components resulted in a network incapable of nominal operation. These findings could help understand the molecular basis of translation deregulation observed in cancer and perhaps lead to new anti-cancer therapeutic strategies. [Includes supplementary material] - Author(s): C. Moya ; Z. Huang ; P. Cheng ; A. Jayaraman ; J. Hahn
- Source: IET Systems Biology, Volume 5, Issue 1, p. 15 –26
- DOI: 10.1049/iet-syb.2009.0060
- Type: Article
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Steatosis, i.e., the accumulation of fat in hepatocytes, plays an important role in the progression of non-alcoholic fatty liver disease (NAFLD). It has been shown that STAT3 activation is involved in a decrease of lipid accumulation while C/EBPβ is correlated with an increase of fat content and steatosis. It is known that STAT3 and C/EBPβ are activated by IL-6 and that IL-6 signalling is also affected by IL-10, even though the exact mechanism is unclear. This paper develops a model for IL-6 and IL-10 signal transduction and then investigates the effect that stimulation with these cytokines has on the transcription factor dynamics. In an initial step, some parameters of a previously developed IL-6 signalling model are re-estimated based upon newly developed experimental data for the Jak-STAT pathway. Furthermore, the Erk-C/EBPβ pathway model is extended to also include the activated transcription factor C/EBPβ in the nucleus. Since IL-10 signals through the Jak-STAT but not the Erk-C/EBPβ pathway, a model was developed which includes interaction between IL-6 and IL-10 signalling as both mechanisms share signal transduction through the Jak-STAT pathway. Based upon the model, the activity ratio of Jak-STAT and Erk-C/EBPβ was investigated for different stimulation levels of IL-6 and IL-10. - Author(s): S. Marjan Varedi K. ; P.J. Woolf ; X.N. Lin
- Source: IET Systems Biology, Volume 5, Issue 1, p. 27 –33
- DOI: 10.1049/iet-syb.2009.0069
- Type: Article
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The authors propose a novel minimum oscillator whereby a protein with multiple phosphorylation sites directly embedded in a negative feedback loop can exhibit oscillation. They demonstrate that if the fully phosphorylated substrate inhibits the first phosphorylation step in a cooperative manner, multisite substrates can exhibit oscillatory behaviour at the presence of a kinase and phosphatase. With a fixed number of sites, the non-linearity of the negative feedback and the substrate/enzyme ratio must be above certain threshold values to generate undamped oscillation. There is an inverse relationship between the number of phosphorylation sites and the minimum non-linearity of the negative feedback required for oscillation; that is, the ultrasensitivity and time delay rooted in multisite phosphorylation compensate for the explicit non-linearity in the negative feedback. The period and amplitude of oscillation are mainly determined by the number of phosphorylation sites and the substrate/enzyme ratio. The authors' results suggest that a multisite protein can be exploited for the construction of a synthetic protein oscillator featuring simplicity, robustness and tunability. - Author(s): M.A. Battaglia and R.S. Parker
- Source: IET Systems Biology, Volume 5, Issue 1, p. 34 –43
- DOI: 10.1049/iet-syb.2009.0073
- Type: Article
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A detailed intracellular (IC) model describing the pharmacokinetics (PK) of gemcitabine (2′,2′-difluoro-2′-deoxycytidine, dFdC) was developed and linked to a systemic plasma dFdC PK model. Based on in vivo PK, pharmacodynamic (PD) effect predictions were made using a simplified cell-cycle model (CCM). A reduced-order compartmental model describing the IC metabolism of dFdC was fit to in vitro data taken from the literature to estimate the kinetic parameters of gemcitabine triphosphate (dFdCTP) generation and elimination in leukaemia cells. For comparison with in vivo patient data, the proposed detailed IC model, coupled with the systemic PK model and the CCM PD model, was simulated; Monte Carlo randomisation of the parameter vector was used to simulate interpatient variability. This comparison of model-generated IC dFdCTP concentrations with literature values in peripheral blood mononuclear cells (PBMCs) revealed qualitative and quantitative agreement. A tumour interstitial compartment connecting the plasma and IC models allowed prediction of solid tumour dFdCTP concentration. - Author(s): J.-C. Leloup and A. Goldbeter
- Source: IET Systems Biology, Volume 5, Issue 1, p. 44 –49
- DOI: 10.1049/iet-syb.2009.0068
- Type: Article
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Circadian clocks are regulated at the post-translational level by a variety of processes among which protein phosphorylation plays a prominent, although complex, role. Thus, the phosphorylation of different sites on the clock protein PER by casein kinase I (CKI) can lead to opposite effects on the stability of the protein and on the period of circadian oscillations. Here the authors extend a computational model previously proposed for the mammalian circadian clock by incorporating two distinct phosphorylations of PER by CKI. On the basis of experimental observations the authors consider that phosphorylation at one site (denoted here PER-P1) enhances the rate of degradation of the protein and decreases the period, while phosphorylation at another site (PER-P2) stabilises the protein, enhances the transcription of the Per gene, and increases the period. The model also incorporates an additional phosphorylation of PER by the Glycogen Synthase Kinase 3 (GSK3). The authors show that the extended model incorporating the antagonistic effects of PER phosphorylations by CKI can account for observations pertaining to (i) the decrease in period in the Tau mutant, because of an increase in phosphorylation by CKI leading to PER-P1, and (ii) the familial advanced sleep phase syndrome (FASPS) in which the period is shortened and the phase of the oscillations is advanced when the rate of phosphorylation leading to PER-P2 is decreased. The model further accounts for the increase in period observed in the presence of CKI inhibitors that decrease the rate of phosphorylation leading to both PER-P1 and PER-P2. A similar increase in period results from inhibition of GSK3. [Includes supplementary material] - Author(s): H.P. Mirsky ; S.R. Taylor ; R.A. Harvey ; J. Stelling ; F.J. Doyle
- Source: IET Systems Biology, Volume 5, Issue 1, p. 50 –57
- DOI: 10.1049/iet-syb.2009.0064
- Type: Article
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Classical sensitivity analysis is routinely used to identify points of fragility or robustness in biochemical networks. However, intracellular systems often contain components that number in the thousands to tens or less and consequently motivate a stochastic treatment. Although methodologies exist to quantify sensitivities in stochastic models, they differ substantially from those used in deterministic regimes. Therefore it is not possible to tell whether observed differences in sensitivity measured in deterministic and stochastic elaborations of the same network are the result of methodology or model form. The authors introduce here a distribution-based methodology to measure sensitivity that is equally applicable in both regimes, and demonstrate its use and applicability on a sophisticated mathematical model of the mouse circadian clock that is available in both deterministic and stochastic variants. The authors use the method to produce sensitivity measurements on both variants. They note that the rank-order sensitivity of the clock to parametric perturbations is extremely well conserved across several orders of magnitude. The data show that the clock is fragile to perturbations in parameters common to the cellular machinery (‘global’ parameters) and robust to perturbations in parameters that are clock-specific (‘local’ parameters). The sensitivity measure can be used to reduce the model from its original 73 ordinary differential equations (ODEs) to 18 ODEs and to predict the degree to which parametric perturbation can distort the phase response curve of the clock. Finally, the method is employed to evaluate the effect of transcriptional and translational noise on clock function. [Includes supplementary material] - Author(s): K.R. Sanft ; D.T. Gillespie ; L.R. Petzold
- Source: IET Systems Biology, Volume 5, Issue 1, p. 58 –69
- DOI: 10.1049/iet-syb.2009.0057
- Type: Article
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Michaelis–Menten kinetics are commonly used to represent enzyme-catalysed reactions in biochemical models. The Michaelis–Menten approximation has been thoroughly studied in the context of traditional differential equation models. The presence of small concentrations in biochemical systems, however, encourages the conversion to a discrete stochastic representation. It is shown that the Michaelis–Menten approximation is applicable in discrete stochastic models and that the validity conditions are the same as in the deterministic regime. The authors then compare the Michaelis–Menten approximation to a procedure called the slow-scale stochastic simulation algorithm (ssSSA). The theory underlying the ssSSA implies a formula that seems in some cases to be different from the well-known Michaelis–Menten formula. Here those differences are examined, and some special cases of the stochastic formulas are confirmed using a first-passage time analysis. This exercise serves to place the conventional Michaelis–Menten formula in a broader rigorous theoretical framework. - Author(s): E.O. Voit and M.L. Kemp
- Source: IET Systems Biology, Volume 5, Issue 1, p. 70 –79
- DOI: 10.1049/iet-syb.2009.0071
- Type: Article
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Systems biology is uniquely situated at the interface of computing, mathematics, engineering and the biological sciences. This positioning creates unique challenges and opportunities over other interdisciplinary studies when developing academic curricula. Integrative systems biology attempts to span the field from observation to innovation, and thus requires successful students to gain skills from mining to manipulation. The authors outline examples of graduate program structures, as well as curricular aspects and assessment metrics that can be customised around the environmental niche of the academic institution towards the formalisation of effective educational opportunities in systems biology. Some of this material was presented at the 2009 Foundations of Systems Biology in Engineering (FOSBE 2009) Conference in Denver, August 2009.
Editorial: Selected papers from the Third International Conference on Foundations of Systems Biology in Engineering (FOSBE 2009)
Modelling and analysis of an ensemble of eukaryotic translation initiation models
Investigation of IL-6 and IL-10 signalling via mathematical modelling
Minimum protein oscillator based on multisite phosphorylation/dephosphorylation
Pharmacokinetic/pharmacodynamic modelling of intracellular gemcitabine triphosphate accumulation: translating in vitro to in vivo
Modelling the dual role of Per phosphorylation and its effect on the period and phase of the mammalian circadian clock
Distribution-based sensitivity metric for highly variable biochemical systems
Legitimacy of the stochastic Michaelis–Menten approximation
So, you want to be a systems biologist? Determinants for creating graduate curricula in systems biology
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