IET Systems Biology
Volume 12, Issue 5, October 2018
Volumes & issues:
Volume 12, Issue 5
October 2018
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- Author(s): Abhilash Patel and Shaunak Sen
- Source: IET Systems Biology, Volume 12, Issue 5, p. 199 –204
- DOI: 10.1049/iet-syb.2018.0008
- Type: Article
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p.
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Non-normality can underlie pulse dynamics in many engineering contexts. However, its role in pulses generated in biomolecular contexts is generally unclear. Here, the authors address this issue using the mathematical tools of linear algebra and systems theory on simple computational models of biomolecular circuits. They find that non-normality is present in standard models of feedforward loops. They used a generalised framework and pseudospectrum analysis to identify non-normality in larger biomolecular circuit models, finding that it correlates well with pulsing dynamics. Finally, they illustrate how these methods can be used to provide analytical support to numerical screens for pulsing dynamics as well as provide guidelines for design.
- Author(s): Krishnamachari Sriram
- Source: IET Systems Biology, Volume 12, Issue 5, p. 205 –212
- DOI: 10.1049/iet-syb.2018.0003
- Type: Article
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p.
205
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Insulin induced mTOR signalling pathway is a complex network implicated in many types of cancers. The molecular mechanism of this pathway is highly complex and the dynamics is tightly regulated by intricate positive and negative feedback loops. In breast cancer cell lines, metformin has been shown to induce phosphorylation at specific serine sites in insulin regulated substrate of mTOR pathway that results in apoptosis over cell proliferation. The author models and performs bifurcation analysis to simulate cell proliferation and apoptosis in mTOR signalling pathway to capture the dynamics both in the presence and absence of metformin in cancer cells. Metformin is shown to negatively regulate PI3K through AMPK induced IRS1 phosphorylation and this brings about a reversal of AKT bistablity in codimension-1 bifurcation diagram from S-shaped, related to cell proliferation in the absence of drug metformin, to Z-shaped, related to apoptosis in the presence of drug metformin. The author hypothesises and explains how this negative regulation acts a circuit breaker, as a result of which mTOR network favours apoptosis of cancer cells over its proliferation. The implication of reversing the shape of bistable dynamics from S to Z or vice-versa in biological networks in general is discussed.
- Author(s): Richa K. Makhijani ; Shital A. Raut ; Hemant J. Purohit
- Source: IET Systems Biology, Volume 12, Issue 5, p. 213 –218
- DOI: 10.1049/iet-syb.2018.0012
- Type: Article
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Cancer belongs to a class of highly aggressive diseases and a leading cause of death in the world. With more than 100 types of cancers, breast, lung and prostate cancer remain to be the most common types. To identify essential network markers (NMs) and therapeutic targets in these cancers, the authors present a novel approach which uses gene expression data from microarray and RNA-seq platforms and utilises the results from this data to evaluate protein–protein interaction (PPI) network. Differentially expressed genes (DEGs) are extracted from microarray data using three different statistical methods in R, to produce a consistent set of genes. Also, DEGs are extracted from RNA-seq data for the same three cancer types. DEG sets found to be common in both platforms are obtained at three fold change (FC) cut-off levels to accurately identify the level of change in expression of these genes in all three cancers. A cancer network is built using PPI data characterising gene sets at log-FC (LFC)>1, LFC>1.5 and LFC>2, and interconnection between principal hub nodes of these networks is observed. Resulting network of hubs at three FC levels highlights prime NMs with high confidence in multiple cancers as validated by Gene Ontology functional enrichment and maximal complete subgraphs from CFinder.
- Author(s): Anirudh Nath ; Dipankar Deb ; Rajeeb Dey ; Sipon Das
- Source: IET Systems Biology, Volume 12, Issue 5, p. 219 –225
- DOI: 10.1049/iet-syb.2017.0093
- Type: Article
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Here, a direct adaptive control strategy with parametric compensation is adopted for an uncertain non-linear model representing blood glucose regulation in type 1 diabetes mellitus patients. The uncertain parameters of the model are updated by appropriate design of adaptation laws using the Lyapunov method. The closed-loop response of the plasma glucose concentration as well as external insulin infusion rate is analysed for a wide range of variation of the model parameters through extensive simulation studies. The result indicates that the proposed adaptive control scheme avoids severe hypoglycaemia and gives satisfactory performance under parametric uncertainty highlighting its ability to address the issue of inter-patient variability.
- Author(s): V.K. Md Aksam ; V.M. Chandrasekaran ; Sundaramurthy Pandurangan
- Source: IET Systems Biology, Volume 12, Issue 5, p. 226 –232
- DOI: 10.1049/iet-syb.2017.0058
- Type: Article
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226
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A new centrality of the nodes in the network is proposed called alternate centrality, which can isolate effective drug targets in the complex signalling network. Alternate centrality metric defined over the network substructure (four nodes – motifs). The nodes involving in alternative activation in the motifs gain in metric values. Targeting high alternative centrality nodes hypothesised to be destructive free to the network due to their alternative activation mechanism. Overlapping and crosstalk among the gene products in the conserved network of MAPK pathways selected for the study. In silico knock-out of high alternate centrality nodes causing rewiring in the network is investigated using MCF-7 breast cancer cell line-based data. Degree of top alternate centrality nodes lies between the degree of bridging and pagerank nodes. Node deletion of high alternate centrality on the centralities such as eccentricity, closeness, betweenness, stress, centroid and radiality causes low perturbation. The authors identified the following alternate centrality nodes ERK1, ERK2, MEKK2, MKK5, MKK4, MLK3, MLK2, MLK1, MEKK4, MEKK1, TAK1, P38alpha, ZAK, DLK, LZK, MLTKa/b and P38beta as efficient drug targets for breast cancer. Alternate centrality identifies effective drug targets and is free from intertwined biological processes and lethality.
Non-normality can facilitate pulsing in biomolecular circuits
Bifurcation analysis of insulin regulated mTOR signalling pathway in cancer cells
Fold change based approach for identification of significant network markers in breast, lung and prostate cancer
Blood glucose regulation in type 1 diabetic patients: an adaptive parametric compensation control-based approach
Topological alternate centrality measure capturing drug targets in the network of MAPK pathways
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