Crosstalk and the Dynamical Modularity of Feed-Forward Loops in Transcriptional Regulatory Networks

Network motifs, such as the feed-forward loop (FFL), introduce a range of complex behaviors to transcriptional regulatory networks, yet such properties are typically determined from their isolated study. We characterize the effects of crosstalk on FFL dynamics by modeling the cross regulation between two different FFLs and evaluate the extent to which these patterns occur in vivo. Analytical modeling suggests that crosstalk should overwhelmingly affect individual protein-expression dynamics. Counter to this expectation we find that entire FFLs are more likely than expected to resist the effects of crosstalk (approximate to 20% for one crosstalk interaction) and remain dynamically modular. The likelihood that cross-linked FFLs are dynamically correlated increases monotonically with additional crosstalk, but is independent of the specific regulation type or connectivity of the interactions. Just one additional regulatory interaction is sufficient to drive the FFL dynamics to a statistically different state. Despite the potential for modularity between sparsely connected network motifs, Escherichia coli (E. coli) appears to favor crosstalk wherein at least one of the cross-linked FFLs remains modular. A gene ontology analysis reveals that stress response processes are significantly overrepresented in the cross-linked motifs found within E. coli. Although the daunting complexity of biological networks affects the dynamical properties of individual network motifs, some resist and remain modular, seemingly insulated from extrinsic perturbations-an intriguing possibility for nature to consistently and reliably provide certain network functionalities wherever the need arise

Elucidation of molecular kinetic schemes from macroscopic traces using system identification

Overall cellular responses to biologically-relevant stimuli are mediated by networks of simpler lower-level processes. Although information about some of these processes can now be obtained by visualizing and recording events at the molecular level, this is still possible only in especially favorable cases. Therefore the development of methods to extract the dynamics and relationships between the different lower-level (microscopic) processes from the overall (macroscopic) response remains a crucial challenge in the understanding of many aspects of physiology. Here we have devised a hybrid computational-analytical method to accomplish this task, the SYStems-based MOLecular kinetic scheme Extractor (SYSMOLE). SYSMOLE utilizes system-identification input-output analysis to obtain a transfer function between the stimulus and the overall cellular response in the Laplace-transformed domain. It then derives a Markov-chain state molecular kinetic scheme uniquely associated with the transfer function by means of a classification procedure and an analytical step that imposes general biological constraints. We first tested SYSMOLE with synthetic data and evaluated its performance in terms of its rate of convergence to the correct molecular kinetic scheme and its robustness to noise. We then examined its performance on real experimental traces by analyzing macroscopic calcium-current traces elicited by membrane depolarization. SYSMOLE derived the correct, previously known molecular kinetic scheme describing the activation and inactivation of the underlying calcium channels and correctly identified the accepted mechanism of action of nifedipine, a calcium-channel blocker clinically used in patients with cardiovascular disease. Finally, we applied SYSMOLE to study the pharmacology of a new class of glutamate antipsychotic drugs and their crosstalk mechanism through a heteromeric complex of G protein-coupled receptors. Our results indicate that our methodology can be successfully applied to accurately derive molecular kinetic schemes from experimental macroscopic traces, and we anticipate that it may be useful in the study of a wide variety of biological systems

Modelling and analysis of biochemical signalling pathway cross-talk

Signalling pathways are abstractions that help life scientists structure the coordination of cellular activity. Cross-talk between pathways accounts for many of the complex behaviours exhibited by signalling pathways and is often critical in producing the correct signal-response relationship. Formal models of signalling pathways and cross-talk in particular can aid understanding and drive experimentation. We define an approach to modelling based on the concept that a pathway is the (synchronising) parallel composition of instances of generic modules (with internal and external labels). Pathways are then composed by (synchronising) parallel composition and renaming; different types of cross-talk result from different combinations of synchronisation and renaming. We define a number of generic modules in PRISM and five types of cross-talk: signal flow, substrate availability, receptor function, gene expression and intracellular communication. We show that Continuous Stochastic Logic properties can both detect and distinguish the types of cross-talk. The approach is illustrated with small examples and an analysis of the cross-talk between the TGF-b/BMP, WNT and MAPK pathways

Secrecy Sum-Rates for Multi-User MIMO Regularized Channel Inversion Precoding

In this paper, we propose a linear precoder for the downlink of a multi-user MIMO system with multiple users that potentially act as eavesdroppers. The proposed precoder is based on regularized channel inversion (RCI) with a regularization parameter $\alpha$ and power allocation vector chosen in such a way that the achievable secrecy sum-rate is maximized. We consider the worst-case scenario for the multi-user MIMO system, where the transmitter assumes users cooperate to eavesdrop on other users. We derive the achievable secrecy sum-rate and obtain the closed-form expression for the optimal regularization parameter $\alpha_{\mathrm{LS}}$ of the precoder using large-system analysis. We show that the RCI precoder with $\alpha_{\mathrm{LS}}$ outperforms several other linear precoding schemes, and it achieves a secrecy sum-rate that has same scaling factor as the sum-rate achieved by the optimum RCI precoder without secrecy requirements. We propose a power allocation algorithm to maximize the secrecy sum-rate for fixed $\alpha$. We then extend our algorithm to maximize the secrecy sum-rate by jointly optimizing $\alpha$ and the power allocation vector. The jointly optimized precoder outperforms RCI with $\alpha_{\mathrm{LS}}$ and equal power allocation by up to 20 percent at practical values of the signal-to-noise ratio and for 4 users and 4 transmit antennas.Comment: IEEE Transactions on Communications, accepted for publicatio

Modular modelling of signalling pathways and their crosstalk

Signalling pathways are well-known abstractions that explain the mechanisms whereby cells respond to signals. Collections of pathways form networks, and interactions between pathways in a network, known as cross-talk, enables further complex signalling behaviours. While there are several formal modelling approaches for signalling pathways, none make cross-talk explicit; the aim of this paper is to define and categorise cross-talk in a rigorous way. We define a modular approach to pathway and network modelling, based on the module construct in the PRISM modelling language, and a set of generic signalling modules. Five different types of cross-talk are defined according to various biologically meaningful combinations of variable sharing, synchronisation labels and reaction renaming. The approach is illustrated with a case-study analysis of cross-talk between the TGF-β, WNT and MAPK pathways

Diffusive MIMO Molecular Communications: Channel Estimation, Equalization and Detection

In diffusion-based communication, as for molecular systems, the achievable data rate is low due to the stochastic nature of diffusion which exhibits a severe inter-symbol-interference (ISI). Multiple-Input Multiple-Output (MIMO) multiplexing improves the data rate at the expense of an inter-link interference (ILI). This paper investigates training-based channel estimation schemes for diffusive MIMO (D-MIMO) systems and corresponding equalization methods. Maximum likelihood and least-squares estimators of mean channel are derived, and the training sequence is designed to minimize the mean square error (MSE). Numerical validations in terms of MSE are compared with Cramer-Rao bound derived herein. Equalization is based on decision feedback equalizer (DFE) structure as this is effective in mitigating diffusive ISI/ILI. Zero-forcing, minimum MSE and least-squares criteria have been paired to DFE, and their performances are evaluated in terms of bit error probability. Since D-MIMO systems are severely affected by the ILI because of short transmitters inter-distance, D-MIMO time interleaving is exploited as countermeasure to mitigate the ILI with remarkable performance improvements. The feasibility of a block-type communication including training and data equalization is explored for D-MIMO, and system-level performances are numerically derived.Comment: Accepted paper at IEEE transaction on Communicatio