9,336 research outputs found
Drug-therapy networks and the predictions of novel drug targets
Recently, a number of drug-therapy, disease, drug, and drug-target networks
have been introduced. Here we suggest novel methods for network-based
prediction of novel drug targets and for improvement of drug efficiency by
analysing the effects of drugs on the robustness of cellular networks.Comment: This is an extended version of the Journal of Biology paper
containing 2 Figures, 1 Table and 44 reference
Generating Robust and Efficient Networks Under Targeted Attacks
Much of our commerce and traveling depend on the efficient operation of large
scale networks. Some of those, such as electric power grids, transportation
systems, communication networks, and others, must maintain their efficiency
even after several failures, or malicious attacks. We outline a procedure that
modifies any given network to enhance its robustness, defined as the size of
its largest connected component after a succession of attacks, whilst keeping a
high efficiency, described in terms of the shortest paths among nodes. We also
show that this generated set of networks is very similar to networks optimized
for robustness in several aspects such as high assortativity and the presence
of an onion-like structure
Switchable Genetic Oscillator Operating in Quasi-Stable Mode
Ring topologies of repressing genes have qualitatively different long-term
dynamics if the number of genes is odd (they oscillate) or even (they exhibit
bistability). However, these attractors may not fully explain the observed
behavior in transient and stochastic environments such as the cell. We show
here that even repressilators possess quasi-stable, travelling-wave periodic
solutions that are reachable, long-lived and robust to parameter changes. These
solutions underlie the sustained oscillations observed in even rings in the
stochastic regime, even if these circuits are expected to behave as switches.
The existence of such solutions can also be exploited for control purposes:
operation of the system around the quasi-stable orbit allows us to turn on and
off the oscillations reliably and on demand. We illustrate these ideas with a
simple protocol based on optical interference that can induce oscillations
robustly both in the stochastic and deterministic regimes.Comment: 24 pages, 5 main figure
Kinetic modelling of competition and depletion of shared miRNAs by competing endogenous RNAs
Non-conding RNAs play a key role in the post-transcriptional regulation of
mRNA translation and turnover in eukaryotes. miRNAs, in particular, interact
with their target RNAs through protein-mediated, sequence-specific binding,
giving rise to extended and highly heterogeneous miRNA-RNA interaction
networks. Within such networks, competition to bind miRNAs can generate an
effective positive coupling between their targets. Competing endogenous RNAs
(ceRNAs) can in turn regulate each other through miRNA-mediated crosstalk.
Albeit potentially weak, ceRNA interactions can occur both dynamically,
affecting e.g. the regulatory clock, and at stationarity, in which case ceRNA
networks as a whole can be implicated in the composition of the cell's
proteome. Many features of ceRNA interactions, including the conditions under
which they become significant, can be unraveled by mathematical and in silico
models. We review the understanding of the ceRNA effect obtained within such
frameworks, focusing on the methods employed to quantify it, its role in the
processing of gene expression noise, and how network topology can determine its
reach.Comment: review article, 29 pages, 7 figure
The Dynamics of Hybrid Metabolic-Genetic Oscillators
The synthetic construction of intracellular circuits is frequently hindered
by a poor knowledge of appropriate kinetics and precise rate parameters. Here,
we use generalized modeling (GM) to study the dynamical behavior of topological
models of a family of hybrid metabolic-genetic circuits known as
"metabolators." Under mild assumptions on the kinetics, we use GM to
analytically prove that all explicit kinetic models which are topologically
analogous to one such circuit, the "core metabolator," cannot undergo Hopf
bifurcations. Then, we examine more detailed models of the metabolator.
Inspired by the experimental observation of a Hopf bifurcation in a
synthetically constructed circuit related to the core metabolator, we apply GM
to identify the critical components of the synthetically constructed
metabolator which must be reintroduced in order to recover the Hopf
bifurcation. Next, we study the dynamics of a re-wired version of the core
metabolator, dubbed the "reverse" metabolator, and show that it exhibits a
substantially richer set of dynamical behaviors, including both local and
global oscillations. Prompted by the observation of relaxation oscillations in
the reverse metabolator, we study the role that a separation of genetic and
metabolic time scales may play in its dynamics, and find that widely separated
time scales promote stability in the circuit. Our results illustrate a generic
pipeline for vetting the potential success of a potential circuit design,
simply by studying the dynamics of the corresponding generalized model
The Inferred Cardiogenic Gene Regulatory Network in the Mammalian Heart
Cardiac development is a complex, multiscale process encompassing cell fate adoption, differentiation and morphogenesis. To elucidate pathways underlying this process, a recently developed algorithm to reverse engineer gene regulatory networks was applied to time-course microarray data obtained from the developing mouse heart. Approximately 200 genes of interest were input into the algorithm to generate putative network topologies that are capable of explaining the experimental data via model simulation. To cull specious network interactions, thousands of putative networks are merged and filtered to generate scale-free, hierarchical networks that are statistically significant and biologically relevant. The networks are validated with known gene interactions and used to predict regulatory pathways important for the developing mammalian heart. Area under the precision-recall curve and receiver operator characteristic curve are 9% and 58%, respectively. Of the top 10 ranked predicted interactions, 4 have already been validated. The algorithm is further tested using a network enriched with known interactions and another depleted of them. The inferred networks contained more interactions for the enriched network versus the depleted network. In all test cases, maximum performance of the algorithm was achieved when the purely data-driven method of network inference was combined with a data-independent, functional-based association method. Lastly, the network generated from the list of approximately 200 genes of interest was expanded using gene-profile uniqueness metrics to include approximately 900 additional known mouse genes and to form the most likely cardiogenic gene regulatory network. The resultant network supports known regulatory interactions and contains several novel cardiogenic regulatory interactions. The method outlined herein provides an informative approach to network inference and leads to clear testable hypotheses related to gene regulation
Nonlinearity arising from noncooperative transcription factor binding enhances negative feedback and promotes genetic oscillations
We study the effects of multiple binding sites in the promoter of a genetic
oscillator. We evaluate the regulatory function of a promoter with multiple
binding sites in the absence of cooperative binding, and consider different
hypotheses for how the number of bound repressors affects transcription rate.
Effective Hill exponents of the resulting regulatory functions reveal an
increase in the nonlinearity of the feedback with the number of binding sites.
We identify optimal configurations that maximize the nonlinearity of the
feedback. We use a generic model of a biochemical oscillator to show that this
increased nonlinearity is reflected in enhanced oscillations, with larger
amplitudes over wider oscillatory ranges. Although the study is motivated by
genetic oscillations in the zebrafish segmentation clock, our findings may
reveal a general principle for gene regulation.Comment: 11 pages, 8 figure
- …