Aneta Koseska

Restoration of rhythmicity in diffusively coupled dynamical networks

Oscillatory behaviour is essential for proper functioning of various physical and biological processes. However, diffusive coupling is capable of suppressing intrinsic oscillations due to the manifestation of the phenomena of amplitude and oscillation deaths. Here we present a scheme to revoke these quenching states in diffusively coupled dynamical networks, and demonstrate the approach in experiments with an oscillatory chemical reaction. By introducing a simple feedback factor in the diffusive coupling, we show that the stable (in)homogeneous steady states can be effectively destabilized to restore dynamic behaviours of coupled systems. Even a feeble deviation from the normal diffusive coupling drastically shrinks the death regions in the parameter space. The generality of our method is corroborated in diverse non-linear systems of diffusively coupled paradigmatic models with various death scenarios. Our study provides a general framework to strengthen the robustness of dynamic activity in diffusively coupled dynamical networks.

Cooperative differentiation through clustering in multicellular populations

The coordinated development of multicellular organisms is driven by intercellular communication. Differentiation into diverse cell types is usually associated with the existence of distinct attractors of gene regulatory networks, but how these attractors emerge from cell-cell coupling is still an open question. In order to understand and characterize the mechanisms through which coexisting attractors arise in multicellular systems, here we systematically investigate the dynamical behavior of a population of synthetic genetic oscillators coupled by chemical means. Using bifurcation analysis and numerical simulations, we identify various attractors and attempt to deduce from these findings a way to predict the organized collective behavior of growing populations. Our results show that dynamical clustering is a generic property of multicellular systems. We argue that such clustering might provide a basis for functional differentiation and variability in biological systems.

Timing Cellular Decision Making Under Noise via Cell–Cell Communication

Many cellular processes require decision making mechanisms, which must act reliably even in the unavoidable presence of substantial amounts of noise. However, the multistable genetic switches that underlie most decision-making processes are dominated by fluctuations that can induce random jumps between alternative cellular states. Here we show, via theoretical modeling of a population of noise-driven bistable genetic switches, that reliable timing of decision-making processes can be accomplished for large enough population sizes, as long as cells are globally coupled by chemical means. In the light of these results, we conjecture that cell proliferation, in the presence of cell–cell communication, could provide a mechanism for reliable decision making in the presence of noise, by triggering cellular transitions only when the whole cell population reaches a certain size. In other words, the summation performed by the cell population would average out the noise and reduce its detrimental impact.

Parameter mismatches and oscillation death in coupled oscillators.

We use a set of qualitatively different models of coupled oscillators (genetic, membrane, Ca-metabolism, and chemical oscillators) to study dynamical regimes in the presence of small detuning. In particular, we focus on a distinct oscillation quenching mechanism, the oscillation death phenomenon. Using bifurcation analysis in general, we demonstrate that under strong coupling via slow variable detuning can eliminate standard oscillatory solutions from a large region of the parameter space, establishing the dominance of oscillation death. We argue furthermore that the oscillation death dominance effect provides a reliable dynamical control mechanism in the general case of N coupled oscillators.

Unraveling gene regulatory networks from time-resolved gene expression data -- a measures comparison study

BackgroundInferring regulatory interactions between genes from transcriptomics time-resolved data, yielding reverse engineered gene regulatory networks, is of paramount importance to systems biology and bioinformatics studies. Accurate methods to address this problem can ultimately provide a deeper insight into the complexity, behavior, and functions of the underlying biological systems. However, the large number of interacting genes coupled with short and often noisy time-resolved read-outs of the system renders the reverse engineering a challenging task. Therefore, the development and assessment of methods which are computationally efficient, robust against noise, applicable to short time series data, and preferably capable of reconstructing the directionality of the regulatory interactions remains a pressing research problem with valuable applications.ResultsHere we perform the largest systematic analysis of a set of similarity measures and scoring schemes within the scope of the relevance network approach which are commonly used for gene regulatory network reconstruction from time series data. In addition, we define and analyze several novel measures and schemes which are particularly suitable for short transcriptomics time series. We also compare the considered 21 measures and 6 scoring schemes according to their ability to correctly reconstruct such networks from short time series data by calculating summary statistics based on the corresponding specificity and sensitivity. Our results demonstrate that rank and symbol based measures have the highest performance in inferring regulatory interactions. In addition, the proposed scoring scheme by asymmetric weighting has shown to be valuable in reducing the number of false positive interactions. On the other hand, Granger causality as well as information-theoretic measures, frequently used in inference of regulatory networks, show low performance on the short time series analyzed in this study.ConclusionsOur study is intended to serve as a guide for choosing a particular combination of similarity measures and scoring schemes suitable for reconstruction of gene regulatory networks from short time series data. We show that further improvement of algorithms for reverse engineering can be obtained if one considers measures that are rooted in the study of symbolic dynamics or ranks, in contrast to the application of common similarity measures which do not consider the temporal character of the employed data. Moreover, we establish that the asymmetric weighting scoring scheme together with symbol based measures (for low noise level) and rank based measures (for high noise level) are the most suitable choices.

Detuning-dependent dominance of oscillation death in globally coupled synthetic genetic oscillators

We study dynamical regimes of globally coupled genetic relaxation oscillators in the presence of small detuning. Using bifurcation analysis, we find that under strong coupling via the slow variable, the detuning can eliminate standard oscillatory solutions in a large region of the parameter space, providing the dominance of oscillation death. This result is substantially different from previous results on oscillation quenching, where for homogeneous populations, the coexistence of oscillation death and limit cycle oscillations is always present. We propose further that this effect of detuning-dependent dominance could be a powerful regulator of genetic networks dynamics.

Time delay control of symmetry-breaking primary and secondary oscillation death

We show that oscillation death as a specific type of oscillation suppression, which implies symmetry breaking, can be controlled by introducing time-delayed coupling. In particular, we demonstrate that time delay influences the stability of an inhomogeneous steady state, providing the opportunity to modulate the threshold for oscillation death. Additionally, we find a novel type of oscillation death representing a secondary bifurcation of an inhomogeneous steady state.

Spatiotemporal dynamics of the Calvin cycle: Multistationarity and symmetry breaking instabilities

The possibility of controlling the Calvin cycle has paramount implications for increasing the production of biomass. Multistationarity, as a dynamical feature of systems, is the first obvious candidate whose control could find biotechnological applications. Here we set out to resolve the debate on the multistationarity of the Calvin cycle. Unlike the existing simulation-based studies, our approach is based on a sound mathematical framework, chemical reaction network theory and algebraic geometry, which results in provable results for the investigated model of the Calvin cycle in which we embed a hierarchy of realistic kinetic laws. Our theoretical findings demonstrate that there is a possibility for multistationarity resulting from two sources, homogeneous and inhomogeneous instabilities, which partially settle the debate on multistability of the Calvin cycle. In addition, our tractable analytical treatment of the bifurcation parameters can be employed in the design of validation experiments.

Cell signaling as a cognitive process

Cellular identity as defined through morphology and function emerges from intracellular signaling networks that communicate between cells. Based on recursive interactions within and among these intracellular networks, dynamical solutions in terms of biochemical behavior are generated that can differ from those in isolated cells. In this way, cellular heterogeneity in tissues can be established, implying that cell identity is not intrinsically predetermined by the genetic code but is rather dynamically maintained in a cognitive manner. We address how to experimentally measure the flow of information in intracellular biochemical networks and demonstrate that even simple causality motifs can give rise to rich, context‐dependent dynamic behavior. The concept how intercellular communication can result in novel dynamical solutions is applied to provide a contextual perspective on cell differentiation and tumorigenesis.

Genome-Wide Identification of Regulatory Elements and Reconstruction of Gene Regulatory Networks of the Green Alga Chlamydomonas reinhardtii under Carbon Deprivation

The unicellular green alga Chlamydomonas reinhardtii is a long-established model organism for studies on photosynthesis and carbon metabolism-related physiology. Under conditions of air-level carbon dioxide concentration [CO2], a carbon concentrating mechanism (CCM) is induced to facilitate cellular carbon uptake. CCM increases the availability of carbon dioxide at the site of cellular carbon fixation. To improve our understanding of the transcriptional control of the CCM, we employed FAIRE-seq (formaldehyde-assisted Isolation of Regulatory Elements, followed by deep sequencing) to determine nucleosome-depleted chromatin regions of algal cells subjected to carbon deprivation. Our FAIRE data recapitulated the positions of known regulatory elements in the promoter of the periplasmic carbonic anhydrase (Cah1) gene, which is upregulated during CCM induction, and revealed new candidate regulatory elements at a genome-wide scale. In addition, time series expression patterns of 130 transcription factor (TF) and transcription regulator (TR) genes were obtained for cells cultured under photoautotrophic condition and subjected to a shift from high to low [CO2]. Groups of co-expressed genes were identified and a putative directed gene-regulatory network underlying the CCM was reconstructed from the gene expression data using the recently developed IOTA (inner composition alignment) method. Among the candidate regulatory genes, two members of the MYB-related TF family, Lcr1 (Low-CO 2 response regulator 1) and Lcr2 (Low-CO 2 response regulator 2), may play an important role in down-regulating the expression of a particular set of TF and TR genes in response to low [CO2]. The results obtained provide new insights into the transcriptional control of the CCM and revealed more than 60 new candidate regulatory genes. Deep sequencing of nucleosome-depleted genomic regions indicated the presence of new, previously unknown regulatory elements in the C. reinhardtii genome. Our work can serve as a basis for future functional studies of transcriptional regulator genes and genomic regulatory elements in Chlamydomonas.