Monostability and multistability of genetic regulatory networks with different types of regulation functions

The official published version of the article can be found at the link below.Monostability and multistability are proven to be two important topics in synthesis biology and system biology. In this paper, both monostability and multistability are analyzed in a unified framework by applying control theory and mathematical tools. The genetic regulatory networks (GRNs) with multiple time-varying delays and different types of regulation functions are considered. By putting forward a general sector-like regulation function and utilizing up-to-date techniques, a novel Lyapunov–Krasovskii functional is introduced for achieving delay dependence to ensure less conservatism. A new condition is then proposed for the general stability of a GRN in the form of linear matrix inequalities (LMIs) that are dependent on the upper and lower bounds of the delays. Our general stability conditions are applicable to several frequently used regulation functions. It is shown that the existing results for monostability of GRNs are special cases of our main results. Five examples are employed to illustrate the applicability and usefulness of the developed theoretical results.This work was supported in part by the Biotechnology and Biological Sciences Research Council (BBSRC) of the U.K. under Grant BB/C506264/1, the Royal Society of the U.K., the National Natural Science Foundation of China under Grants 60504008 and 60804028, the Program for New Century Excellent Talents in Universities of China, and the Alexander von Humboldt Foundation of Germany

The cultural epigenetics of psychopathology: The missing heritability of complex diseases found?

We extend a cognitive paradigm for gene expression based on the asymptotic limit theorems of information theory to the epigenetic epidemiology of mental disorders. In particular, we recognize the fundamental role culture plays in human biology, another heritage mechanism parallel to, and interacting with, the more familiar genetic and epigenetic systems. We do this via a model through which culture acts as another tunable epigenetic catalyst that both directs developmental trajectories, and becomes convoluted with individual ontology, via a mutually-interacting crosstalk mediated by a social interaction that is itself culturally driven. We call for the incorporation of embedding culture as an essential component of the epigenetic regulation of human mental development and its dysfunctions, bringing what is perhaps the central reality of human biology into the center of biological psychiatry. Current US work on gene-environment interactions in psychiatry must be extended to a model of gene-environment-culture interaction to avoid becoming victim of an extreme American individualism that threatens to create paradigms particular to that culture and that are, indeed, peculiar in the context of the world's cultures. The cultural and epigenetic systems of heritage may well provide the 'missing' heritability of complex diseases now under so much intense discussion

The Origins of Time-Delay in Template Biopolymerization Processes

Time-delays are common in many physical and biological systems and they give rise to complex dynamic phenomena. The elementary processes involved in template biopolymerization, such as mRNA and protein synthesis, introduce significant time delays. However, there is not currently a systematic mapping between the individual mechanistic parameters and the time delays in these networks. We present here the development of mathematical, time-delay models for protein translation, based on PDE models, which in turn are derived through systematic approximations of first-principles mechanistic models. Theoretical analysis suggests that the key features that determine the time-delays and the agreement between the time-delay and the mechanistic models are ribosome density and distribution, i.e., the number of ribosomes on the mRNA chain relative to their maximum and their distribution along the mRNA chain. Based on analytical considerations and on computational studies, we show that the steady-state and dynamic responses of the time-delay models are in excellent agreement with the detailed mechanistic models, under physiological conditions that correspond to uniform ribosome distribution and for ribosome density up to 70%. The methodology presented here can be used for the development of reduced time-delay models of mRNA synthesis and large genetic networks. The good agreement between the time-delay and the mechanistic models will allow us to use the reduced model and advanced computational methods from nonlinear dynamics in order to perform studies that are not practical using the large-scale mechanistic models

Synchrony and bifurcations in coupled dynamical systems and effects of time delay

Dynamik auf Netzwerken ist ein mathematisches Feld, das in den letzten Jahrzehnten schnell gewachsen ist und Anwendungen in zahlreichen Disziplinen wie z.B. Physik, Biologie und Soziologie findet. Die Funktion vieler Netzwerke hängt von der Fähigkeit ab, die Elemente des Netzwerkes zu synchronisieren. Mit anderen Worten, die Existenz und die transversale Stabilität der synchronen Mannigfaltigkeit sind zentrale Eigenschaften. Erst seit einigen Jahren wird versucht, den verwickelten Zusammenhang zwischen der Kopplungsstruktur und den Stabilitätseigenschaften synchroner Zustände zu verstehen. Genau das ist das zentrale Thema dieser Arbeit. Zunächst präsentiere ich erste Ergebnisse zur Klassifizierung der Kanten eines gerichteten Netzwerks bezüglich ihrer Bedeutung für die Stabilität des synchronen Zustands. Folgend untersuche ich ein komplexes Verzweigungsszenario in einem gerichteten Ring von Stuart-Landau Oszillatoren und zeige, dass das Szenario persistent ist, wenn dem Netzwerk eine schwach gewichtete Kante hinzugefügt wird. Daraufhin untersuche ich synchrone Zustände in Ringen von Phasenoszillatoren die mit Zeitverzögerung gekoppelt sind. Ich bespreche die Koexistenz synchroner Lösungen und analysiere deren Stabilität und Verzweigungen. Weiter zeige ich, dass eine Zeitverschiebung genutzt werden kann, um Muster im Ring zu speichern und wiederzuerkennen. Diese Zeitverschiebung untersuche ich daraufhin für beliebige Kopplungsstrukturen. Ich zeige, dass invariante Mannigfaltigkeiten des Flusses sowie ihre Stabilität unter der Zeitverschiebung erhalten bleiben. Darüber hinaus bestimme ich die minimale Anzahl von Zeitverzögerungen, die gebraucht werden, um das System äquivalent zu beschreiben. Schließlich untersuche ich das auffällige Phänomen eines nichtstetigen Übergangs zu Synchronizität in Klassen großer Zufallsnetzwerke indem ich einen kürzlich eingeführten Zugang zur Beschreibung großer Zufallsnetzwerke auf den Fall zeitverzögerter Kopplungen verallgemeinere.Since a couple of decades, dynamics on networks is a rapidly growing branch of mathematics with applications in various disciplines such as physics, biology or sociology. The functioning of many networks heavily relies on the ability to synchronize the network’s nodes. More precisely, the existence and the transverse stability of the synchronous manifold are essential properties. It was only in the last few years that people tried to understand the entangled relation between the coupling structure of a network, given by a (di-)graph, and the stability properties of synchronous states. This is the central theme of this dissertation. I first present results towards a classification of the links in a directed, diffusive network according to their impact on the stability of synchronization. Then I investigate a complex bifurcation scenario observed in a directed ring of Stuart-Landau oscillators. I show that under the addition of a single weak link, this scenario is persistent. Subsequently, I investigate synchronous patterns in a directed ring of phase oscillators coupled with time delay. I discuss the coexistence of multiple of synchronous solutions and investigate their stability and bifurcations. I apply these results by showing that a certain time-shift transformation can be used in order to employ the ring as a pattern recognition device. Next, I investigate the same time-shift transformation for arbitrary coupling structures in a very general setting. I show that invariant manifolds of the flow together with their stability properties are conserved under the time-shift transformation. Furthermore, I determine the minimal number of delays needed to equivalently describe the system’s dynamics. Finally, I investigate a peculiar phenomenon of non-continuous transition to synchrony observed in certain classes of large random networks, generalizing a recently introduced approach for the description of large random networks to the case of delayed couplings