Quantitative Biology - Molecular Networks Publications (50)


Quantitative Biology - Molecular Networks Publications

While all organisms on Earth descend from a common ancestor, there is no consensus on whether the origin of this ancestral self-replicator was a one-off event or whether it was only the final survivor of multiple origins. Here we use the digital evolution system Avida to study the origin of self-replicating computer programs. By using a computational system, we avoid many of the uncertainties inherent in any biochemical system of self-replicators (while running the risk of ignoring a fundamental aspect of biochemistry). Read More

We introduce diffusively coupled networks where the dynamical system at each vertex is planar Hamiltonian. The problems we address are synchronisation and an analogue of diffusion-driven Turing instability for time-dependent homogeneous states. As a consequence of the underlying Hamiltonian structure there exist unusual behaviours compared with networks of coupled limit cycle oscillators or activator-inhibitor systems. Read More

We prove a sample path Large Deviation Principle (LDP) for a class of jump processes whose rates are not uniformly Lipschitz continuous in phase space. Building on it we further establish the corresponding Wentzell-Freidlin (W-F) (infinite time horizon) asymptotic theory. These results apply to jump Markov processes that model the dynamics of chemical reaction networks under mass action kinetics, on a microscopic scale. Read More

Background: The Epithelial-Mesenchymal Transition (EMT) endows epithelial-looking cells with enhanced migratory ability during embryonic development and tissue repair. EMT can also be co-opted by cancer cells to acquire metastatic potential and drug-resistance. Recent research has argued that epithelial (E) cells can undergo either a partial EMT to attain a hybrid epithelial/mesenchymal (E/M) phenotype that typically displays collective migration, or a complete EMT to adopt a mesenchymal (M) phenotype that shows individual migration. Read More

Genetic and environmental perturbation experiments have been used to study microbes in a bid to gain insight into transcriptional regulation, adaptive evolution, and other cellular dynamics. These studies have potential in enabling rational strain design. Unfortunately, experimentally determined intracellular flux distribution are often inconsistent or incomparable due to different experimental conditions and methodologies. Read More

The cell has the ability to convert an extracellular biochemical change into the expression of genetic information through a chain of intracellular cycle reactions with information conversion. Here, we show that an individual reaction cycle can be regarded as a kind of Szilard engine. Accordingly, the work done at the individual cycle level can be calculated by measuring the amount of information transmitted. Read More

In order to function reliably, synthetic molecular circuits require mechanisms that allow them to adapt to environmental disturbances. Least mean squares (LMS) schemes, such as commonly encountered in signal processing and control, provide a powerful means to accomplish that goal. In this paper we show how the traditional LMS algorithm can be implemented at the molecular level using only a few elementary biomolecular reactions. Read More

Complex diseases can be modeled as damage to intracellular networks that results in abnormal cell behaviors. Network-based dynamic models such as Boolean models have been employed to model a variety of biological systems including those corresponding to disease. Previous work designed compensatory interactions to stabilize an attractor of a Boolean network after single node damage. Read More

We introduce a general framework for biological systems, called MESSI systems, that describe Modifications of type Enzyme-Substrate or Swap with Intermediates, and we prove general results based on the network structure. Many post-translational modification networks are MESSI systems. For example: the motifs in Feliu-Wiuf'12, sequential distributive multisite phosphorylation networks, sequential processive multisite phosphorylation networks, most of the examples in Angeli et al. Read More

Circadian clocks must be able to entrain to time-varying signals to keep their oscillations in phase with the day-night rhythm. On the other hand, they must also exhibit input compensation: their period must remain about one day in different constant environments. The post-translational oscillator of the Kai system can be entrained by transient or oscillatory changes in the ATP fraction, yet is insensitive to constant changes in this fraction. Read More

We introduce a tensor-based algebraic clustering method to extract sparse, low-dimensional structure from multidimensional arrays of experimental data. Our methodology is applicable to high dimensional data structures that arise across the sciences. Specifically we introduce a new way to cluster data subject to multi-indexed structural constraints via integer programming. Read More

Gene expression levels carry information about signals that have functional significance for the organism. Using the gap gene network in the fruit fly embryo as an example, we show how this information can be decoded, building a dictionary that translates expression levels into a map of implied positions. The optimal decoder makes use of graded variations in absolute expression level, resulting in positional estimates that are precise to ~1% of the embryo's length. Read More

We construct a model of cell reprogramming (the conversion of fully differentiated cells to a state of pluripotency, known as induced pluripotent stem cells, or iPSCs) which builds on key elements of cell biology viz. cell cycles and cell lineages. Although reprogramming has been demonstrated experimentally, much of the underlying processes governing cell fate decisions remain unknown. Read More

The properties and fundamental limits of chemical computers have recently attracted significant interest as a model of computation, an unifying principle of cellular organisation and in the context of bio-engineering. As of yet, research in this topic is based on case-studies. There exists no generally accepted criterion to distinguish between chemical processes that compute and those that do not. Read More

Reconstructing the causal network in a complex dynamical system plays a crucial role in many applications, from sub-cellular biology to economic systems. Here we focus on inferring gene regulation networks (GRNs) from perturbation or gene deletion experiments. Despite their scientific merit, such perturbation experiments are not often used for such inference due to their costly experimental procedure, requiring significant resources to complete the measurement of every single experiment. Read More

We investigate the influence of intrinsic noise on stable states of a one-dimensional dynamical system that shows in its deterministic version a saddle-node bifurcation between monostable and bistable behaviour. The system is a modified version of the Schl\"ogl model, which is a chemical reaction system with only one type of molecule. The strength of the intrinsic noise is varied without changing the deterministic description by introducing bursts in the autocatalytic production step. Read More

Revealing how a biological network is organized to realize its function is one of the main topics in systems biology. The functional backbone network, defined as the primary structure of the biological network, is of great importance in maintaining the main function of the biological network. We propose a new algorithm, the tinker algorithm, to determine this core structure and apply it in the cell-cycle system. Read More

Motivation: Biological data and knowledge bases increasingly rely on Semantic Web technologies and the use of knowledge graphs for data integration, retrieval and federated queries. In the past years, feature learning methods that are applicable to graph-structured data are becoming available, but have not yet widely been applied and evaluated on structured biological knowledge. Results: We develop a novel method for feature learning on biological knowledge graphs. Read More

The dominant paradigm in origin of life research is that of an RNA world. However, despite experimental progress towards the spontaneous formation of RNA, the RNA world hypothesis still has its problems. Here, we introduce a novel computational model of chemical reaction networks based on RNA secondary structure, and analyze the emergence of autocatalytic sub-networks in random instances of this model, by combining two well-established computational tools. Read More

The principal pacemaker of the circadian clock of the cyanobacterium S. elongatus is a protein phosphorylation cycle consisting of three proteins, KaiA, KaiB and KaiC. KaiC forms a homohexamer, with each monomer consisting of two domains, CI and CII. Read More

Signal processing in biological systems is delicately executed by specialised networks, which are modular assemblies of network motifs. The motifs are independently functional circuits found in enormous numbers in any living cell. A very common network motif is the feed-forward loop (FFL), which regulates a downstream node by an upstream one in a direct and an indirect way within the network. Read More

RNA interference (RNAi) is a fundamental cellular process that inhibits gene expression through cleavage and destruction of target mRNA. It is responsible for a number of important intracellular functions, from being the first line of immune defence against pathogens to regulating development and morphogenesis. In this paper we consider a mathematical model of RNAi with particular emphasis on time delays associated with two aspects of primed amplification: binding of siRNA to aberrant RNA, and binding of siRNA to mRNA, both of which result in the expanded production of dsRNA responsible for RNA silencing. Read More

Affiliations: 1School of Life Sciences, Peking University, Beijing, China, 2School of Physics, Peking University, Beijing, China, 3School of Physics, Peking University, Beijing, China

Fission yeast G2/M transition is regulated by a biochemical reaction networks which contains four components: Cdc13, Cdc2, Wee1, and Cdc25. This circuit is characterized by the ultrasensitive responses of Wee1 or Cdc25 to Cdc13/Cdc2 activity, and the bistability of Cdc2 activation. Previous work has shown that this bistability is governed by phosphorylation energy. Read More

Gene expression is a noisy process that leads to regime shift between alternative steady states among individual living cells, inducing phenotypic variability. The effects of white noise on the regime shift in bistable systems have been well characterized, however little is known about such effects of colored noise (noise with non-zero correlation time). Here, we show that noise correlation time, by considering a genetic circuit of autoactivation, can have significant effect on the regime shift in gene expression. Read More

The pathogenesis and progression of many tumors, including hematologic malignancies is highly dependent on enhanced lipogenesis. De novo fatty-acid synthesis permits accelerated proliferation of tumor cells by providing structural components to build the membranes. It may also lead to alterations of physicochemical properties of the formed membranes, which can have an impact on signaling or even increase resistance to drugs in cancer cells. Read More

We apply a Gaussian variational approximation to model reduction in large biochemical networks of unary and binary reactions. We focus on a small subset of variables (subnetwork) of interest, e.g. Read More

The modeling of complex reaction-diffusion processes in, for instance, cellular biochemical networks or self-assembling soft matter can be tremendously sped up by employing a multiscale algorithm which combines the mesoscopic Green's Function Reaction Dynamics (GFRD) method with explicit stochastic Brownian, Langevin, or deterministic Molecular Dynamics to treat reactants at the microscopic scale [A. Vijaykumar, P.G. Read More

Gonadotropin-releasing hormone (GnRH) is reported to control mammalian reproductive processes. GnRH a neurohormone which is pulsatile released into the pituitary portal blood by hypothalamic GnRH neurons. In the present study, the phase synchronization among a population of identical neurons subjected to a pool of coupling molecules GnRH in extracellular medium via mean-field coupling mechanism is investigated. Read More

Studies on the role of fluctuations in signal propagation and on gene regulation in monoclonal bacterial population have been extensively pursued based on the machinery of two-component system. The bacterial two-component system shows noise utilisation through its inherent plasticity. The fluctuations propagation takes place using the phosphotransfer module and the feedback mechanism during gene regulation. Read More

The notion that transcription factors bind DNA only through specific, consensus binding sites has been recently questioned. In a pioneering study by Pugh and Venters no specific consensus motif for the positioning of the human pre-initiation complex (PIC) has been identified. Here, we reveal that nonconsensus, statistical, DNA triplet code provides specificity for the positioning of the human PIC. Read More

The spindle checkpoint assembly (SAC) ensures genome fidelity by temporarily delaying anaphase onset, until all chromosomes are properly attached to the mitotic spindle. The SAC delays mitotic progression by preventing activation of the ubiquitin ligase anaphase-promoting complex (APC/C) or cyclosome; whose activation by Cdc20 is required for sister-chromatid separation marking the transition into anaphase. The mitotic checkpoint complex (MCC), which contains Cdc20 as a subunit, binds stably to the APC/C. Read More

Specific interactions between receptors and their target ligands in the presence of non-target ligands are crucial for biological processes such as T cell ligand discrimination. To discriminate between the target and non-target ligands, cells have to increase specificity by amplifying the small differences in affinity among ligands. In addition, sensitivity to ligand concentration and quick discrimination are also important to detect low amounts of target ligands and facilitate fast cellular decision making after ligand recognition. Read More

Chemical reaction networks with generalized mass-action kinetics lead to power-law dynamical systems. As a simple example, we consider the Lotka reactions with two chemical species and arbitrary power-law kinetics. We study existence, uniqueness, and stability of the positive equilibrium, in particular, we characterize its global asymptotic stability in terms of the kinetic orders. Read More

The highly conserved spindle assembly checkpoint (SAC) ensures that the sister chromatids of the duplicated genome are not separated and distributed to the spindle poles before all chromosomes have been properly linked to the microtubules of the mitotic spindle. Biochemically, the SAC delays cell cycle progression by preventing activation of the anaphase-promoting complex (APC/C) or cyclosome; whose activation by Cdc20 is required for sister-chromatid separation, which marks the transition into anaphase. In response to activation of the checkpoint, various species control the activity of both APC/C and Cdc20. Read More

Reproduction and natural selection are the key elements of life. In order to reproduce, the genetic material must be doubled, separated and placed into two new daughter cells, each containing a complete set of chromosomes and organelles. In mitosis, transition from one process to the next is guided by intricate surveillance mechanisms, known as the mitotic checkpoints. Read More

Engineering systems modelling and analysis based on the bond graph approach has been applied to biomolecular systems. In this context, the notion of a Faraday-equivalent chemical potential is introduced which allows chemical potential to be expressed in an analogous manner to electrical volts thus allowing engineering intuition to be applied to biomolecular systems. Redox reactions, and their representation by half-reactions, are key components of biological systems which involve both electrical and chemical domains. Read More

In a previous article, an algorithm for discovering therapeutic targets in Boolean networks modeling disease mechanisms was introduced. In the present article, the updates made on this algorithm, named kali, are described. These updates are: i) the possibility to work on asynchronous Boolean networks, ii) a smarter search for therapeutic targets, and iii) the possibility to use multivalued logic. Read More

The lactose operon in Escherichia coli was the first known gene regulatory network, and it is frequently used as a prototype for new modeling paradigms. Historically, many of these modeling frameworks use differential equations. More recently, Stigler and Veliz-Cuba proposed a Boolean network model that captures the bistability of the system and all of the biological steady states. Read More

Decomposition of biomolecular reaction networks into pathways is a powerful approach to the analysis of metabolic and signalling networks. Current approaches based on analysis of the stoichiometric matrix reveal information about steady-state mass flows (reaction rates) through the network. In this work we show how pathway analysis of biomolecular networks can be extended using an energy-based approach to provide information about energy flows through the network. Read More

Natural genetic variation between individuals in a population leads to variations in gene expression that are informative for the inference of gene regulatory networks. Particularly, genome-wide genotype and transcriptome data from the same samples allow for causal inference between gene expression traits using the DNA variations in cis-regulatory regions as causal anchors. However, existing causal inference programs are not efficient enough for contemporary datasets, and unrealistically assume the absence of hidden confounders affecting the coexpression of causally related gene pairs. Read More

Several studies pointed out the relevance of extrinsic noise in molecular networks in shaping cell decision making and differentiation. Interestingly, bimodal distributions of gene expression levels, that may be a feature of phenotypic differentiation, are a common phenomenon in gene expression data. The modes of the distribution often correspond to different physiological states of the system. Read More

The physical basis of shortcut edges in a Protein Residue Network (PRN) and their applicability to a simplified protein folding pathway problem is investigated. The results show promise, and suggest the dominant influence of native-state topology even for structurally homologous proteins with different preferred folding pathways. Shortcut edges are enriched with hydrogen bonds, and there is a significant strong negative correlation (Pearson's rho -0. Read More

We consider two approaches to modelling of cell metabolism of 6-mercaptopurine, which is one of the important chemotherapy drugs used for treating of acute lymphocytic leukemia: kinetic ordinary differential equations and random Boolean networks, and analyse their interplay with respect to taking into account ATP concentration as a key parameter of switching between different pathways. It is shown that Boolean networks, which allow for avoiding complexity of general kinetic modelling, preserve an opportunity to the reproduction of the principal switching mechanism. To keep a detailed quantitative measure of the control parameter, a combined Boolean-ODE method is proposed. Read More

Affiliations: 1Peking University, Beijing, 2Chinese Academy of Sciences, Beijing, 3Peking University, Beijing, 4University of Washington, Seattle, 5Chinese Academy of Sciences, Beijing, 6Peking University, Beijing

The living cell is an open nonequilibrium biochemical system, where ATP hydrolysis serves as the energy source for a wide range of intracellular processes including the assurance for decision-making. In the fission yeast cell cycle, the transition from G2 phase to M phase is triggered by the activation of Cdc13/Cdc2 and Cdc25, and the deactivation of Wee1. Each of these three events involves a phosphorylation-dephosphorylation (PdP) cycle, and together they form a regulatory circuit with feedback loops. Read More

A system level view of cellular processes for human and several organisms can be cap- tured by analyzing molecular interaction networks. A molecular interaction network formed of differentially expressed genes and their interactions helps to understand key players behind disease development. So, if the functions of these genes are blocked by altering their interactions, it would have a great impact in controlling the disease. Read More

The value of research containing novel combinations of molecules can be seen in many innovative and award-winning research programs. Despite calls to use innovative approaches to address common diseases, an increasing majority of research funding goes toward "safe" incremental research. Counteracting this trend by nurturing novel and potentially transformative scientific research is challenging, it must be supported in competition with established research programs. Read More

Motivation: The investigation of topological modifications of the gene interaction networks in cancer cells is essential for understanding the desease. We study gene interaction networks in various human cancer cells with the random matrix theory. This study is based on the Cancer Network Galaxy (TCNG) database which is the repository of huge gene interactions inferred by Bayesian network algorithms from 256 microarray experimental data downloaded from NCBI GEO. Read More

Corynebacterium glutamicum is a Gram-positive, anaerobic, rod-shaped soil bacterium able to grow on a diversity of carbon sources like sugars and organic acids. It is a biotechnological relevant organism because of its highly efficient ability to biosynthesize amino acids, such as L-glutamic acid and L-lysine. Here, we reconstructed the most complete C. Read More

Intrinsic noise, the stochastic cell-to-cell fluctuations in mRNAs and proteins, has been observed and proved to play important roles in cellular systems. Due to the recent development in single-cell-level measurement technology, the studies on intrinsic noise are becoming increasingly popular among scholars. The chemical master equation (CME) has been used to model the evolutions of complex chemical and biological systems since 1940, and are often served as the standard tool for modeling intrinsic noise in gene regulation system. Read More

Studying metabolic networks is vital for many areas such as novel drugs and bio-fuels. For biologists, a key challenge is that many reactions are impractical or expensive to be found through experiments. Our task is to recover the missing reactions. Read More