Computational modelling and analysis of the molecular network regulating sporulation initiation in Bacillus subtilis

BACKGROUND: Bacterial spores are important contaminants in food, and the spore forming bacteria are often implicated in food safety and food quality considerations. Spore formation is a complex developmental process involving the expression of more than 500 genes over the course of 6 to 8 hrs. The process culminates in the formation of resting cells capable of resisting environmental extremes and remaining dormant for long periods of time, germinating when conditions promote further vegetative growth. Experimental observations of sporulation and germination are problematic and time consuming so that reliable models are an invaluable asset in terms of prediction and risk assessment. In this report we develop a model which assists in the interpretation of sporulation dynamics. RESULTS: This paper defines and analyses a mathematical model for the network regulating Bacillus subtilis sporulation initiation, from sensing of sporulation signals down to the activation of the early genes under control of the master regulator Spo0A. Our model summarises and extends other published modelling studies, by allowing the user to execute sporulation initiation in a scenario where Isopropyl β-D-1-thiogalactopyranoside (IPTG) is used as an artificial sporulation initiator as well as in modelling the induction of sporulation in wild-type cells. The analysis of the model results and the comparison with experimental data indicate that the model is good at predicting inducible responses to sporulation signals. However, the model is unable to reproduce experimentally observed accumulation of phosphorelay sporulation proteins in wild type B. subtilis. This model also highlights that the phosphorelay sub-component, which relays the signals detected by the sensor kinases to the master regulator Spo0A, is crucial in determining the response dynamics of the system. CONCLUSION: We show that there is a complex connectivity between the phosphorelay features and the master regulatory Spo0A. Additional we discovered that the experimentally observed regulation of the phosphotransferase Spo0B for wild-type B. subtilis may be playing an important role in the network which suggests that modelling of sporulation initiation may require additional experimental support. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12918-014-0119-x) contains supplementary material, which is available to authorized users

Book of abstracts: Scientific Opening of The Microsoft Reasearch Centre for Computational and Systems Biology, Trento, Italy, April 3-5, 2006

Abstracts of the talks of the Scientific Opening of the Microsoft Research - University of Trento Centre for Computational and Systems Biology held in Trento on April 3-5, 200

Understanding the disorder of the DNA base cytosine on the Au(111) surface

Using ultrahigh vacuum scanning tunneling microscopy (STM) and ab initio density functional theory, we have investigated in detail structures formed by cytosine on the Au(111) surface in clean ultrahigh vacuum conditions. In spite of the fact that the ground state of this DNA base on the surface is shown to be an ordered arrangement of cytosine one-dimensional branches (filaments), this structure has never been observed in our STM experiments. Instead, disordered structures are observed, which can be explained by only a few elementary structural motifs: filaments, five- and sixfold rings, which randomly interconnect with each other forming bent chains, T junctions, and nanocages. The latter may have trapped smaller structures inside. The formation of such an unusual assembly is explained by simple kinetic arguments as a liquid-glass transition. © 2008 American Institute of Physics

Time series analysis of the Bacillus subtilis sporulation network reveals low dimensional chaotic dynamics

Chaotic behavior refers to a behavior which, albeit irregular, is generated by an underlying deterministic process. Therefore, a chaotic behavior is potentially controllable. This possibility becomes practically amenable especially when chaos is shown to be low-dimensional, i.e., to be attributable to a small fraction of the total systems components. In this case, indeed, including the major drivers of chaos in a system into the modeling approach allows us to improve predictability of the systems dynamics. Here, we analyzed the numerical simulations of an accurate ordinary differential equation model of the gene network regulating sporulation initiation in Bacillus subtilis to explore whether the non-linearity underlying time series data is due to low-dimensional chaos. Low-dimensional chaos is expectedly common in systems with few degrees of freedom, but rare in systems with many degrees of freedom such as the B. subtilis sporulation network. The estimation of a number of indices, which reflect the chaotic nature of a system, indicates that the dynamics of this network is affected by deterministic chaos. The neat separation between the indices obtained from the time series simulated from the model and those obtained from time series generated by Gaussian white and colored noise confirmed that the B. subtilis sporulation network dynamics is affected by low dimensional chaos rather than by noise. Furthermore, our analysis identifies the principal driver of the networks chaotic dynamics to be sporulation initiation phosphotransferase B (Spo0B). We then analyzed the parameters and the phase space of the system to characterize the instability points of the network dynamics, and, in turn, to identify the ranges of values of Spo0B and of the other drivers of the chaotic dynamics, for which the whole system is highly sensitive to minimal perturbation. In summary, we described an unappreciated source of complexity in the B. subtilis sporulation network by gathering evidence for the chaotic behavior of the system, and by suggesting candidate molecules driving chaos in the system. The results of our chaos analysis can increase our understanding of the intricacies of the regulatory network under analysis, and suggest experimental work to refine our behavior of the mechanisms underlying B. subtilis sporulation initiation control

An Integrative Approach to Computational Modelling of the Gene Regulatory Network Controlling Clostridium botulinum Type A1 Toxin Production

Clostridium botulinum produces botulinum neurotoxins (BoNTs), highly potent substances responsible for botulism. Currently, mathematical models of C. botulinum growth and toxigenesis are largely aimed at risk assessment and do not include explicit genetic information beyond group level but integrate many component processes, such as signalling, membrane permeability and metabolic activity. In this paper we present a scheme for modelling neurotoxin production in C. botulinum Group I type A1, based on the integration of diverse information coming from experimental results available in the literature. Experiments show that production of BoNTs depends on the growth-phase and is under the control of positive and negative regulatory elements at the intracellular level. Toxins are released as large protein complexes and are associated with non-toxic components. Here, we systematically review and integrate those regulatory elements previously described in the literature for C. botulinum Group I type A1 into a population dynamics model, to build the very first computational model of toxin production at the molecular level. We conduct a validation of our model against several items of published experimental data for different wild type and mutant strains of C. botulinum Group I type A1. The result of this process underscores the potential of mathematical modelling at the cellular level, as a means of creating opportunities in developing new strategies that could be used to prevent botulism; and potentially contribute to improved methods for the production of toxin that is used for therapeutics

Bacterial-foraging optimization algorithm for non-hazardous plant layouts

PresentationThe following article approaches a safe plant layout design problem based on a bacterial-foraging optimization algorithm. Our approach finds the position in the two dimensional plane for each main process unit and evaluates the possibility of secondary contention for pertinent units, in order to minimize capital costs associated to equipment loss, piping, secondary contention, and usage of area. Fire and Explosion hazard is considered as the relevant safety aspect for distribution, and it is assessed through Dow’s Fire and Explosion Index. The proposed solution approach provides an alternative to hard-optimization methods, by allowing greater flexibility in accounting for both safety and economic aspects, while providing high quality solutions in a limited computation time. The aim of our proposed solution approach is to provide support to expert decision-making during the early plant layout design steps. A case study based on an acrylic-acid production plant, which has been used by several other papers that appeared in the literature, serves the purposes of showing the appropriateness and effectiveness of the method

A decade of air quality in Bogotá: a descriptive analysis

In this work we apply a rigorous and reproducible data analytics process for validation and analysis of the historical data from Bogotá (Colombia) air quality monitoring network since 1998. The reasons for addressing this research study stem from the lack of a consistent approach for cleaning, validating and reporting air quality data. By analyzing the whole dataset, we are aiming at providing citizens and the city authorities with a clear view of the current situation of air quality and of its historical evolution. Without any loss of generality, we focus our analysis on both respirable and fine particulate matter (PM10 and PM2.5) concentrations, which in Bogotá and worldwide are source of concern for their negative impacts on human health. We develop a reproducible and flexible data cleaning methodology for particulate matter concentration data reported by the local authorities, which allows customizing and applying configurable validation rules. Then, we present statistical descriptive analyses by providing intuitive data visualizations, characterizing historical and spatial change of air pollutant levels. Results raise concerns for the high percentage of invalid data, as well as the high levels of PM2.5 and PM10 ambient concentrations as observed in the valid portion of the available data, which frequently exceed national and international air quality standards. The data exhibit encouraging signs of air quality improvement, particularly for PM10. However, the analyses indicate that significant differences exist across Bogotá, and particularly in the south-west zone of the city annual concentrations of particulate matter are up to three or four times the WHO recommendations. We are confident on the methodology and results from our analysis are useful both for local environmental authority and the general public to help in obtaining consistent conclusions from the available data

Resonating Behaviour of Nanomachined Holed Microcantilevers

The nanofabrication of a nanomachined holed structure localized on the free end of a microcantilever is here presented, as a new tool to design micro-resonators with enhanced mass sensitivity. The proposed method allows both for the reduction of the sensor oscillating mass and the increment of the resonance frequency, without decreasing the active surface of the device. A theoretical analysis based on the Rayleigh method was developed to predict resonance frequency, effective mass, and effective stiffness of nanomachined holed microresonators. Analytical results were checked by Finite Element simulations, confirming an increase of the theoretical mass sensitivity up to 250%, without altering other figures of merit. The nanomachined holed resonators were vibrationally characterized, and their Q-factor resulted comparable with solid microcantilevers with same planar dimensions