Rule-based modelling of iron homeostasis in tuberculosis

To establish itself within the host system, Mycobacterium tuberculosis (Mtb) has formulated various means of attacking the host system. One such crucial strategy is the exploitation of the iron resources of the host system. Obtaining and maintaining the required concentration of iron becomes a matter of contest between the host and the pathogen, both trying to achieve this through complex molecular networks. The extent of complexity makes it important to obtain a systems perspective of the interplay between the host and the pathogen with respect to iron homeostasis. We have reconstructed a systems model comprising 92 components and 85 protein-protein or protein-metabolite interactions, which have been captured as a set of 194 rules. Apart from the interactions, these rules also account for protein synthesis and decay, RBC circulation and bacterial production and death rates. We have used a rule-based modelling approach, Kappa, to simulate the system separately under infection and non-infection conditions. Various perturbations including knock-outs and dual perturbation were also carried out to monitor the behavioral change of important proteins and metabolites. From this, key components as well as the required controlling factors in the model that are critical for maintaining iron homeostasis were identified. The model is able to re-establish the importance of iron-dependent regulator (ideR) in Mtb and transferrin (Tf) in the host. Perturbations, where iron storage is increased, appear to enhance nutritional immunity and the analysis indicates how they can be harmful for the host. Instead, decreasing the rate of iron uptake by Tf may prove to be helpful. Simulation and perturbation studies help in identifying Tf as a possible drug target. Regulating the mycobactin (myB) concentration was also identified as a possible strategy to control bacterial growth. The simulations thus provide significant insight into iron homeostasis and also for identifying possible drug targets for tuberculosis.

Spatio-temporal landscape modelling for natural hazard vulnerability analysis in select watersheds of Central Western Ghats

Natural hazards such as landslides are triggered by numerous factors such as ground movements, rock falls, slope failure, debris flows, slope instability, etc. Changes in slope stability happen due to human intervention, anthropogenic activities, change in soil structure, loss or absence of vegetation (changes in land cover), etc. Loss of vegetation happens when the forest is fragmented due to anthropogenic activities. Hence land cover mapping with forest fragmentation can provide vital information for visualising the regions that require immediate attention from slope stability aspects. The main objective of this paper is to understand the rate of change in forest landscape from 1973 to 2004 through multi-sensor remote sensing data analysis. The forest fragmentation index presented here is based on temporal land use information and forest fragmentation model, in which the forest pixels are classified as patch, transitional, edge, perforated, and interior, that give a measure of forest continuity. The analysis carried out for five prominent watersheds of Uttara Kannada district– Aganashini, Bedthi, Kali, Sharavathi and Venkatpura revealed that interior forest is continuously decreasing while patch, transitional, edge and perforated forest show increasing trend. The effect of forest fragmentation on landslide occurrence was visualised by overlaying the landslide occurrence points on classified image and forest fragmentation map. The increasing patch and transitional forest on hill slopes are the areas prone to landslides, evident from the field verification, indicating that deforestation is a major triggering factor for landslides. This emphasises the need for immediate conservation measures for sustainable management of the landscape. Quantifying and describing land use - land cover change and fragmentation is crucial for assessing the effect of land management policies and environmental protection decisions.

Constraining complex aquifer geometry with geophysics (2-D ERT and MRS measurements) for stochastic modelling of groundwater flow

Stochastic modelling is a useful way of simulating complex hard-rock aquifers as hydrological properties (permeability, porosity etc.) can be described using random variables with known statistics. However, very few studies have assessed the influence of topological uncertainty (i.e. the variability of thickness of conductive zones in the aquifer), probably because it is not easy to retrieve accurate statistics of the aquifer geometry, especially in hard rock context. In this paper, we assessed the potential of using geophysical surveys to describe the geometry of a hard rock-aquifer in a stochastic modelling framework. The study site was a small experimental watershed in South India, where the aquifer consisted of a clayey to loamy-sandy zone (regolith) underlain by a conductive fissured rock layer (protolith) and the unweathered gneiss (bedrock) at the bottom. The spatial variability of the thickness of the regolith and fissured layers was estimated by electrical resistivity tomography (ERT) profiles, which were performed along a few cross sections in the watershed. For stochastic analysis using Monte Carlo simulation, the generated random layer thickness was made conditional to the available data from the geophysics. In order to simulate steady state flow in the irregular domain with variable geometry, we used an isoparametric finite element method to discretize the flow equation over an unstructured grid with irregular hexahedral elements. The results indicated that the spatial variability of the layer thickness had a significant effect on reducing the simulated effective steady seepage flux and that using the conditional simulations reduced the uncertainty of the simulated seepage flux. As a conclusion, combining information on the aquifer geometry obtained from geophysical surveys with stochastic modelling is a promising methodology to improve the simulation of groundwater flow in complex hard-rock aquifers. (C) 2013 Elsevier B.V. All rights reserved.

Average Modelling of a Voltage Source Inverter with Dead-Time in a Synchronous Reference Frame

Voltage source inverters are an integral part of renewable power sources and smart grid systems. Computationally efficient and fairly accurate models for the voltage source inverter are required to carry out extensive simulation studies on complex power networks. Accuracy requires that the effect of dead-time be incorporated in the inverter model. The dead-time is essentially a short delay introduced between the gating pulses to the complementary switches in an inverter leg for the safety of power devices. As the modern voltage source inverters switch at fairly high frequencies, the dead-time significantly influences the output fundamental voltage. Dead-time also causes low-frequency harmonic distortion and is hence important from a power quality perspective. This paper studies the dead-time effect in a synchronous dq reference frame, since dynamic studies and controller design are typically carried out in this frame of reference. For the sake of computational efficiency, average models are derived, incorporating the dead-time effect, in both RYB and dq reference frames. The average models are shown to consume less computation time than their corresponding switching models, the accuracies of the models being comparable. The proposed average synchronous reference frame model, including effect of dead-time, is validated through experimental results.

Forest observational studies in India: Past developments and considerations for the future

Long term forest research sites in India, going by different names including Linear Tree Increment Plots, Linear Increment Plots, Linear Sample Plots and Permanent Preservation Plots, cover diverse plant communities and environmental conditions. Presently, some of these long-term observational studies are functional, some are disturbed and others have almost been lost. The accumulated data will become increasingly important in the context of environmental modelling and climate change, especially if the plots and data can be maintained and/or revived. This contribution presents the history and current state of forest research plots in India, including details of locations and re-measurements. We provide a brief introduction of the National Forest Inventory (NFI), Preservation Plots in natural forests, the 50-ha Mudumalai Forest Dynamics Plot as part of the Centre for Tropical Forest Science and Smithsonian Institution Global Earth Observatories network (CTFS-SIGEO), and research plots established in plantations for tree growth studies and modelling. We also present some methodological details including assessment and analysis for two types of observational studies, the Tree Count Plots (TCP) and Tree Re-measurement Plots (TRP). Arguments are presented in favour of enumeration and analysis methods which are consistent with current approaches in forest ecological research. (c) 2013 Elsevier B.V. All rights reserved.

Hybrid Elements for Modelling Squeeze Film Effects Coupled with Structural Interactions in Vibratory MEMS Devices

We present a hybrid finite element based methodology to solve the coupled fluid structure problem of squeeze film effects in vibratory MEMS devices, such as gyroscopes, RF switches, and 2D resonators. The aforementioned devices often have a thin plate like structure vibrating normally to a fixed substrate, and are generally not perfectly vacuum packed. This results in a thin air film being trapped between the vibrating plate and the fixed substrate which behaves like a squeeze film offering both stiffness and damping. For accurate modelling of such devices the squeeze film effects must be incorporated. Extensive literature is available on squeeze film modelling, however only a few studies address the coupled fluid elasticity problem. The majority of the studies that account for the plate elasticity coupled with the fluid equation, either use approximate mode shapes for the plate or use iterative solution strategies. In an earlier work we presented a single step coupled methodology using only one type of displacement based element to solve the coupled problem. The displacement based finite element models suffer from locking issues when it comes to modelling very thin structures with the lateral dimensions much larger than the plate thickness as is typical in MEMS devices with squeeze film effects. In this work we present another coupled formulation where we have used hybrid elements to model the structural domain. The numerical results show a huge improvement in convergence and accuracy with coarse hybrid mesh as compared to displacement based formulations. We further compare our numerical results with experimental data from literature and find them to be in good accordance.

Modelling staphylococcal pneumonia in a human 3D lung tissue model system delineates toxin-mediated pathology

Staphylococcus aureus necrotizing pneumonia is recognized as a toxin-mediated disease, yet the tissue-destructive events remain elusive, partly as a result of lack of mechanistic studies in human lung tissue. In this study, a three-dimensional (3D) tissue model composed of human lung epithelial cells and fibroblasts was used to delineate the role of specific staphylococcal exotoxins in tissue pathology associated with severe pneumonia. To this end, the models were exposed to the mixture of exotoxins produced by S. aureus strains isolated from patients with varying severity of lung infection, namely necrotizing pneumonia or lung empyema, or to purified toxins. The necrotizing pneumonia strains secreted high levels of alpha-toxin and Panton-Valentine leukocidin (PVL), and triggered high cytotoxicity, inflammation, necrosis and loss of E-cadherin from the lung epithelium. In contrast, the lung empyema strain produced moderate levels of PVL, but negligible amounts of alpha-toxin, and triggered limited tissue damage. alpha-toxin had a direct damaging effect on the epithelium, as verified using toxin-deficient mutants and pure alpha-toxin. Moreover, PVL contributed to pathology through the lysis of neutrophils. A combination of alpha-toxin and PVL resulted in the most severe epithelial injury. In addition, toxin-induced release of pro-inflammatory mediators from lung tissue models resulted in enhanced neutrophil migration. Using a collection of 31 strains from patients with staphylococcal pneumonia revealed that strains producing high levels of alpha-toxin and PVL were cytotoxic and associated with fatal outcome. Also, the strains that produced the highest toxin levels induced significantly greater epithelial disruption. Of importance, toxin-mediated lung epithelium destruction could be inhibited by polyspecific intravenous immunoglobulin containing antibodies against alpha-toxin and PVL. This study introduces a novel model system for study of staphylococcal pneumonia in a human setting. The results reveal that the combination and levels of alpha-toxin and PVL correlate with tissue pathology and clinical outcome associated with pneumonia.

Docking, molecular dynamics and QM/MM studies to delineate the mode of binding of CucurbitacinE to F-actin

CucurbitacinE (CurE) has been known to bind covalently to F-actin and inhibit depolymerization. However, the mode of binding of CurE to F-actin and the consequent changes in the F-actin dynamics have not been studied. Through quantum mechanical/molecular mechanical (QM/MM) and density function theory (DFT) simulations after the molecular dynamics (MD) simulations of the docked complex of F-actin and CurE, a detailed transition state (TS) model for the Michael reaction is proposed. The TS model shows nucleophilic attack of the sulphur of Cys257 at the beta-carbon of Michael Acceptor of CurE producing an enol intermediate that forms a covalent bond with CurE. The MD results show a clear difference between the structure of the F-actin in free form and F-actin complexed with CurE. CurE affects the conformation of the nucleotide binding pocket increasing the binding affinity between F-actin and ADP, which in turn could affect the nucleotide exchange. CurE binding also limits the correlated displacement of the relatively flexible domain 1 of F-actin causing the protein to retain a flat structure and to transform into a stable ``tense'' state. This structural transition could inhibit depolymerization of F-actin. In conclusion, CurE allosterically modulates ADP and stabilizes F-actin structure, thereby affecting nucleotide exchange and depolymerization of F-actin. (C) 2015 Elsevier Inc. All rights reserved.

Campylobacter jejuni colonization and transmission in broiler chickens: a modelling perspective.

Campylobacter jejuni is one of the most common causes of acute enteritis in the developed world. The consumption of contaminated poultry, where C. jejuni is believed to be a commensal organism, is a major risk factor. However, the dynamics of this colonization process in commercially reared chickens is still poorly understood. Quantification of these dynamics of infection at an individual level is vital to understand transmission within populations and formulate new control strategies. There are multiple potential routes of introduction of C. jejuni into a commercial flock. Introduction is followed by a rapid increase in environmental levels of C. jejuni and the level of colonization of individual broilers. Recent experimental and epidemiological evidence suggest that the celerity of this process could be masking a complex pattern of colonization and extinction of bacterial strains within individual hosts. Despite the rapidity of colonization, experimental transmission studies exhibit a highly variable and unexplained delay time in the initial stages of the process. We review past models of transmission of C. jejuni in broilers and consider simple modifications, motivated by the plausible biological mechanisms of clearance and latency, which could account for this delay. We show how simple mathematical models can be used to guide the focus of experimental studies by providing testable predictions based on our hypotheses. We conclude by suggesting that competition experiments could be used to further understand the dynamics and mechanisms underlying the colonization process. The population models for such competition processes have been extensively studied in other ecological and evolutionary contexts. However, C. jejuni can potentially adapt phenotypically through phase variation in gene expression, leading to unification of ecological and evolutionary time-scales. For a theoretician, the colonization dynamics of C. jejuni offer an experimental system to explore these 'phylodynamics', the synthesis of population dynamics and evolutionary biology.

The design of an agent for modelling supply chain network dynamics

A useful insight into managerial decision making can be found from simulation of business systems, but existing work on simulation of supply chain behaviour has largely considered non-competitive chains. Where competitive agents have been examined, they have generally had a simple structure and been used for fundamental examination of stability and equilibria rather than providing practical guidance to managers. In this paper, a new agent for the study of competitive supply chain network dynamics is proposed. The novel features of the agent include the ability to select between competing vendors, distribute orders preferentially among many customers, manage production and inventory, and determine price based on competitive behaviour. The structure of the agent is related to existing business models and sufficient details are provided to allow implementation. The agent is tested to demonstrate that it recreates the main results of the existing modelling and management literature on supply chain dynamics. A brief exploration of competitive dynamics is given to confirm that the proposed agent can respond to competition. The results demonstrate that overall profitability for a supply chain network is maximised when businesses operate collectively. It is possible for an individual business to achieve higher profits by adopting a more competitive stance, but the consequence of this is that the overall profitability of the network is reduced. The agent will be of use for a broad range of studies on the long-run effect of management decisions on their network of suppliers and customers.

Attenuation tomography. Modelling regional love waves: Imperial Valley to Pasadena

Abstract to Part I

The inverse problem of seismic wave attenuation is solved by an iterative back-projection method. The seismic wave quality factor, Q, can be estimated approximately by inverting the S-to-P amplitude ratios. Effects of various uncertain ties in the method are tested and the attenuation tomography is shown to be useful in solving for the spatial variations in attenuation structure and in estimating the effective seismic quality factor of attenuating anomalies.

Back-projection attenuation tomography is applied to two cases in southern California: Imperial Valley and the Coso-Indian Wells region. In the Coso-Indian Wells region, a highly attenuating body (S-wave quality factor (Q_β ≈ 30) coincides with a slow P-wave anomaly mapped by Walck and Clayton (1987). This coincidence suggests the presence of a magmatic or hydrothermal body 3 to 5 km deep in the Indian Wells region. In the Imperial Valley, slow P-wave travel-time anomalies and highly attenuating S-wave anomalies were found in the Brawley seismic zone at a depth of 8 to 12 km. The effective S-wave quality factor is very low (Q_β ≈ 20) and the P-wave velocity is 10% slower than the surrounding areas. These results suggest either magmatic or hydrothermal intrusions, or fractures at depth, possibly related to active shear in the Brawley seismic zone.

No-block inversion is a generalized tomographic method utilizing the continuous form of an inverse problem. The inverse problem of attenuation can be posed in a continuous form , and the no-block inversion technique is applied to the same data set used in the back-projection tomography. A relatively small data set with little redundancy enables us to apply both techniques to a similar degree of resolution. The results obtained by the two methods are very similar. By applying the two methods to the same data set, formal errors and resolution can be directly computed for the final model, and the objectivity of the final result can be enhanced.

Both methods of attenuation tomography are applied to a data set of local earthquakes in Kilauea, Hawaii, to solve for the attenuation structure under Kilauea and the East Rift Zone. The shallow Kilauea magma chamber, East Rift Zone and the Mauna Loa magma chamber are delineated as attenuating anomalies. Detailed inversion reveals shallow secondary magma reservoirs at Mauna Ulu and Puu Oo, the present sites of volcanic eruptions. The Hilina Fault zone is highly attenuating, dominating the attenuating anomalies at shallow depths. The magma conduit system along the summit and the East Rift Zone of Kilauea shows up as a continuous supply channel extending down to a depth of approximately 6 km. The Southwest Rift Zone, on the other hand, is not delineated by attenuating anomalies, except at a depth of 8-12 km, where an attenuating anomaly is imaged west of Puu Kou. The Ylauna Loa chamber is seated at a deeper level (about 6-10 km) than the Kilauea magma chamber. Resolution in the Mauna Loa area is not as good as in the Kilauea area, and there is a trade-off between the depth extent of the magma chamber imaged under Mauna Loa and the error that is due to poor ray coverage. Kilauea magma chamber, on the other hand, is well resolved, according to a resolution test done at the location of the magma chamber.

Abstract to Part II

Long period seismograms recorded at Pasadena of earthquakes occurring along a profile to Imperial Valley are studied in terms of source phenomena (e.g., source mechanisms and depths) versus path effects. Some of the events have known source parameters, determined by teleseismic or near-field studies, and are used as master events in a forward modeling exercise to derive the Green's functions (SH displacements at Pasadena that are due to a pure strike-slip or dip-slip mechanism) that describe the propagation effects along the profile. Both timing and waveforms of records are matched by synthetics calculated from 2-dimensional velocity models. The best 2-dimensional section begins at Imperial Valley with a thin crust containing the basin structure and thickens towards Pasadena. The detailed nature of the transition zone at the base of the crust controls the early arriving shorter periods (strong motions), while the edge of the basin controls the scattered longer period surface waves. From the waveform characteristics alone, shallow events in the basin are easily distinguished from deep events, and the amount of strike-slip versus dip-slip motion is also easily determined. Those events rupturing the sediments, such as the 1979 Imperial Valley earthquake, can be recognized easily by a late-arriving scattered Love wave that has been delayed by the very slow path across the shallow valley structure.

Development of a new modelling framework to estimate the C footprint from Basque dairy farms

19 p.

Modelling the Effect of Climate Change on Environmental Pollution Losses from Dairy Systems in the UK

21 p.

Testable models of aquatic systems: A NERC special topic for integrating experiments and modelling

A major part of the support for fundamental research on aquatic ecosystems continues to be provided by the Natural Environment Research Council (NERC). Funds are released for ”thematic” studies in a selected special topic or programme. ”Testable Models of Aquatic Ecosystems” was a Special Topic of the NERC, initiated in 1995, the aim of which was to promote ecological modelling by making new links between experimental aquatic biologists and state-of-the-art modellers. The Topic covered both marine and freshwater systems. This paper summarises projects on aspects of the responses of individual organisms to the effects of environmental variability, on the assembly, permanence and resilience of communities, and on aspects of spatial models. The authors conclude that the NERC Special Topic has been highly successful in promoting the development and application of models, most particularly through the interplay between experimental ecologists and formal modellers.