An epidemic model with transport-related infection incorporating awareness and screening.

In this paper, an SWEIQR epidemic model with transport-related infection is proposed. The model considers inter-patch travel with entry-departure screening. The reproduction number, R ed ϕ , is computed and analyzed with respect to awareness and screening parameters. The analytic computations show that the disease-free equilibrium in the absence of travel is globally asymptotically stable when R ω ≤ 1 and unstable otherwise. The trans-critical bifurcation occurs at R ω = 1 and the locally stable endemic equilibrium point appears if R ω > 1 near to R ω = 1 . The numerical simulations are performed to verify the analytical computation and explore the dynamic behavior with respect to different model parameters. The result shows that disseminating awareness through the population reduces the spread of disease. Furthermore, the full model results show that the departure screening may reduce the spread of disease in each patch.

Non-linear Dynamics of Two-Patch Model Incorporating Secondary Dengue Infection.

In this paper, the impact of human migration on the dynamics of dengue epidemic has been discussed. The vector-host model considers two patches with different dengue serotype in each patch. The model considers the constant rate of migration in susceptible and recovered class from one patch to other. Recovered migrants from prior infection are exposed to secondary infection in the patch where different serotype is present. The basic reproduction number is computed and analyzed in terms of migration parameters. The model is analyzed for the existence and local stability of various equilibrium states in terms of migration parameters. The numerical simulations for the choice of relevant data from literature have been performed to verify analytical results and to further explore the dynamics of the system. The sensitivity analysis of basic reproduction number with respect to migration parameters is carried out. It is found that immigration in a patch increases the basic reproduction in respective patch and vice-versa. The basic reproduction number has been estimated for the two states of Brazil which verifies the occurrence of severe epidemic in one of the states of Brazil.

A network model for control of dengue epidemic using sterile insect technique.

In this paper, a network model has been proposed to control dengue disease transmission considering host-vector dynamics in n patches. The control of mosquitoes is performed by SIT. In SIT, the male insects are sterilized in the laboratory and released into the environment to control the number of offsprings. The basic reproduction number has been computed. The existence and stability of various states have been discussed. The bifurcation diagram has been plotted to show the existence and stability regions of disease-free and endemic states for an isolated patch. The critical level of sterile male mosquitoes has been obtained for the control of disease. The basic reproduction number for n patch network model has been computed. It is evident from numerical simulations that SIT control in one patch may control the disease in the network having two/three patches with suitable coupling among them.

Comparative Genome and Network Centrality Analysis to Identify Drug Targets of Mycobacterium tuberculosis H37Rv.

Potential drug targets of Mycobacterium tuberculosis H37Rv were identified through systematically integrated comparative genome and network centrality analysis. The comparative analysis of the complete genome of Mycobacterium tuberculosis H37Rv against Database of Essential Genes (DEG) yields a list of proteins which are essential for the growth and survival of the pathogen. Those proteins which are nonhomologous with human were selected. The resulting proteins were then prioritized by using the four network centrality measures: degree, closeness, betweenness, and eigenvector. Proteins whose centrality value is close to the centre of gravity of the interactome network were proposed as a final list of potential drug targets for the pathogen. The use of an integrated approach is believed to increase the success of the drug target identification process. For the purpose of validation, selective comparisons have been made among the proposed targets and previously identified drug targets by various other methods. About half of these proteins have been already reported as potential drug targets. We believe that the identified proteins will be an important input to experimental study which in the way could save considerable amount of time and cost of drug target discovery.

Maximum flow approach to prioritize potential drug targets of Mycobacterium tuberculosis H37Rv from protein-protein interaction network.

BACKGROUND: In spite of the implementations of several strategies, tuberculosis (TB) is overwhelmingly a serious global public health problem causing millions of infections and deaths every year. This is mainly due to the emergence of drug-resistance varieties of TB. The current treatment strategies for the drug-resistance TB are of longer duration, more expensive and have side effects. This highlights the importance of identification and prioritization of targets for new drugs. This study has been carried out to prioritize potential drug targets of Mycobacterium tuberculosis H37Rv based on their flow to resistance genes. METHODS: The weighted proteome interaction network of the pathogen was constructed using a dataset from STRING database. Only a subset of the dataset with interactions that have a combined score value ≥770 was considered. Maximum flow approach has been used to prioritize potential drug targets. The potential drug targets were obtained through comparative genome and network centrality analysis. The curated set of resistance genes was retrieved from literatures. Detail literature review and additional assessment of the method were also carried out for validation. RESULTS: A list of 537 proteins which are essential to the pathogen and non-homologous with human was obtained from the comparative genome analysis. Through network centrality measures, 131 of them were found within the close neighborhood of the centre of gravity of the proteome network. These proteins were further prioritized based on their maximum flow value to resistance genes and they are proposed as reliable drug targets of the pathogen. Proteins which interact with the host were also identified in order to understand the infection mechanism. CONCLUSION: Potential drug targets of Mycobacterium tuberculosis H37Rv were successfully prioritized based on their flow to resistance genes of existing drugs which is believed to increase the druggability of the targets since inhibition of a protein that has a maximum flow to resistance genes is more likely to disrupt the communication to these genes. Purposely selected literature review of the top 14 proteins showed that many of them in this list were proposed as drug targets of the pathogen.

Potential non homologous protein targets of mycobacterium tuberculosis H37Rv identified from protein-protein interaction network.

Bacillus mycobacterium tuberculosis (Mtb) is the causative agent of tuberculosis and H37Rv is the most studied strain. Identification of new drug targets for Mtb is among one of the priorities since it is still a major global health problem by being a cause of morbidity and mortality for millions of people each year. We used centrality measures to identify the most central proteins from protein-protein interaction network of mycobacterium tuberculosis H37Rv which was retrieved from STRING database by hypothesizing these proteins would be important to alter the function of the network. We then refined the result by using a dataset obtained from Drug Target Protein Database to identify non-human homologous proteins since in host-parasite diseases like tuberculosis; non-homologous proteins (enzymes) as drug target are the primary choices. We also tried to compare our proposed potential non-human homologous protein target lists against previously reported targets. Moreover, the structural coverage of the proposed target list has been identified. The analysis shows that 807 proteins in mycobacterium tuberculosis H37Rv were found at the center of gravity of the functional network of which 390 were non-human homologous, which are thought to be potential drug targets. 119 (30.51%) of the 390 proteins were reported as drug targets and only 33 (8.46%) of the non-human homologous proposed target lists have solved structure.

Modeling the dynamics of hepatitis C virus with combined antiviral drug therapy: interferon and ribavirin.

A mathematical modeling of hepatitis C virus (HCV) dynamics and antiviral therapy has been presented in this paper. The proposed model, which involves four coupled ordinary differential equations, describes the interaction of target cells (hepatocytes), infected cells, infectious virions and non-infectious virions. The model takes into consideration the addition of ribavirin to interferon therapy and explains the dynamics regarding a biphasic and triphasic decline of viral load in the model. A critical drug efficacy parameter has been defined and it is shown that for an efficacy above this critical value, HCV is eradicated whereas for efficacy lower this critical value, a new steady state for infectious virions is reached, which is lower than the previous steady state value.

HORIBALFRE program: Higher Order Residue Interactions Based ALgorithm for Fold REcognition.

Understanding the functional and structural implication of a protein encoded in novel genes using function association or fold recognition approaches remains to be a challenging task in the current era of genomes, metagenomes and personal genomes. In an attempt to enhance potential-based fold-recognition methods in recognizing remote homology between proteins, we propose a new approach "Higher Order Residue Interaction Based ALgorithm for Fold REcognition (HORIBALFRE)". Higher order residue interactions refer to a class of interactions in protein structures mediated by C(α) or C(ß) atoms within a pre-defined distance cut-off. Higher order residue interactions (pairwise, triplet and quadruplet interactions) play a vital role in attaining the stable conformation of a protein structure. In HORIBALFRE, we incorporated the potential contributions from two body (pairwise) interactions, three body (triplet interactions) and four-body (quadruple interaction) interactions, to implement a new fold recognition algorithm. Core of HORIBALFRE algorithm includes the potentials generated from a library of protein structure derived from manually curated CAMPASS database of structure based sequence alignment. We used Fischer's dataset, with 68 templates and 56 target sequences, derived from SCOP database and performed one-against-all sequence alignment using TCoffee. Various potentials were derived using custom scripts and these potentials were incorporated in the HORIBALFRE algorithm. In this manuscript, we report outline of a novel fold recognition algorithm and initial results. Our results show that inclusion of quadruplet class of higher order residue interaction improves fold recognition.

Dynamic modeling and simulation of JNK and P38 kinase cascades with feedbacks and crosstalks.

All cells receive and respond to signals from their environment, whether they live freely or are part of a tissue. Feedback loops are one among the interactions in signal-transduction cascades, in which the information from the downstream components is sent back to the upstream components of the system. Crosstalks between signal-transduction cascades are able to combine the information's received and processed to trigger the appropriate response. To understand how signaling networks make decisions, the dynamic interactions of proteins in the signal-transduction cascades are important rather than just creating static maps of pathways. Based on reaction kinetics, we have developed mathematical models to predict and analyze the impacts of the feedback loops in JNK cascades and the crosstalks between JNK and P38 kinase cascades. Feedback loops in JNK cascades and crosstalks between JNK and P38 kinase cascades plays the complementary roles in making the impacts on the activation of JNK and P38 kinases. JNK and P38 kinase cascades with feedbacks and crosstalks is a robust system.

HORI: a web server to compute Higher Order Residue Interactions in protein structures.

BACKGROUND: Folding of a protein into its three dimensional structure is influenced by both local and global interactions within a protein. Higher order residue interactions, like pairwise, triplet and quadruplet ones, play a vital role in attaining the stable conformation of the protein structure. It is generally agreed that higher order interactions make significant contribution to the potential energy landscape of folded proteins and therefore it is important to identify them to estimate their contributions to overall stability of a protein structure. RESULTS: We developed HORI [Higher order residue interactions in proteins], a web server for the calculation of global and local higher order interactions in protein structures. The basic algorithm of HORI is designed based on the classical concept of four-body nearest-neighbour propensities of amino-acid residues. It has been proved that higher order residue interactions up to the level of quadruple interactions plays a major role in the three-dimensional structure of proteins and is an important feature that can be used in protein structure analysis. CONCLUSION: HORI server will be a useful resource for the structural bioinformatics community to perform analysis on protein structures based on higher order residue interactions. HORI server is a highly interactive web server designed in three modules that enables the user to analyse higher order residue interactions in protein structures. HORI server is available from the URL: http://caps.ncbs.res.in/hori.

Lose and gain: impacts of ERK5 and JNK cascades on each other.

UNLABELLED: Kinase cascades in ERK5 (Extracellular signal-regulated kinases) and JNK (c-Jun N-terminal kinases) signaling pathways mediate the sensing and processing of stimuli. Cross-talks between signaling cascades is a likely phenomenon that can cause apparently different biological responses from a single pathway, on its activation. Feedback loops have the potential to greatly alter the properties of a pathway and its response to stimuli. Based on enzyme kinetic reactions, mathematical models have been developed to predict and analyze the impacts of cross-talks and feedback loops in ERK5 and JNK cascades. It has been observed that, there is no significant impact on neither ERK5 activation nor JNKs' activation due to cross-talks between them. But it is due to cross-talks and feedback loops in ERK5 and JNK cascade, ERK5 gets activated in a transient manner in the absence of input signals. Planning to obtain the parameter values from the experimentalist and the result should be validated by experimental verification. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s11693-010-9061-4) contains supplementary material, which is available to authorized users.

Analysis of the impact of ERK5, JNK, and P38 kinase cascades on each other: a systems approach.

The classical concept of linear pathways is being increasingly challenged by network representations, which emphasize the importance of interactions between components of a biological system, and motivates for adopting a system-level approach in biology. We have developed a dynamical system that integrates quantitative, dynamic and topological representation of network of ERK5 (Extracellular signal-regulated kinases 5), JNK(c-Jun N-terminal kinases) and P38 kinase cascades. We have observered that, the transient activation of ERK5, JNK1 and P38beta kinase, and the persistent activation of JNK2, JNK3 and P38 delta kinase does not get affected due to the cross-talks between ERK5, JNK and P38 kinase cascades. But it is due to the cross - talks, the transiently activated P38alpha kinase become inactivated, and the transiently activated P38gamma kinase become persistently activated. The impacts of one-way cross-talks between the cascades are insignificant and differ from the impact of two-way cross-talks. We generate a hypothesis that, signaling pathways should be studied as a system by considering the cross-talks between the two adjacent cascades.

Computational prediction and analysis of impact of the cross-talks between JNK and P38 kinase cascades.

Signal transduction is a complex protein signaling process with a rich network of multifunctional interactions that occur in a non-linear fashion. Mitogen-activated protein kinase (MAPK) signal transduction pathways regulate diverse cellular processes ranging from proliferation and differentiation to apoptosis. In mammals, out of five, there are three well characterized subfamilies of MAPKs - ERKs (Extracellular signal-regulated kinases), JNKs (c-Jun N-terminal kinases), and P38 kinases, and their activators, are implicated in human diseases and are targets for drug development. Kinase cascades in MAPK pathways mediate the sensing and processing of stimuli. To understand how cells makes decisions, the dynamic interactions of components of signaling cascades are important rather than just creating static maps. Based on enzyme kinetic reactions, we have developed a mathematical model to analyze the impact of the cross-talks between JNK and P38 kinase cascades. Cross-talks between JNK and P38 kinase cascades influence the activities of P38 kinases. Responses of the signals should be studied for network of kinase cascades by considering cross-talks.

Modified scheme for one-dimensional BOD-DO models.

An alternative numerical scheme for predicting the BOD variation with time at various successive distances from a wastewater outfall in a stream, is presented in this paper. The presented scheme (for the solution of differential equations incorporating the advection, dispersion, and biochemical decay) removes unnecessary restrictions imposed on the grid size ä(x) and ä(t) in the existing MAD scheme.The concept of numerical dispersion is exploited to model the physical dispersion process, and the presented scheme manifests explicity and stability. The robustness of the presented scheme in real life situations is demonstrated through an illustrative example based on hypothetical but rational and realistic data.

Dynamical behavior of two predators competing over a single prey.

Dynamical behavior of a food web comprising two predators competing over a single prey has been investigated. The analysis of the food web model shows that the persistence is not possible for two competing predators sharing a single prey species in the cases when any one of the boundary prey-predator planes has a stable equilibrium point. The principle of competitive exclusion holds in such cases. However, numerical simulations exhibit persistence in the presence of periodic solutions in the boundary planes. The system exhibits quasi-periodic behavior in the positive octant. The co-existence in the form of a limit cycle is also possible in some cases.