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Theor Biol Med Model [journal]
- Structural mimicry between SLA/LP and Rickettsia surface antigens as a driver of autoimmune hepatitis: insights from an in silico study. [Journal Article]
- Theor Biol Med Model 2013; 10(1):25.
Autoimmune hepatitis (AIH) is a chronic, progressive liver disease, characterized by continuing hepatocellular inflammation and necrosis. A subgroup of AIH patients presents specific autoantibodies to soluble liver antigen/liver-pancreas (SLA/LP) protein, which is regarded as a highly specific diagnostic marker. Autoantigenic SLA/LP peptides are targeted by CD4+ T cells, and restricted by the allele HLA-DRB1*03:01, which confers disease susceptibility in Europeans and Americans. A positively charged residue at position 71 has been indicated as critical for AIH susceptibility in all of the HLA alleles identified to date. Though the exact molecular mechanisms underlying pathogenesis of AIH are not clear, molecular mimicry between SLA/LP and viral/bacterial antigens has been invoked.The immunodominant region of SLA/LP was used as query in databank searches to identify statistically significant similarities with viral/bacterial peptides. Homology modeling and docking was used to investigate the potential interaction of HLA-DRB1*03:01 with the identified peptides. By molecular mechanics means, the interactions and energy of binding at the HLA binding site was also scrutinized.A statistically significant structural similarity between the immunodominant regions of SLA/LP and a region of the surface antigen PS 120 from Rickettsia spp. has been detected. The interaction of the SLA/LP autoepitope and the corresponding Rickettsia sequence with the allele HLA-DRB1*03:01 has been simulated. The obtained results predict for both peptides a similar binding mode and affinity to HLA-DRB1*03:01. A "hot spot" of interaction between HLA-DRB1*03:01 and PS 120 is located at the P4 binding pocket, and is represented by a salt bridge involving Lys at position 71 of the HLA protein, and Glu 795 of PS120 peptide.These findings strongly support the notion that a molecular mimicry mechanism can trigger AIH onset. CD4+ T cells recognizing peptides of SLA/LP could indeed cross-react with foreign Rickettsia spp. antigens. Finally, the same analysis suggests a molecular explanation for the importance of position 71 in conferring the susceptibility of the allele HLA-DRB1*03:01 to AIH. The lack of a positive charge at such position could prevent HLA alleles from binding the foreign peptides and triggering the molecular mimicry event.
- Development of global consensus sequence of HCV glycoproteins involved in viral entry. [Journal Article]
- Theor Biol Med Model 2013; 10(1):24.
HCV affects >170 million people worldwide and is a leading cause of liver diseases such as hepatocellular carcinoma. Each year, Pakistan reports hundreds of cases and now it has become a serious health issue. HCV has two transmembrane glycoproteins (E1 and E2) that are involved in virus entry through viral attachment, but because of their hypervariable nature they have become difficult targets for vaccine development.A total of 150 protein sequences of E1 and E2 belonging to genotypes 3a and 1a were retrieved from the NCBI protein database and were subjected to conservation and variation analysis using the multiple sequence alignment feature of the CLC workbench. A consensus sequence of each genotype of E1 and E2 was obtained and these consensus sequences were further analyzed to construct a global consensus sequence, which was used to design potentially conserved peptides.From the sequence conservation analysis, highly conserved residues were identified and were used to design peptides. Only two peptides were found to be conserved in the E1 protein of genotypes 3a and 1a and a total of nine conserved peptides were designed for the HCV E2 protein of those genotypes. These designed peptides could serve as useful targets in developing new inhibitory compounds.This study was designed to perform conservation and variability analysis of HCV glycoproteins and to find potentially conserved peptides among genotypes 3a and 1a (the most prevalent genotypes in Pakistan) that could serve as useful targets in the development of novel inhibitory compounds, thus reducing the threat of HCV infection in Pakistan.
- Agent-based modeling of competence phenotype switching in Bacillus subtilis. [Journal Article]
- Theor Biol Med Model 2013; 10(1):23.
It is a fascinating phenomenon that in genetically identical bacteria populations of Bacillus subtilis, a distinct DNA uptake phenotype called the competence phenotype may emerge in 10-20% of the population. Many aspects of the phenomenon are believed to be due to the variable expression of critical genes: a stochastic occurrence termed "noise" which has made the phenomenon difficult to examine directly by lab experimentation.To capture and model noise in this system and further understand the emergence of competence both at the intracellular and culture levels in B. subtilis, we developed a novel multi-scale, agent-based model. At the intracellular level, our model recreates the regulatory network involved in the competence phenotype. At the culture level, we simulated growth conditions, with our multi-scale model providing feedback between the two levels.Our model predicted three potential sources of genetic "noise". First, the random spatial arrangement of molecules may influence the manifestation of the competence phenotype. In addition, the evidence suggests that there may be a type of epigenetic heritability to the emergence of competence, influenced by the molecular concentrations of key competence molecules inherited through cell division. Finally, the emergence of competence during the stationary phase may in part be due to the dilution effect of cell division upon protein concentrations.The competence phenotype was easily translated into an agent-based model - one with the ability to illuminate complex cell behavior. Models such as the one described in this paper can simulate cell behavior that is otherwise unobservable in vivo, highlighting their potential usefulness as research tools.
- Homology modeling and virtual screening approaches to identify potent inhibitors of VEB-1 beta-lactamase. [JOURNAL ARTICLE]
- Theor Biol Med Model 2013 Apr 2; 10(1):22.
BACKGROUND:blaVEB-1 is an integron-located extended-spectrum beta-lactamase gene initially detected in Escherichia coli and Pseudomonas aeruginosa strains from south-east Asia. Several recent studies have reported that VEB-1-positive strains are highly resistant to ceftazidime, cefotaxime and aztreonam antibiotics. One strategy to overcome resistance involves administering antibiotics together with beta-lactamase inhibitors during the treatment of infectious diseases. During this study, four VEB-1 beta-lactamase inhibitors were identified using computer-aided drug design.
METHODS:The SWISS-MODEL tool was utilized to generate three dimensional structures of VEB-1 beta-lactamase, and the 3D model VEB-1 was verified using PROCHECK, ERRAT and VERIFY 3D programs. Virtual screening was performed by docking inhibitors obtained from the ZINC Database to the active site of the VEB-1 protein using AutoDock Vina software.Results and conclusion: Homology modeling studies were performed to obtain a three-dimensional structure of VEB-1 beta-lactamase. The generated model was validated, and virtual screening of a large chemical ligand library with docking simulations was performed using AutoDock software with the ZINC database. On the basis of the dock-score, four molecules were subjected to ADME/TOX analysis, with ZINC4085364 emerging as the most potent inhibitor of the VEB-1 beta-lactamase.
- Experimental designs for a Benign Paroxysmal Positional Vertigo model. [Journal Article]
- Theor Biol Med Model 2013.:21.
The pathology of the Benign Paroxysmal Positional Vertigo (BPPV) is detected by a clinician through maneuvers consisting of a series of consecutive head turns that trigger the symptoms of vertigo in patient. A statistical model based on a new maneuver has been developed in order to calculate the volume of endolymph displaced after the maneuver.A simplification of the Navier-Stokes problem from the fluids theory has been used to construct the model. In addition, the same cubic splines that are commonly used in kinematic control of robots were used to obtain an appropriate description of the different maneuvers. Then experimental designs were computed to obtain an optimal estimate of the model.D-optimal and c-optimal designs of experiments have been calculated. These experiments consist of a series of specific head turns of duration Δt and angle α that should be performed by the clinician on the patient. The experimental designs obtained indicate the duration and angle of the maneuver to be performed as well as the corresponding proportion of replicates. Thus, in the D-optimal design for 100 experiments, the maneuver consisting of a positive 30° pitch from the upright position, followed by a positive 30° roll, both with a duration of one and a half seconds is repeated 47 times. Then the maneuver with 60° /6° pitch/roll during half a second is repeated 16 times and the maneuver 90° /90° pitch/roll during half a second is repeated 37 times. Other designs with significant differences are computed and compared.A biomechanical model was derived to provide a quantitative basis for the detection of BPPV. The robustness study for the D-optimal design, with respect to the choice of the nominal values of the parameters, shows high efficiencies for small variations and provides a guide to the researcher. Furthermore, c-optimal designs give valuable assistance to check how efficient the D-optimal design is for the estimation of each of the parameters. The experimental designs provided in this paper allow the physician to validate the model. The authors of the paper have held consultations with an ENT consultant in order to align the outline more closely to practical scenarios.
- Effect of blood protein concentrations on drug-dosing regimes: practical guidance. [Journal Article]
- Theor Biol Med Model 2013.:20.
In this article the importance of blood proteins for drug dosing regimes is discussed. A simple mathematical model is presented for estimating recommended drug doses when the concentration of blood proteins is decreased. Practical guidance for drug dosing regimes is discussed and given in the form of a figure. It is demonstrated that correction of drug dosing regimes is needed only for when there is a high level of drug conjugation with blood proteins and a high degree of hypoalbuminaemia. An example of the use of this model is given.
- Stochastic time-concentration activity models for in vitro neurotoxicity. [JOURNAL ARTICLE]
- Theor Biol Med Model 2013 Mar 14; 10(1):19.
In vitro aggregating brain cell cultures containing all types of brain cells have been shown to be useful for neurotoxicological investigations. The cultures are used for the detection of nervous system specific effects of compounds by measuring multiple endpoints including changes of enzyme activities. Concentration-dependent neurotoxicity is determined at several time points. A Markov model is set up to describe dynamics of brain cell populations exposed to potentially neurotoxic compounds. Brain cells are assumed to be either in a healthy or stressed state and only stressed cells are susceptible to cell death. Cells may switch between these states or die with concentration-dependent transition rates. Since cell numbers are not directly measurable, intracellular lactate dehydrogenase (LDH) activity is used as a surrogate. Assuming that changes in cell numbers are proportional to changes in intracellular LDH activity, stochastic enzyme activity models are derived. Maximum likelihood and least squares regression techniques are applied for estimation of the transition rates. Likelihood ratio tests are performed to test hypotheses about the transition rates. Simulation studies are used to investigate the performance of the transition rate estimators and to analyze the error rates of the likelihood ratio tests. The stochastic time-concentration activity model is applied to intracellular LDH activity measurements after 7 and 14 days of continuous exposure to propofol. The model describes transitions from healthy to stressed cells and from stressed cells to death. The model predicts that propofol affects stressed cells more than healthy cells. Increasing propofol concentration from 10 to 100 micro M reduces the mean waiting time for transition to the stressed state by about 50% from 11.5 to 6.3 days whereas the mean duration to cellular death reduces more dramatically from 1.8 days to 5 hours.
- Toll-like receptor 9 interaction with CpG ODN--an in silico analysis approach. [Journal Article, Research Support, Non-U.S. Gov't]
- Theor Biol Med Model 2013.:18.
Toll-like receptor 9 (TLR9) recognises unmethylated CpG DNA and activates a signalling cascade, leading to the production of inflammatory cytokines such as TNF-α, IL-1, IL-6 and IL-12 via the adaptor protein MyD88. However, the specific sequence and structural requirements of the CpG DNA for the recognition of and binding to TLR9 are unknown. Moreover, the 3D structures of TLR9 and the TLR9-ODN complex have not been determined. In this study, we propose a reliable model of the interaction of the TLR9 ECD with CpG ODN using bioinformatics tools.The three-dimensional structures of two TLR9 ECD-CpG ODN complexes were constructed using a homology modelling and docking strategy. Based on the models of these complexes, the TLR9 ECD-CpG ODN interaction patterns were calculated. The results showed that the interface between the human TLR9 and the CpG ODN molecule is geometrically complementary. The computed molecular interactions indicated that LRR11 is the main region of TLR9 that binds to CpG ODN and that five positively charged residues within LRR11 are involved in the binding of the TLR9 ECD to the CpG ODN. Observations in the close-up view of these interactions indicated that these five positively charged residues contribute differently to the binding region within the TLR9 ECD-CpG ODN complex. 337Arg and 338Lys reside in the binding sites of ODN, forming hydrogen bonds and direct contacts with the CpG ODN, whereas 347Lys, 348Arg, and 353His do not directly contact the CpG ODN. These results are in agreement with previously reported experimental data.In this study, we present two structural models for the human and mouse TLR9 ECD in a complex with CpG ODN. Some features predicted by this model are consistent with previously reported experimental data. This complex model may lead to a better understanding of the function of TLR9 and its interaction with CpG ODN and will improve our understanding of TLR9-ligand interaction in general.
- Modeling the obesity epidemic: social contagion and its implications for control. [Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't]
- Theor Biol Med Model 2013.:17.
As an obesity epidemic has grown worldwide, a variety of intervention programs have been considered, but a scientific approach to comparatively assessing the control programs has still to be considered. The present study aims to describe an obesity epidemic by employing a simple mathematical model that accounts for both social contagion and non-contagious hazards of obesity, thereby comparing the effectiveness of different types of interventions.An epidemiological model is devised to describe the time- and age-dependent risk of obesity, the hazard of which is dealt with as both dependent on and independent of obesity prevalence, and parameterizing the model using empirically observed data. The equilibrium prevalence is investigated as our epidemiological outcome, assessing its sensitivity to different parameters that regulate the impact of intervention programs and qualitatively comparing the effectiveness. We compare the effectiveness of different types of interventions, including those directed to never-obese individuals (i.e. primary prevention) and toward obese and ex-obese individuals (i.e. secondary prevention).The optimal choice of intervention programs considerably varies with the transmission coefficient of obesity, and a limited transmissibility led us to favour preventing weight gain among never-obese individuals. An abrupt decline in the prevalence is expected when the hazards of obesity through contagious and non-contagious routes fall into a particular parameter space, with a high sensitivity to the transmission potential of obesity from person to person. When a combination of two control strategies can be selected, primary and secondary preventions yielded similar population impacts and the superiority of the effectiveness depends on the strength of the interventions at an individual level.The optimality of intervention programs depends on the contagiousness of obesity. Filling associated data gaps of obesity transmission would help systematically understand the epidemiological dynamics and consider required control programs.
- Fluctuations in Tat copy number when it counts the most: a possible mechanism to battle the HIV latency. [JOURNAL ARTICLE]
- Theor Biol Med Model 2013 Mar 5; 10(1):16.
The HIV-1 virus can enter a dormant state and become inactive, which reduces accessibility by antiviral drugs. We approach this latency problem from an unconventional point of view, withthe focus on understanding how intrinsic chemical noise (copy number fluctuations of the Tat protein) can be used to assist the activation process of the latent virus. Several phase diagrams have been constructed in order to visualize in which regions of the parameter space noise can drive the activation process. Essential to the study is the use of a hyperbolic coordinate system, which greatly facilitates quantification of how the various reaction rate combinations shape the noise behavior of the Tat protein feedback system. We have designed a mathematical manual of how to approach the problem of activation quantitatively, and introduce the notion of an ``operating point'' of the virus. For both noise-free and noise-based strategies we show how operating point off-sets induce changes in the number of Tat molecules. The major result of the analysis is that for every noise-free strategy there is a noise-based strategy that requires lower dosage, but achieves the same anti-latency effect. It appears that the noise-based activation is advantageous for every operating point.