Theoretical Biology and Medical Modelling - Latest articles

Construction and analysis of a modular model of caspase activation in apoptosis

Heather A Harrington, Kenneth L Ho, Samik Ghosh and K C Tung — 2008-12-10

Background: A key physiological mechanism employed by multicellular organisms is apoptosis, or programmed cell death. Apoptosis is triggered by the activation of caspases in response to both extracellular (extrinsic) and intracellular (intrinsic) signals. The extrinsic and intrinsic pathways are characterized by the formation of the death-inducing signaling complex (DISC) and the apoptosome, respectively; both the DISC and the apoptosome are oligomers with complex formation dynamics. Additionally, the extrinsic and intrinsic pathways are coupled through the mitochondrial apoptosis-induced channel via the Bcl-2 family of proteins. Results: A model of caspase activation is constructed and analyzed. The apoptosis signaling network is simplified through modularization methodologies and equilibrium abstractions for three functional modules. The mathematical model is composed of a system of ordinary differential equations which is numerically solved. Multiple linear regression analysis investigates the role of each module and reduced models are constructed to identify key contributions of the extrinsic and intrinsic pathways in triggering apoptosis for different cell lines. Conclusions: Through linear regression techniques, we identified the feedbacks, dissociation of complexes, and negative regulators as the key components in apoptosis. The analysis and reduced models for our model formulation reveal that the chosen cell lines predominately exhibit strong extrinsic caspase, typical of type I cell, behavior. Furthermore, under the simplified model framework, the selected cells lines exhibit different modes by which caspase activation may occur. Finally the proposed modularized model of apoptosis may generalize behavior for additional cells and tissues, specifically identifying and predicting components responsible for the transition from type I to type II cell behavior.

Transient antiretroviral therapy selecting for common HIV-1 mutations substantially accelerates the appearance of rare mutations

Tinevimbo Shiri and Alex Welte — 2008-11-14

Background: Highly selective antiretroviral (ARV) regimens such as single dose nevirapine (NVP) used for prevention of mother to child transmission (PMTCT) in resource-limited settings produce transient increases in otherwise marginal subpopulations of cells infected by mutant genomes. The longer term implications for accumulation of further resistance mutations are not fully understood. Methods: We develop a new strain-differentiated hybrid deterministic-stochastic population dynamic type model of healthy and infected cells. We explore how the transient increase in a population of cells transcribed with a common mutation (modelled deterministically), which occurs in response to a short course of monotherapy, has an impact on the risk of appearance of rarer, higher-order, therapy-defeating mutations (modelled stochastically). Results: Scenarios with a transient of a magnitude and duration such as is known to occur under NVP monotherapy exhibit significantly accelerated viral evolution compared to no-treatment scenarios. We identify a possibly important new biological timescale; namely, the duration of persistence, after a seminal mutation, of a sub-population of cells bearing the new mutant gene, and we show how increased persistence leads to an increased probability that a rare mutant will be present at the moment at which a new treatment regimen is initiated. Conclusion: Even transient increases in subpopulations of common mutants are associated with accelerated appearance of further rarer mutations. Experimental data on the persistence of small subpopulations of rare mutants, in unfavourable environments, should be sought, as this affects the risk of subverting later regimens.

Activation instead of blocking mesolimbic dopaminergic reward circuitry is a preferred modality in the long term treatment of reward deficiency syndrome (RDS): a commentary

2008-11-12

Background and hypothesis Based on neurochemical and genetic evidence, we suggest that both prevention and treatment of multiple addictions, such as dependence to alcohol, nicotine and glucose, should involve a biphasic approach. Thus, acute treatment should consist of preferential blocking of postsynaptic Nucleus Accumbens (NAc) dopamine receptors (D1-D5), whereas long term activation of the mesolimbic dopaminergic system should involve activation and/or release of Dopamine (DA) at the NAc site. Failure to do so will result in abnormal mood, behavior and potential suicide ideation. Individuals possessing a paucity of serotonergic and/or dopaminergic receptors, and an increased rate of synaptic DA catabolism due to high catabolic genotype of the COMT gene, are predisposed to self-medicating any substance or behavior that will activate DA release, including alcohol, opiates, psychostimulants, nicotine, gambling, sex, and even excessive internet gaming. Acute utilization of these substances and/or stimulatory behaviors induces a feeling of well being. Unfortunately, sustained and prolonged abuse leads to a toxic" pseudo feeling" of well being resulting in tolerance and disease or discomfort. Thus, a reduced number of DA receptors, due to carrying the DRD2 A1 allelic genotype, results in excessive craving behavior; whereas a normal or sufficient amount of DA receptors results in low craving behavior. In terms of preventing substance abuse, one goal would be to induce a proliferation of DA D2 receptors in genetically prone individuals. While in vivo experiments using a typical D2 receptor agonist induce down regulation, experiments in vitro have shown that constant stimulation of the DA receptor system via a known D2 agonist results in significant proliferation of D2 receptors in spite of genetic antecedents. In essence, D2 receptor stimulation signals negative feedback mechanisms in the mesolimbic system to induce mRNA expression causing proliferation of D2 receptors. Proposal and conclusions The authors propose that D2 receptor stimulation can be accomplished via the use of Synapatmine TM , a natural but therapeutic nutraceutical formulation that potentially induces DA release, causing the same induction of D2-directed mRNA and thus proliferation of D2 receptors in the human. This proliferation of D2 receptors in turn will induce the attenuation of craving behavior. In fact as mentioned earlier, this model has been proven in research showing DNA-directed compensatory overexpression (a form of gene therapy) of the DRD2 receptors, resulting in a significant reduction in alcohol craving behavior in alcohol preferring rodents. Utilizing natural dopaminergic repletion therapy to promote long term dopaminergic activation will ultimately lead to a common, safe and effective modality to treat Reward Deficiency Syndrome (RDS) behaviors including Substance Use Disorders (SUD), Attention Deficit Hyperactivity Disorder (ADHD), Obesity and other reward deficient aberrant behaviors. This concept is further supported by the more comprehensive understanding of the role of dopamine in the NAc as a "wanting" messenger in the meso-limbic DA system.

Mitochondrial concept of leukemogenesis: key role of oxygen-peroxide effects

Boris N Lyu, Sanzhar B Ismailov, Bolat Ismailov and Marina B Lyu — 2008-11-11

Background and hypothesisThe high sensitivity of hematopoietic cells, especially stem cells, to radiation and to pro-oxidative and other leukemogenic agents is related to certain of their morphological and metabolic features. It is attributable to the low (minimal) number of active mitochondria and the consequently slow utilization of O2 entering the cell. This results in an increased intracellular partial pressure of O2 (pO2) and increased levels of reactive oxygen (ROS) and nitrogen (RNS) species, and a Δ(PO – AO) imbalance between the pro-oxidative (PO) and antioxidative (AO) constituents.Proposed mechanismBecause excessive O2 is toxic, we suggest that hematopoietic cells exist in a kind of unstable dynamic balance. This suggestion is based on the idea that mitochondria not only consume O2 in the process of ATP production but also constitute the main anti-oxygenic stage in the cell's protective antioxidative system. Variations in the mitochondrial base capacity (quantity and quality of mitochondria) constitute an important and highly efficient channel for regulating the oxidative stress level within a cell.The primary target for leukemogenic agents is the few mitochondria within the hematopoietic stem cell. Disturbance and weakening of their respiratory function further enhances the initial pro-oxidative state of the cell. This readily results in peroxygenation stress, creating the necessary condition for inducing leukemogenesis. We propose that this is the main cause of all related genetic and other disorders in the cell. ROS, RNS and peroxides act as signal molecules affecting redox-sensitive transcription factors, enzymes, oncogenes and other effectors. Thereby, they influence the expression and suppression of many genes, as well as the course and direction of proliferation, differentiation, leukemogenesis and apoptosis.Differentiation of leukemic cells is blocked at the precursor stage. While the transformation of non-hematopoietic cells into tumor cells starts during proliferation, hematopoietic cells become leukemic at one of the interim stages in differentiation, and differentiation does not continue beyond that point. Proliferation is switched to differentiation and back according to a trigger principle, again involving ROS and RNS. When the leukemogenic ΔL(PO – AO) imbalance decreases in an under-differentiated leukemia cell to the differentiation level ΔD(PO – AO), the cell may continue to differentiate to the terminal stage. Conclusion: The argument described in this article is used to explain the causes of congenital and children's leukemia, and the induction of leukemia by certain agents (vitamin K3, benzene, etc.). Specific research is required to validate the proposals made in this article. This will require accurate and accessible methods for measuring and assessing oxidative stress in different types of cells in general, and in hematopoietic cells in particular, in their different functional states.

Analysis of novel geometry-independent method for dialysis access pressure-flow monitoring

2008-11-05

Background: End-stage renal disease (ESRD) confers a large health-care burden for the United States, and the morbidity associated with vascular access failure has stimulated research into detection of vascular access stenosis and low flow prior to thrombosis. We present data investigating the possibility of using differential pressure (ΔP) monitoring to estimate access flow (Q) for dialysis access monitoring, with the goal of utilizing micro-electro-mechanical systems (MEMS) pressure sensors integrated within the shaft of dialysis needles. Methods: A model of the arteriovenous graft fluid circuit was used to study the relationship between Q and the ΔP between two dialysis needles placed 2.5–20.0 cm apart. Tubing was varied to simulate grafts with inner diameters of 4.76–7.95 mm. Data were compared with values from two steady-flow models. These results, and those from computational fluid dynamics (CFD) modeling of ΔP as a function of needle position, were used to devise and test a method of estimating Q using ΔP and variable dialysis pump speeds (variable flow) that diminishes dependence on geometric factors and fluid characteristics. Results: In the fluid circuit model, ΔP increased with increasing volume flow rate and with increasing needle-separation distance. A nonlinear model closely predicts this ΔP-Q relationship (R2 > 0.98) for all graft diameters and needle-separation distances tested. CFD modeling suggested turbulent needle effects are greatest within 1 cm of the needle tip. Utilizing linear, quadratic and combined variable flow algorithms, dialysis access flow was estimated using geometry-independent models and an experimental dialysis system with the pressure sensors separated from the dialysis needle tip by distances ranging from 1 to 5 cm. Real-time ΔP waveform data were also observed during the mock dialysis treatment, which may be useful in detecting low or reversed flow within the access. Conclusion: With further experimentation and needle design, this geometry-independent approach may prove to be a useful access flow monitoring method.

Feature context-dependency and complexity-reduction in probability landscapes for integrative genomics

Annick Lesne and Arndt Benecke — 2008-09-10

Background: The question of how to integrate heterogeneous sources of biological information into a coherent framework that allows the gene regulatory code in eukaryotes to be systematically investigated is one of the major challenges faced by systems biology. Probability landscapes, which include as reference set the probabilistic representation of the genomic sequence, have been proposed as a possible approach to the systematic discovery and analysis of correlations amongst initially heterogeneous and un-relatable descriptions and genome-wide measurements. Much of the available experimental sequence and genome activity information is de facto, but not necessarily obviously, context dependent. Furthermore, the context dependency of the relevant information is itself dependent on the biological question addressed. It is hence necessary to develop a systematic way of discovering the context-dependency of functional genomics information in a flexible, question-dependent manner. Results: We demonstrate here how feature context-dependency can be systematically investigated using probability landscapes. Furthermore, we show how different feature probability profiles can be conditionally collapsed to reduce the computational and formal, mathematical complexity of probability landscapes. Interestingly, the possibility of complexity reduction can be linked directly to the analysis of context-dependency. Conclusion: These two advances in our understanding of the properties of probability landscapes not only simplify subsequent cross-correlation analysis in hypothesis-driven model building and testing, but also provide additional insights into the biological gene regulatory problems studied. Furthermore, insights into the nature of individual features and a classification of features according to their minimal context-dependency are achieved. The formal structure proposed contributes to a concrete and tangible basis for attempting to formulate novel mathematical structures for describing gene regulation in eukaryotes on a genome-wide scale.

Extracting key information from historical data to quantify the transmission dynamics of smallpox

Hiroshi Nishiura, Stefan O Brockmann and Martin Eichner — 2008-08-20

Background: Quantification of the transmission dynamics of smallpox is crucial for optimizing intervention strategies in the event of a bioterrorist attack. This article reviews basic methods and findings in mathematical and statistical studies of smallpox which estimate key transmission parameters from historical data.Main findingsFirst, critically important aspects in extracting key information from historical data are briefly summarized. We mention different sources of heterogeneity and potential pitfalls in utilizing historical records. Second, we discuss how smallpox spreads in the absence of interventions and how the optimal timing of quarantine and isolation measures can be determined. Case studies demonstrate the following. (1) The upper confidence limit of the 99th percentile of the incubation period is 22.2 days, suggesting that quarantine should last 23 days. (2) The highest frequency (61.8%) of secondary transmissions occurs 3–5 days after onset of fever so that infected individuals should be isolated before the appearance of rash. (3) The U-shaped age-specific case fatality implies a vulnerability of infants and elderly among non-immune individuals. Estimates of the transmission potential are subsequently reviewed, followed by an assessment of vaccination effects and of the expected effectiveness of interventions. Conclusion: Current debates on bio-terrorism preparedness indicate that public health decision making must account for the complex interplay and balance between vaccination strategies and other public health measures (e.g. case isolation and contact tracing) taking into account the frequency of adverse events to vaccination. In this review, we summarize what has already been clarified and point out needs to analyze previous smallpox outbreaks systematically.

Utility of a single adjusting compartment: a novel methodology for whole body physiologically-based pharmacokinetic modelling

Hirotaka Ando, Shigeru Izawa, Wataru Hori and Ippei Nakagawa — 2008-08-08

Background: There are various methods for predicting human pharmacokinetics. Among these, a whole body physiologically-based pharmacokinetic (WBPBPK) model is useful because it gives a mechanistic description. However, WBPBPK models cannot predict human pharmacokinetics with enough precision. This study was conducted to elucidate the primary reason for poor predictions by WBPBPK models, and to enable better predictions to be made without reliance on complex concepts. Methods: The primary reasons for poor predictions of human pharmacokinetics were investigated using a generic WBPBPK model that incorporated a single adjusting compartment (SAC), a virtual organ compartment with physiological parameters that can be adjusted arbitrarily. The blood flow rate, organ volume, and the steady state tissue-plasma partition coefficient of a SAC were calculated to fit simulated to observed pharmacokinetics in the rat. The adjusted SAC parameters were fixed and scaled up to the human using a newly developed equation. Using the scaled-up SAC parameters, human pharmacokinetics were simulated and each pharmacokinetic parameter was calculated. These simulated parameters were compared to the observed data. Simulations were performed to confirm the relationship between the precision of prediction and the number of tissue compartments, including a SAC. Results: Increasing the number of tissue compartments led to an improvement of the average-fold error (AFE) of total body clearances (CLtot) and half-lives (T1/2) calculated from the simulated human blood concentrations of 14 drugs. The presence of a SAC also improved the AFE values of a ten-organ model from 6.74 to 1.56 in CLtot, and from 4.74 to 1.48 in T1/2. Moreover, the within-2-fold errors were improved in all models; incorporating a SAC gave results from 0 to 79% in CLtot, and from 14 to 93% in T1/2 of the ten-organ model. Conclusion: By using a SAC in this study, we were able to show that poor prediction resulted mainly from such physiological factors as organ blood flow rate and organ volume, which were not satisfactorily accounted for in previous WBPBPK models. The SAC also improved precision in the prediction of human pharmacokinetics. This finding showed that the methodology of our study may be useful for functionally reinforcing a WBPBPK model.

Identification of restriction endonuclease with potential ability to cleave the HSV-2 genome: Inherent potential for biosynthetic versus live recombinant microbicides

Misaki Wayengera, Henry Kajumbula and Wilson Byarugaba — 2008-08-07

Background: Herpes Simplex virus types 1 and 2 are enveloped viruses with a linear dsDNA genome of ~120–200 kb. Genital infection with HSV-2 has been denoted as a major risk factor for acquisition and transmission of HIV-1. Developing biomedical strategies for HSV-2 prevention is thus a central strategy in reducing global HIV-1 prevalence. This paper details the protocol for the isolation of restriction endunucleases (REases) with potent activity against the HSV-2 genome and models two biomedical interventions for preventing HSV-2.Methods and ResultsUsing the whole genome of HSV-2, 289 REases and the bioinformatics software Webcutter2; we searched for potential recognition sites by way of genome wide palindromics. REase application in HSV-2 biomedical therapy was modeled concomitantly. Of the 289 enzymes analyzed; 77(26.6%) had potential to cleave the HSV-2 genome in > 100 but < 400 sites; 69(23.9%) in > 400 but < 700 sites; and the 9(3.1%) enzymes: BmyI, Bsp1286I, Bst2UI, BstNI, BstOI, EcoRII, HgaI, MvaI, and SduI cleaved in more than 700 sites. But for the 4: PacI, PmeI, SmiI, SwaI that had no sign of activity on HSV-2 genomic DNA, all 130(45%) other enzymes cleaved < 100 times. In silico palindromics has a PPV of 99.5% for in situ REase activity (2) Two models detailing how the REase EcoRII may be applied in developing interventions against HSV-2 are presented: a nanoparticle for microbicide development and a "recombinant lactobacillus" expressing cell wall anchored receptor (truncated nectin-1) for HSV-2 plus EcoRII. Conclusion: Viral genome slicing by way of these bacterially- derived R-M enzymatic peptides may have therapeutic potential in HSV-2 infection; a cofactor for HIV-1 acquisition and transmission.

The hyperbolic effect of density and strength of inter beta-cell coupling on islet bursting: a theoretical investigation

Aparna Nittala and Xujing Wang — 2008-08-03

Background: Insulin, the principal regulating hormone of blood glucose, is released through the bursting of the pancreatic islets. Increasing evidence indicates the importance of islet morphostructure in its function, and the need of a quantitative investigation. Recently we have studied this problem from the perspective of islet bursting of insulin, utilizing a new 3D hexagonal closest packing (HCP) model of islet structure that we have developed. Quantitative non-linear dependence of islet function on its structure was found. In this study, we further investigate two key structural measures: the number of neighboring cells that each β-cell is coupled to, nc, and the coupling strength, gc. Results: β-cell clusters of different sizes with number of β-cells nβ ranging from 1–343, nc from 0–12, and gc from 0–1000 pS, were simulated. Three functional measures of islet bursting characteristics – fraction of bursting β-cells fb, synchronization index λ, and bursting period Tb, were quantified. The results revealed a hyperbolic dependence on the combined effect of nc and gc. From this we propose to define a dimensionless cluster coupling index or CCI, as a composite measure for islet morphostructural integrity. We show that the robustness of islet oscillatory bursting depends on CCI, with all three functional measures fb, λ and Tb increasing monotonically with CCI when it is small, and plateau around CCI = 1. Conclusion: CCI is a good islet function predictor. It has the potential of linking islet structure and function, and providing insight to identify therapeutic targets for the preservation and restoration of islet β-cell mass and function.