http://www.tbiomed.com The latest research articles published by Theoretical Biology and Medical Modelling 2009-07-03T00:00:00Z This is an RSS newsfeed from BioMed Central It is intended to be used with an RSS reader. For more information about RSS newsfeeds from BioMed Central, visit http://www.biomedcentral.com/info/about/rss/ Background: Rat models are frequently used to find genomic regions that contribute to complex diseases, so called quantitative trait loci (QTLs). In general, the genomic regions found to be associated with a quantitative trait are rather large, covering hundreds of genes. To help selecting appropriate candidate genes from QTLs associated with type 2 diabetes models in rat, we have developed a web tool called Candidate Gene Capture (CGC), specifically adopted for this disorder. Methods: CGC combines diabetes-related genomic regions in rat with rat/human homology data, textual descriptions of gene effects and an array of 789 keywords. Each keyword is assigned values that reflect its co-occurrence with 25 different reference terms describing sub-phenotypes of type 2 diabetes (for example "insulin resistance"). The genes are then ranked based on the occurrences of keywords in the describing texts. Results: CGC includes QTLs from type 2 diabetes models in rat. When comparing gene rankings from CGC based on one sub-phenotype, with manual gene ratings for four QTLs, very similar results were obtained. In total, 25 different sub-phenotypes are available as reference terms in the application and based on differences in gene ranking, they fall into separate clusters. Conclusions: The very good agreement between CGC gene rankings and manual ratings confirms that CGC is as a reliable tool for interpreting textual information. This, together with the possibility to select many different sub-phenotypes, makes CGC a versatile tool for finding candidate genes. CGC is publicly available at http://ratmap.org/CGC. http://www.tbiomed.com/content/6/1/12 Lars Andersson Greta Petersen Fredrik Stahl Theoretical Biology and Medical Modelling 2009, 6:12 2009-07-03T00:00:00Z doi:10.1186/1742-4682-6-12 Theoretical Biology and Medical Modelling 1742-4682 6 12 2009-07-03T00:00:00Z PDF Background: The spread of infectious disease is determined by biological factors, e.g. the duration of the infectious period, and social factors, e.g. the arrangement of potentially contagious contacts. Repetitiveness and clustering of contacts are known to be relevant factors influencing the transmission of droplet or contact transmitted diseases. However, we do not yet completely know under what conditions repetitiveness and clustering should be included for realistically modelling disease spread. Methods: We compare two different types of individual-based models: One assumes random mixing without repetition of contacts, whereas the other assumes that the same contacts repeat day-by-day. The latter exists in two variants, with and without clustering. We systematically test and compare how the total size of an outbreak differs between these model types depending on the key parameters transmission probability, number of contacts per day, duration of the infectious period, different levels of clustering and varying proportions of repetitive contacts. Results: The simulation runs under different parameter constellations provide the following results: The difference between both model types is highest for low numbers of contacts per day and low transmission probabilities. The number of contacts and the transmission probability have a higher influence on this difference than the duration of the infectious period. Even when only minor parts of the daily contacts are repetitive and clustered can there be relevant differences compared to a purely random mixing model. Conclusions: We show that random mixing models provide acceptable estimates of the total outbreak size if the number of contacts per day is high or if the per-contact transmission probability is high, as seen in typical childhood diseases such as measles. In the case of very short infectious periods, for instance, as in Norovirus, models assuming repeating contacts will also behave similarly as random mixing models. If the number of daily contacts or the transmission probability is low, as assumed for MRSA or Ebola, particular consideration should be given to the actual structure of potentially contagious contacts when designing the model. http://www.tbiomed.com/content/6/1/11 Timo Smieszek Lena Fiebig Roland Scholz Theoretical Biology and Medical Modelling 2009, 6:11 2009-06-29T00:00:00Z doi:10.1186/1742-4682-6-11 Theoretical Biology and Medical Modelling 1742-4682 6 11 2009-06-29T00:00:00Z PDF Background: Pharmacokinetic and pharmacodynamic (PK/PD) indices are increasingly being used in the microbiological field to assess efficacy of a dosing regimen. Contrary to methods using MIC, PK/PD-based methods reflect the in vivo conditions and are more predictive of efficacy. Unfortunately, these methods are based on the use of one PK-derived value such as AUC or Cmax and may thus lead to biased efficiency information when a large variability exists. The aim of the present work was to evaluate the efficacy of a treatment by adjusting classical breakpoints estimation methods to the situation of variable PK profiles.Methods and results:We propose here a logical generalisation of the usual AUC methods by introducing the concept of "efficiency" for a PK profile which involves the efficacy function as a weight. We formulated these methods for both classes of concentration- and time-dependent antibiotics. Using drug models and in silico approaches, we try to give a theoretical basis to characterize the efficiency of a PK profile under in vivo conditions. We also used the particular case of variable drug intake to assess the effect of generated variable PK profiles and to analyse the implications for breakpoints estimation. Conclusion: Compared to traditional methods, our weighted AUC approach gives a more powerful PK/PD link and revealed, through some examples, interesting issues about uniqueness of therapeutic outcome indices and antibiotic resistance problems. http://www.tbiomed.com/content/6/1/10 Goue Denis Gohore Bi Jun Li Fahima Nekka Theoretical Biology and Medical Modelling 2009, 6:10 2009-06-26T00:00:00Z doi:10.1186/1742-4682-6-10 Theoretical Biology and Medical Modelling 1742-4682 6 10 2009-06-26T00:00:00Z PDF Background: Usutu virus belongs to the Flaviviridae viral family and constitutes an important pathogen. The viral helicase is an ideal target for inhibitor design, since this enzyme is essential for the survival, proliferation and transmission of the virus. Results: Towards a drug-design approach, the 3D model of the Usutu virus helicase structure has been designed, using conventional homology modelling techniques and the known 3D-structure of the Murray Valley Encephalitis virus helicase, of the same viral family, as template. The model was then subjected to extended molecular dynamics simulations in a periodic box, filled with explicit water molecules for 10 nanoseconds. The reliability of the model was confirmed by obtaining acceptable scores from a variety of in silico scoring tools, including Procheck and Verify3D.Conlcusions:The 3D model of the Usutu virus helicase exhibits in silico all known structural characteristics of the Flaviviridae viral family helicase enzymes and could provide the platform for further de novo structure-based design of novel anti-Usutu agents. http://www.tbiomed.com/content/6/1/9 Dimitrios Vlachakis Theoretical Biology and Medical Modelling 2009, 6:9 2009-06-25T00:00:00Z doi:10.1186/1742-4682-6-9 Theoretical Biology and Medical Modelling 1742-4682 6 9 2009-06-25T00:00:00Z PDF Background: When grown in three-dimensional (3D) cultures, epithelial cells typically form cystic organoids that recapitulate cardinal features of in vivo epithelial structures. Characterizing essential cell actions and their roles, which constitute the system's dynamic phenotype, is critical to gaining deeper insight into the cystogenesis phenomena. Methods: Starting with an earlier in silico epithelial analogue (ISEA1) that validated for several Madin-Darby canine kidney (MDCK) epithelial cell culture attributes, we built a revised analogue (ISEA2) to increase overlap between analogue and cell culture traits. Both analogues used agent-based, discrete event methods. A set of axioms determined ISEA behaviors; together, they specified the analogue's operating principles. A new experimentation framework enabled tracking relative axiom use and roles during simulated cystogenesis along with establishment of the consequences of their disruption. Results: ISEA2 consistently produced convex cystic structures in a simulated embedded culture. Axiom use measures provided detailed descriptions of the analogue's dynamic phenotype. Dysregulating key cell death and division axioms led to disorganized structures. Adhering to either axiom less than 80% of the time caused ISEA1 to form easily identified morphological changes. ISEA2 was more robust to identical dysregulation. Both dysregulated analogues exhibited characteristics that resembled those associated with an in vitro model of early glandular epithelial cancer. Conclusion: We documented the causal chains of events, and their relative roles, responsible for simulated cystogenesis. The results stand as an early hypothesis–a theory–of how individual MDCK cell actions give rise to consistently roundish, cystic organoids. http://www.tbiomed.com/content/6/1/8 Sean Kim Sunwoo Park Keith Mostov Jayanta Debnath C Anthony Hunt Theoretical Biology and Medical Modelling 2009, 6:8 2009-05-28T00:00:00Z doi:10.1186/1742-4682-6-8 Theoretical Biology and Medical Modelling 1742-4682 6 8 2009-05-28T00:00:00Z XML Background: So far, none of the existing methods on Murray's law deal with the non-Newtonian behavior of blood flow although the non-Newtonian approach for blood flow modelling looks more accurate.ModelingIn the present paper, Murray's law which is applicable to an arterial bifurcation, is generalized to a non-Newtonian blood flow model (power-law model). When the vessel size reaches the capillary limitation, blood can be modeled using a non-Newtonian constitutive equation. It is assumed two different constraints in addition to the pumping power: the volume constraint or the surface constraint (related to the internal surface of the vessel). For a seek of generality, the relationships are given for an arbitrary number of daughter vessels. It is shown that for a cost function including the volume constraint, classical Murray's law remains valid (i.e. ΣRc = cste with c = 3 is verified and is independent of n, the dimensionless index in the viscosity equation; R being the radius of the vessel). On the contrary, for a cost function including the surface constraint, different values of c may be calculated depending on the value of n. Results: We find that c varies for blood from 2.42 to 3 depending on the constraint and the fluid properties. For the Newtonian model, the surface constraint leads to c = 2.5. The cost function (based on the surface constraint) can be related to entropy generation, by dividing it by the temperature. Conclusion: It is demonstrated that the entropy generated in all the daughter vessels is greater than the entropy generated in the parent vessel. Furthermore, it is shown that the difference of entropy generation between the parent and daughter vessels is smaller for a non-Newtonian fluid than for a Newtonian fluid. http://www.tbiomed.com/content/6/1/7 Remi Revellin Francois Rousset David Baud Jocelyn Bonjour Theoretical Biology and Medical Modelling 2009, 6:7 2009-05-15T00:00:00Z doi:10.1186/1742-4682-6-7 Theoretical Biology and Medical Modelling 1742-4682 6 7 2009-05-15T00:00:00Z XML The present work is intended to demonstrate that most of the paradoxes, controversies, and contradictions accumulated in molecular and cell biology over many years of research can be readily resolved if the cell and living systems in general are re-interpreted within an alternative paradigm of biological organization that is based on the concepts and empirical laws of nonequilibrium thermodynamics. In addition to resolving paradoxes and controversies, the proposed re-conceptualization of the cell and biological organization reveals hitherto unappreciated connections among many seemingly disparate phenomena and observations, and provides new and powerful insights into the universal principles governing the emergence and organizational dynamics of living systems on each and every scale of biological organizational hierarchy, from proteins and cells to economies and ecologies. http://www.tbiomed.com/content/6/1/6 Alexei Kurakin Theoretical Biology and Medical Modelling 2009, 6:6 2009-05-05T00:00:00Z doi:10.1186/1742-4682-6-6 Theoretical Biology and Medical Modelling 1742-4682 6 6 2009-05-05T00:00:00Z XML Background: The function and viability of cultured, transplanted, or encapsulated pancreatic islets is often limited by hypoxia because these islets have lost their vasculature during the isolation process and have to rely on gradient-driven passive diffusion, which cannot provide adequate oxygen transport. Pancreatic islets (islets of Langerhans) are particularly susceptible due to their relatively large size, large metabolic demand, and increased sensitivity to hypoxia. Here, finite element method (FEM) based multiphysics models are explored to describe oxygen transport and cell viability in avascular islets both in static and in moving culture media. Methods: Two- and three-dimensional models were built in COMSOL Multiphysics using the convection and diffusion as well as the incompressible Navier-Stokes fluid dynamics application modes. Oxygen consumption was assumed to follow Michaelis-Menten-type kinetics and to cease when local concentrations fell below a critical threshold; in a dynamic model, it was also allowed to increase with increasing glucose concentration. Results: Partial differential equation (PDE) based exploratory cellular-level oxygen consumption and cell viability models incorporating physiologically realistic assumptions have been implemented for fully scaled cell culture geometries with 100, 150, and 200 μm diameter islets as representative. Calculated oxygen concentrations and intra-islet regions likely to suffer from hypoxia-related necrosis obtained for traditional flask-type cultures, oxygen-permeable silicone-rubber membrane bottom cultures, and perifusion chambers with flowing media and varying incoming glucose levels are presented in detail illustrated with corresponding colour-coded figures and animations. Conclusion: Results of the computational models are, as a first estimate, in good quantitative agreement with existing experimental evidence, and they confirm that during culture, hypoxia is often a problem for non-vascularised islet and can lead to considerable cell death (necrosis), especially in the core region of larger islets. Such models are of considerable interest to improve the function and viability of cultured, transplanted, or encapsulated islets. The present implementation allows convenient extension to true multiphysics applications that solve coupled physics phenomena such as diffusion and consumption with convection due to flowing or moving media. http://www.tbiomed.com/content/6/1/5 Peter Buchwald Theoretical Biology and Medical Modelling 2009, 6:5 2009-04-16T00:00:00Z doi:10.1186/1742-4682-6-5 Theoretical Biology and Medical Modelling 1742-4682 6 5 2009-04-16T00:00:00Z XML Background: In vitro culture of pathogens on growth media forms a "pillar" for both infectious disease diagnosis and drug sensitivity profiling. Conventional cultures of Mycobacterium tuberculosis (M.tb) on Lowenstein Jensen (LJ) medium, however, take over two months to yield observable growth, thereby delaying diagnosis and appropriate intervention. Since DNA duplication during interphase precedes microbial division, "para-DNA synthesis assays" could be used to predict impending microbial growth. Mycobacterial thymidylate kinase (TMKmyc) is a phosphotransferase critical for the synthesis of the thymidine triphosphate precursor necessary for M.tb DNA synthesis. Assays based on high-affinity detection of secretory TMKmyc levels in culture using specific antibodies are considered. The aim of this study was to define algorithms for predicting positive TB cultures using antibody-based assays of TMKmyc levels in vitro.Methods and resultsSystems and chemical biology were used to derive parallel correlation of "M.tb growth curves" with "TMKmyc curves" theoretically in four different scenarios, showing that changes in TMKmyc levels in culture would in each case be predictive of M.tb growth through a simple quadratic curvature, |tmk| = at2+ bt + c, consistent with the "S" pattern of microbial growth curves. Two drug resistance profiling scenarios are offered: isoniazid (INH) resistance and sensitivity. In the INH resistance scenario, it is shown that despite the presence of optimal doses of INH in LJ to stop M.tb proliferation, bacilli grow and the resulting phenotypic growth changes in colonies/units are predictable through the TMKmyc assay. According to our current model, the areas under TMKmyc curves (AUC, calculated as the integral ∫(at2+ bt + c)dt or ~1/3 at3+ 1/2 bt2+ct) could directly reveal the extent of prevailing drug resistance and thereby aid decisions about the usefulness of a resisted drug in devising "salvage combinations" within resource-limited settings, where second line TB chemotherapy options are limited. Conclusion: TMKmyc assays may be useful for reducing the time-lines to positive identification of Mycobacterium tuberculosis (M.tb) cultures, thereby accelerating disease diagnosis and drug resistance profiling. Incorporating "chemiluminiscent or fluorescent" strategies may enable "photo-detection of TMKmyc changes" and hence automation of the entire assay. http://www.tbiomed.com/content/6/1/4 Misaki Wayengera Theoretical Biology and Medical Modelling 2009, 6:4 2009-03-18T00:00:00Z doi:10.1186/1742-4682-6-4 Theoretical Biology and Medical Modelling 1742-4682 6 4 2009-03-18T00:00:00Z XML Background: The details of interaction in a complex between potent antagonists such as long chain α-neurotoxins and α-conotoxins with nicotinic acetylcholine receptor (nAChR), and conformational changes induced by these antagonists, are not yet clear.ModelingIn order to uncover some of these critical structural features, we conducted a docking simulation and a molecular dynamics simulation (MD) of a model of the ligand binding domain of nAChR in complex with a long-chain α-neurotoxin and an α-conotoxin. Results: Our docking results confirm the claim that T.nAChR is in the basal or resting state, which favors binding to the alpha-neurotoxins. Moreover, more correct "hits" for the α/γ interface upon docking for conotoxin-nAChR confirm the preference of conotoxin GI for the α/γ interface. More importantly, upon binding of α-neurotoxin, ligand-bonded nAChR is less dynamic in certain domains than the apo form of the conotoxin-AChR complex. Some critical interactions in the binding site such as the salt bridge formed between K145/D200 in the neurotoxin-nAChR complex is further stabilized during the MD simulation, while it is obviously more labile in the apo form. Conclusion: These observations could support the claim that alpha neurotoxins stabilize the nAChR resting state. http://www.tbiomed.com/content/6/1/3 Adak Nasiripourdori Bijan Ranjbar Hossein Naderi-manesh Theoretical Biology and Medical Modelling 2009, 6:3 2009-02-11T00:00:00Z doi:10.1186/1742-4682-6-3 Theoretical Biology and Medical Modelling 1742-4682 6 3 2009-02-11T00:00:00Z XML