Theoretical Biology and Medical Modelling最新文献

{"title":"Site-specific dose-response relationships for cancer induction from the combined Japanese A-bomb and Hodgkin cohorts for doses relevant to radiotherapy.","authors":"Uwe Schneider,&nbsp;Marcin Sumila,&nbsp;Judith Robotka","doi":"10.1186/1742-4682-8-27","DOIUrl":"https://doi.org/10.1186/1742-4682-8-27","url":null,"abstract":"<p><strong>Background and purpose: </strong>Most information on the dose-response of radiation-induced cancer is derived from data on the A-bomb survivors. Since, for radiation protection purposes, the dose span of main interest is between zero and one Gy, the analysis of the A-bomb survivors is usually focused on this range. However, estimates of cancer risk for doses larger than one Gy are becoming more important for radiotherapy patients. Therefore in this work, emphasis is placed on doses relevant for radiotherapy with respect to radiation induced solid cancer.</p><p><strong>Materials and methods: </strong>For various organs and tissues the analysis of cancer induction was extended by an attempted combination of the linear-no-threshold model from the A-bomb survivors in the low dose range and the cancer risk data of patients receiving radiotherapy for Hodgkin's disease in the high dose range. The data were fitted using organ equivalent dose (OED) calculated for a group of different dose-response models including a linear model, a model including fractionation, a bell-shaped model and a plateau-dose-response relationship.</p><p><strong>Results: </strong>The quality of the applied fits shows that the linear model fits best colon, cervix and skin. All other organs are best fitted by the model including fractionation indicating that the repopulation/repair ability of tissue is neither 0 nor 100% but somewhere in between. Bone and soft tissue sarcoma were fitted well by all the models. In the low dose range beyond 1 Gy sarcoma risk is negligible. For increasing dose, sarcoma risk increases rapidly and reaches a plateau at around 30 Gy.</p><p><strong>Conclusions: </strong>In this work OED for various organs was calculated for a linear, a bell-shaped, a plateau and a mixture between a bell-shaped and plateau dose-response relationship for typical treatment plans of Hodgkin's disease patients. The model parameters (α and R) were obtained by a fit of the dose-response relationships to these OED data and to the A-bomb survivors. For any three-dimensional inhomogenous dose distribution, cancer risk can be compared by computing OED using the coefficients obtained in this work.</p>","PeriodicalId":51195,"journal":{"name":"Theoretical Biology and Medical Modelling","volume":" ","pages":"27"},"PeriodicalIF":0.0,"publicationDate":"2011-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/1742-4682-8-27","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"30033543","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A biochemical hypothesis on the formation of fingerprints using a turing patterns approach.","authors":"Diego A Garzón-Alvarado,&nbsp;Angelica M Ramírez Martinez","doi":"10.1186/1742-4682-8-24","DOIUrl":"https://doi.org/10.1186/1742-4682-8-24","url":null,"abstract":"<p><strong>Background: </strong>Fingerprints represent a particular characteristic for each individual. Characteristic patterns are also formed on the palms of the hands and soles of the feet. Their origin and development is still unknown but it is believed to have a strong genetic component, although it is not the only thing determining its formation. Each fingerprint is a papillary drawing composed by papillae and rete ridges (crests). This paper proposes a phenomenological model describing fingerprint pattern formation using reaction diffusion equations with Turing space parameters.</p><p><strong>Results: </strong>Several numerical examples were solved regarding simplified finger geometries to study pattern formation. The finite element method was used for numerical solution, in conjunction with the Newton-Raphson method to approximate nonlinear partial differential equations.</p><p><strong>Conclusions: </strong>The numerical examples showed that the model could represent the formation of different types of fingerprint characteristics in each individual.</p>","PeriodicalId":51195,"journal":{"name":"Theoretical Biology and Medical Modelling","volume":" ","pages":"24"},"PeriodicalIF":0.0,"publicationDate":"2011-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/1742-4682-8-24","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"29969145","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A nucleotide binding rectification Brownian ratchet model for translocation of Y-family DNA polymerases.","authors":"Ping Xie","doi":"10.1186/1742-4682-8-22","DOIUrl":"https://doi.org/10.1186/1742-4682-8-22","url":null,"abstract":"<p><p>Y-family DNA polymerases are characterized by low-fidelity synthesis on undamaged DNA and ability to catalyze translesion synthesis over the damaged DNA. Their translocation along the DNA template is an important event during processive DNA synthesis. In this work we present a Brownian ratchet model for this translocation, where the directed translocation is rectified by the nucleotide binding to the polymerase. Using the model, different features of the available structures for Dpo4, Dbh and polymerase ι in binary and ternary forms can be easily explained. Other dynamic properties of the Y-family polymerases such as the fast translocation event upon dNTP binding for Dpo4 and the considerable variations of the processivity among the polymerases can also be well explained by using the model. In addition, some predicted results of the DNA synthesis rate versus the external force acting on Dpo4 and Dbh polymerases are presented. Moreover, we compare the effect of the external force on the DNA synthesis rate of the Y-family polymerase with that of the replicative DNA polymerase.</p>","PeriodicalId":51195,"journal":{"name":"Theoretical Biology and Medical Modelling","volume":" ","pages":"22"},"PeriodicalIF":0.0,"publicationDate":"2011-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/1742-4682-8-22","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"29959740","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Donnan effect on chloride ion distribution as a determinant of body fluid composition that allows action potentials to spread via fast sodium channels.","authors":"Sven Kurbel","doi":"10.1186/1742-4682-8-16","DOIUrl":"https://doi.org/10.1186/1742-4682-8-16","url":null,"abstract":"<p><p>Proteins in any solution with a pH value that differs from their isoelectric point exert both an electric Donnan effect (DE) and colloid osmotic pressure. While the former alters the distribution of ions, the latter forces water diffusion. In cells with highly Cl--permeable membranes, the resting potential is more dependent on the cytoplasmic pH value, which alters the Donnan effect of cell proteins, than on the current action of Na/K pumps. Any weak (positive or negative) electric disturbances of their resting potential are quickly corrected by chloride shifts.In many excitable cells, the spreading of action potentials is mediated through fast, voltage-gated sodium channels. Tissue cells share similar concentrations of cytoplasmic proteins and almost the same exposure to the interstitial fluid (IF) chloride concentration. The consequence is that similar intra- and extra-cellular chloride concentrations make these cells share the same Nernst value for Cl-.Further extrapolation indicates that cells with the same chloride Nernst value and high chloride permeability should have similar resting membrane potentials, more negative than -80 mV. Fast sodium channels require potassium levels >20 times higher inside the cell than around it, while the concentration of Cl- ions needs to be >20 times higher outside the cell.When osmotic forces, electroneutrality and other ions are all taken into account, the overall osmolarity needs to be near 280 to 300 mosm/L to reach the required resting potential in excitable cells. High plasma protein concentrations keep the IF chloride concentration stable, which is important in keeping the resting membrane potential similar in all chloride-permeable cells. Probable consequences of this concept for neuron excitability, erythrocyte membrane permeability and several features of circulation design are briefly discussed.</p>","PeriodicalId":51195,"journal":{"name":"Theoretical Biology and Medical Modelling","volume":" ","pages":"16"},"PeriodicalIF":0.0,"publicationDate":"2011-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/1742-4682-8-16","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"30201732","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Can molecular cell biology explain chromosome motions?","authors":"Daniel H Shain,&nbsp;L John Gagliardi","doi":"10.1186/1742-4682-8-15","DOIUrl":"https://doi.org/10.1186/1742-4682-8-15","url":null,"abstract":"<p><strong>Background: </strong>Mitotic chromosome motions have recently been correlated with electrostatic forces, but a lingering \"molecular cell biology\" paradigm persists, proposing binding and release proteins or molecular geometries for force generation.</p><p><strong>Results: </strong>Pole-facing kinetochore plates manifest positive charges and interact with negatively charged microtubule ends providing the motive force for poleward chromosome motions by classical electrostatics. This conceptual scheme explains dynamic tracking/coupling of kinetochores to microtubules and the simultaneous depolymerization of kinetochore microtubules as poleward force is generated.</p><p><strong>Conclusion: </strong>We question here why cells would prefer complex molecular mechanisms to move chromosomes when direct electrostatic interactions between known bound charge distributions can accomplish the same task much more simply.</p>","PeriodicalId":51195,"journal":{"name":"Theoretical Biology and Medical Modelling","volume":" ","pages":"15"},"PeriodicalIF":0.0,"publicationDate":"2011-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/1742-4682-8-15","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"30199434","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Modeling left ventricular diastolic dysfunction: classification and key indicators.","authors":"Chuan Luo,&nbsp;Deepa Ramachandran,&nbsp;David L Ware,&nbsp;Tony S Ma,&nbsp;John W Clark","doi":"10.1186/1742-4682-8-14","DOIUrl":"https://doi.org/10.1186/1742-4682-8-14","url":null,"abstract":"<p><strong>Background: </strong>Mathematical modeling can be employed to overcome the practical difficulty of isolating the mechanisms responsible for clinical heart failure in the setting of normal left ventricular ejection fraction (HFNEF). In a human cardiovascular respiratory system (H-CRS) model we introduce three cases of left ventricular diastolic dysfunction (LVDD): (1) impaired left ventricular active relaxation (IR-type); (2) increased passive stiffness (restrictive or R-type); and (3) the combination of both (pseudo-normal or PN-type), to produce HFNEF. The effects of increasing systolic contractility are also considered. Model results showing ensuing heart failure and mechanisms involved are reported.</p><p><strong>Methods: </strong>We employ our previously described H-CRS model with modified pulmonary compliances to better mimic normal pulmonary blood distribution. IR-type is modeled by changing the activation function of the left ventricle (LV), and R-type by increasing diastolic stiffness of the LV wall and septum. A 5th-order Cash-Karp Runge-Kutta numerical integration method solves the model differential equations.</p><p><strong>Results: </strong>IR-type and R-type decrease LV stroke volume, cardiac output, ejection fraction (EF), and mean systemic arterial pressure. Heart rate, pulmonary pressures, pulmonary volumes, and pulmonary and systemic arterial-venous O2 and CO2 differences increase. IR-type decreases, but R-type increases the mitral E/A ratio. PN-type produces the well-described, pseudo-normal mitral inflow pattern. All three types of LVDD reduce right ventricular (RV) and LV EF, but the latter remains normal or near normal. Simulations show reduced EF is partly restored by an accompanying increase in systolic stiffness, a compensatory mechanism that may lead clinicians to miss the presence of HF if they only consider LVEF and other indices of LV function. Simulations using the H-CRS model indicate that changes in RV function might well be diagnostic. This study also highlights the importance of septal mechanics in LVDD.</p><p><strong>Conclusion: </strong>The model demonstrates that abnormal LV diastolic performance alone can result in decreased LV and RV systolic performance, not previously appreciated, and contribute to the clinical syndrome of HF. Furthermore, alterations of RV diastolic performance are present and may be a hallmark of LV diastolic parameter changes that can be used for better clinical recognition of LV diastolic heart disease.</p>","PeriodicalId":51195,"journal":{"name":"Theoretical Biology and Medical Modelling","volume":" ","pages":"14"},"PeriodicalIF":0.0,"publicationDate":"2011-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/1742-4682-8-14","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"30171128","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A simple intravenous glucose tolerance test for assessment of insulin sensitivity.","authors":"Robert G Hahn,&nbsp;Stefan Ljunggren,&nbsp;Filip Larsen,&nbsp;Thomas Nyström","doi":"10.1186/1742-4682-8-12","DOIUrl":"https://doi.org/10.1186/1742-4682-8-12","url":null,"abstract":"<p><strong>Background: </strong>The aim of the study was to find a simple intravenous glucose tolerance test (IVGTT) that can be used to estimate insulin sensitivity.</p><p><strong>Methods: </strong>In 20 healthy volunteers aged between 18 and 51 years (mean, 28) comparisons were made between kinetic parameters derived from a 12-sample, 75-min IVGTT and the M(bw) (glucose uptake) obtained during a hyperinsulinemic euglycemic glucose clamp. Plasma glucose was used to calculate the volume of distribution (V(d)) and the clearance (CL) of the injected glucose bolus. The plasma insulin response was quantified by the area under the curve (AUC(ins)). Uptake of glucose during the clamp was corrected for body weight (M(bw)).</p><p><strong>Results: </strong>There was a 7-fold variation in M(bw). Algorithms based on the slope of the glucose-elimination curve (CL/V(d)) in combination with AUC(ins) obtained during the IVGTT showed statistically significant correlations with M(bw), the linearity being r(2) = 0.63-0.83. The best algorithms were associated with a 25-75th prediction error ranging from -10% to +10%. Sampling could be shortened to 30-40 min without loss of linearity or precision.</p><p><strong>Conclusion: </strong>Simple measures of glucose and insulin kinetics during an IVGTT can predict between 2/3 and 4/5 of the insulin sensitivity.</p>","PeriodicalId":51195,"journal":{"name":"Theoretical Biology and Medical Modelling","volume":" ","pages":"12"},"PeriodicalIF":0.0,"publicationDate":"2011-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/1742-4682-8-12","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"29852044","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Insights gained from the reverse engineering of gene networks in keloid fibroblasts.","authors":"Brandon N S Ooi,&nbsp;Toan Thang Phan","doi":"10.1186/1742-4682-8-13","DOIUrl":"https://doi.org/10.1186/1742-4682-8-13","url":null,"abstract":"<p><strong>Background: </strong>Keloids are protrusive claw-like scars that have a propensity to recur even after surgery, and its molecular etiology remains elusive. The goal of reverse engineering is to infer gene networks from observational data, thus providing insight into the inner workings of a cell. However, most attempts at modeling biological networks have been done using simulated data. This study aims to highlight some of the issues involved in working with experimental data, and at the same time gain some insights into the transcriptional regulatory mechanism present in keloid fibroblasts.</p><p><strong>Methods: </strong>Microarray data from our previous study was combined with microarray data obtained from the literature as well as new microarray data generated by our group. For the physical approach, we used the fREDUCE algorithm for correlating expression values to binding motifs. For the influence approach, we compared the Bayesian algorithm BANJO with the information theoretic method ARACNE in terms of performance in recovering known influence networks obtained from the KEGG database. In addition, we also compared the performance of different normalization methods as well as different types of gene networks.</p><p><strong>Results: </strong>Using the physical approach, we found consensus sequences that were active in the keloid condition, as well as some sequences that were responsive to steroids, a commonly used treatment for keloids. From the influence approach, we found that BANJO was better at recovering the gene networks compared to ARACNE and that transcriptional networks were better suited for network recovery compared to cytokine-receptor interaction networks and intracellular signaling networks. We also found that the NFKB transcriptional network that was inferred from normal fibroblast data was more accurate compared to that inferred from keloid data, suggesting a more robust network in the keloid condition.</p><p><strong>Conclusions: </strong>Consensus sequences that were found from this study are possible transcription factor binding sites and could be explored for developing future keloid treatments or for improving the efficacy of current steroid treatments. We also found that the combination of the Bayesian algorithm, RMA normalization and transcriptional networks gave the best reconstruction results and this could serve as a guide for future influence approaches dealing with experimental data.</p>","PeriodicalId":51195,"journal":{"name":"Theoretical Biology and Medical Modelling","volume":" ","pages":"13"},"PeriodicalIF":0.0,"publicationDate":"2011-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/1742-4682-8-13","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"29852031","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Improving the prediction of yeast protein function using weighted protein-protein interactions.","authors":"Khaled S Ahmed,&nbsp;Nahed H Saloma,&nbsp;Yasser M Kadah","doi":"10.1186/1742-4682-8-11","DOIUrl":"https://doi.org/10.1186/1742-4682-8-11","url":null,"abstract":"<p><strong>Background: </strong>Bioinformatics can be used to predict protein function, leading to an understanding of cellular activities, and equally-weighted protein-protein interactions (PPI) are normally used to predict such protein functions. The present study provides a weighting strategy for PPI to improve the prediction of protein functions. The weights are dependent on the local and global network topologies and the number of experimental verification methods. The proposed methods were applied to the yeast proteome and integrated with the neighbour counting method to predict the functions of unknown proteins.</p><p><strong>Results: </strong>A new technique to weight interactions in the yeast proteome is presented. The weights are related to the network topology (local and global) and the number of identified methods, and the results revealed improvement in the sensitivity and specificity of prediction in terms of cellular role and cellular locations. This method (new weights) was compared with a method that utilises interactions with the same weight and it was shown to be superior.</p><p><strong>Conclusions: </strong>A new method for weighting the interactions in protein-protein interaction networks is presented. Experimental results concerning yeast proteins demonstrated that weighting interactions integrated with the neighbor counting method improved the sensitivity and specificity of prediction in terms of two functional categories: cellular role and cell locations.</p>","PeriodicalId":51195,"journal":{"name":"Theoretical Biology and Medical Modelling","volume":" ","pages":"11"},"PeriodicalIF":0.0,"publicationDate":"2011-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/1742-4682-8-11","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"29843366","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Safe uses of Hill's model: an exact comparison with the Adair-Klotz model.","authors":"Zoran Konkoli","doi":"10.1186/1742-4682-8-10","DOIUrl":"https://doi.org/10.1186/1742-4682-8-10","url":null,"abstract":"<p><strong>Background: </strong>The Hill function and the related Hill model are used frequently to study processes in the living cell. There are very few studies investigating the situations in which the model can be safely used. For example, it has been shown, at the mean field level, that the dose response curve obtained from a Hill model agrees well with the dose response curves obtained from a more complicated Adair-Klotz model, provided that the parameters of the Adair-Klotz model describe strongly cooperative binding. However, it has not been established whether such findings can be extended to other properties and non-mean field (stochastic) versions of the same, or other, models.</p><p><strong>Results: </strong>In this work a rather generic quantitative framework for approaching such a problem is suggested. The main idea is to focus on comparing the particle number distribution functions for Hill's and Adair-Klotz's models instead of investigating a particular property (e.g. the dose response curve). The approach is valid for any model that can be mathematically related to the Hill model. The Adair-Klotz model is used to illustrate the technique. One main and two auxiliary similarity measures were introduced to compare the distributions in a quantitative way. Both time dependent and the equilibrium properties of the similarity measures were studied.</p><p><strong>Conclusions: </strong>A strongly cooperative Adair-Klotz model can be replaced by a suitable Hill model in such a way that any property computed from the two models, even the one describing stochastic features, is approximately the same. The quantitative analysis showed that boundaries of the regions in the parameter space where the models behave in the same way exhibit a rather rich structure.</p>","PeriodicalId":51195,"journal":{"name":"Theoretical Biology and Medical Modelling","volume":" ","pages":"10"},"PeriodicalIF":0.0,"publicationDate":"2011-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/1742-4682-8-10","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"29839756","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}