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Mathematical Biosciences & Engineering
2012 , Volume 9 , Issue 4
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2012, 9(4): 699-736
doi: 10.3934/mbe.2012.9.699
+[Abstract](2776)
+[PDF](814.2KB)
Abstract:
Some key features of a mathematical description of an immune response are an estimate of the number of responding cells and the manner in which those cells divide, differentiate, and die. The intracellular dye CFSE is a powerful experimental tool for the analysis of a population of dividing cells, and numerous mathematical treatments have been aimed at using CFSE data to describe an immune response [30,31,32,37,38,42,48,49]. Recently, partial differential equation structured population models, with measured CFSE fluorescence intensity as the structure variable, have been shown to accurately fit histogram data obtained from CFSE flow cytometry experiments [18,19,52,54]. In this report, the population of cells is mathematically organized into compartments, with all cells in a single compartment having undergone the same number of divisions. A system of structured partial differential equations is derived which can be fit directly to CFSE histogram data. From such a model, cell counts (in terms of the number of divisions undergone) can be directly computed and thus key biological parameters such as population doubling time and precursor viability can be determined. Mathematical aspects of this compartmental model are discussed, and the model is fit to a data set. As in [18,19], we find temporal and division dependence in the rates of proliferation and death to be essential features of a structured population model for CFSE data. Variability in cellular autofluorescence is found to play a significant role in the data, as well. Finally, the compartmental model is compared to previous work, and statistical aspects of the experimental data are discussed.
Some key features of a mathematical description of an immune response are an estimate of the number of responding cells and the manner in which those cells divide, differentiate, and die. The intracellular dye CFSE is a powerful experimental tool for the analysis of a population of dividing cells, and numerous mathematical treatments have been aimed at using CFSE data to describe an immune response [30,31,32,37,38,42,48,49]. Recently, partial differential equation structured population models, with measured CFSE fluorescence intensity as the structure variable, have been shown to accurately fit histogram data obtained from CFSE flow cytometry experiments [18,19,52,54]. In this report, the population of cells is mathematically organized into compartments, with all cells in a single compartment having undergone the same number of divisions. A system of structured partial differential equations is derived which can be fit directly to CFSE histogram data. From such a model, cell counts (in terms of the number of divisions undergone) can be directly computed and thus key biological parameters such as population doubling time and precursor viability can be determined. Mathematical aspects of this compartmental model are discussed, and the model is fit to a data set. As in [18,19], we find temporal and division dependence in the rates of proliferation and death to be essential features of a structured population model for CFSE data. Variability in cellular autofluorescence is found to play a significant role in the data, as well. Finally, the compartmental model is compared to previous work, and statistical aspects of the experimental data are discussed.
2012, 9(4): 737-765
doi: 10.3934/mbe.2012.9.737
+[Abstract](2412)
+[PDF](865.3KB)
Abstract:
In this paper a mathematical model of the population dynamics of a bacteriophage-sensitive and a bacteriophage-resistant bacteria in a chemostat where the resistant bacteria is an inferior competitor for nutrient is studied. The focus of the study is on persistence and extinction of bacterial strains and bacteriophage.
In this paper a mathematical model of the population dynamics of a bacteriophage-sensitive and a bacteriophage-resistant bacteria in a chemostat where the resistant bacteria is an inferior competitor for nutrient is studied. The focus of the study is on persistence and extinction of bacterial strains and bacteriophage.
2012, 9(4): 767-784
doi: 10.3934/mbe.2012.9.767
+[Abstract](1836)
+[PDF](447.8KB)
Abstract:
In this paper, a simple parasite-host model proposed by Ebert et al.(2000) is reconsidered. The basic epidemiological reproduction number of parasite infection ($R_0$) and the basic demographic reproduction number of infected hosts ($R_1$) are given. The global dynamics of the model is completely investigated, and the existence of heteroclinic and homoclinic orbits is theoretically proved, which implies that the outbreak of parasite infection may happen. The thresholds determining the host extinction in the presence of parasite infection and variation in the equilibrium level of the infected hosts with $R_0$ are found. The effects of $R_0$ and $R_1$ on dynamics of the model are considered and we show that the equilibrium level of the infected host may not be monotone with respect to $R_0$. In particular, it is found that full loss of fecundity of infected hosts may lead to appearance of the singular case.
In this paper, a simple parasite-host model proposed by Ebert et al.(2000) is reconsidered. The basic epidemiological reproduction number of parasite infection ($R_0$) and the basic demographic reproduction number of infected hosts ($R_1$) are given. The global dynamics of the model is completely investigated, and the existence of heteroclinic and homoclinic orbits is theoretically proved, which implies that the outbreak of parasite infection may happen. The thresholds determining the host extinction in the presence of parasite infection and variation in the equilibrium level of the infected hosts with $R_0$ are found. The effects of $R_0$ and $R_1$ on dynamics of the model are considered and we show that the equilibrium level of the infected host may not be monotone with respect to $R_0$. In particular, it is found that full loss of fecundity of infected hosts may lead to appearance of the singular case.
2012, 9(4): 785-807
doi: 10.3934/mbe.2012.9.785
+[Abstract](2731)
+[PDF](968.8KB)
Abstract:
A tuberculosis (TB) transmission model involving migrant workers is proposed and investigated. The basic reproduction number $\mathcal{R}_{0}$ is calculated, and is shown to be a threshold parameter for the disease to persist or become extinct in the population. The existence and global attractivity of an endemic equilibrium, if $\mathcal{R}_{0}>1$, is also established under some technical conditions. A case study, based on the TB epidemiological and other statistical data in China, indicates that the disease spread can be controlled if effective measures are taken to reduce the reactivation rate of exposed/latent migrant workers. Impact of the migration rate and direction, as well as the duration of home visit stay, on the control of disease spread is also examined numerically.
A tuberculosis (TB) transmission model involving migrant workers is proposed and investigated. The basic reproduction number $\mathcal{R}_{0}$ is calculated, and is shown to be a threshold parameter for the disease to persist or become extinct in the population. The existence and global attractivity of an endemic equilibrium, if $\mathcal{R}_{0}>1$, is also established under some technical conditions. A case study, based on the TB epidemiological and other statistical data in China, indicates that the disease spread can be controlled if effective measures are taken to reduce the reactivation rate of exposed/latent migrant workers. Impact of the migration rate and direction, as well as the duration of home visit stay, on the control of disease spread is also examined numerically.
2012, 9(4): 809-817
doi: 10.3934/mbe.2012.9.809
+[Abstract](2480)
+[PDF](418.9KB)
Abstract:
Hepatitis B virus can persist at very low levels in the body in the face of host immunity, and reactive during immunosuppression and sustain the immunological memory to lead to the possible state of 'infection immunity'. To analyze this phenomena quantitatively, a mathematical model which is described by DDEs with relative to cytotoxic T lymphocyte (CTL) response to Hepatitis B virus is used. Using the knowledge of DDEs and the numerical bifurcation analysis techniques, the dynamical behavior of Hopf bifurcation which may lead to the periodic oscillation of populations is analyzed. Domains of low level viral persistence which is possible, either as a stable equilibrium or a stable oscillatory pattern, are identified in parameter space. The virus replication rate appears to have influence to the amplitude of the persisting oscillatory population densities.
Hepatitis B virus can persist at very low levels in the body in the face of host immunity, and reactive during immunosuppression and sustain the immunological memory to lead to the possible state of 'infection immunity'. To analyze this phenomena quantitatively, a mathematical model which is described by DDEs with relative to cytotoxic T lymphocyte (CTL) response to Hepatitis B virus is used. Using the knowledge of DDEs and the numerical bifurcation analysis techniques, the dynamical behavior of Hopf bifurcation which may lead to the periodic oscillation of populations is analyzed. Domains of low level viral persistence which is possible, either as a stable equilibrium or a stable oscillatory pattern, are identified in parameter space. The virus replication rate appears to have influence to the amplitude of the persisting oscillatory population densities.
2012, 9(4): 819-841
doi: 10.3934/mbe.2012.9.819
+[Abstract](3042)
+[PDF](459.2KB)
Abstract:
We study a model of disease transmission with continuous age-structure for latently infected individuals and for infectious individuals. The model is very appropriate for tuberculosis. Key theorems, including asymptotic smoothness and uniform persistence, are proven by reformulating the system as a system of Volterra integral equations. The basic reproduction number $\mathcal{R}_{0}$ is calculated. For $\mathcal{R}_{0}<1$, the disease-free equilibrium is globally asymptotically stable. For $\mathcal{R}_{0}>1$, a Lyapunov functional is used to show that the endemic equilibrium is globally stable amongst solutions for which the disease is present. Finally, some special cases are considered.
We study a model of disease transmission with continuous age-structure for latently infected individuals and for infectious individuals. The model is very appropriate for tuberculosis. Key theorems, including asymptotic smoothness and uniform persistence, are proven by reformulating the system as a system of Volterra integral equations. The basic reproduction number $\mathcal{R}_{0}$ is calculated. For $\mathcal{R}_{0}<1$, the disease-free equilibrium is globally asymptotically stable. For $\mathcal{R}_{0}>1$, a Lyapunov functional is used to show that the endemic equilibrium is globally stable amongst solutions for which the disease is present. Finally, some special cases are considered.
2012, 9(4): 843-876
doi: 10.3934/mbe.2012.9.843
+[Abstract](2333)
+[PDF](1084.3KB)
Abstract:
The major goal of evolutionary oncology is to explain how malignant traits evolve to become cancer "hallmarks." One such hallmark---the angiogenic switch---is difficult to explain for the same reason altruism is difficult to explain. An angiogenic clone is vulnerable to "cheater" lineages that shunt energy from angiogenesis to proliferation, allowing the cheater to outcompete cooperative phenotypes in the environment built by the cooperators. Here we show that cell- or clone-level selection is sufficient to explain the angiogenic switch, but not because of direct selection on angiogenesis factor secretion---angiogenic potential evolves only as a pleiotropic afterthought. We study a multiscale mathematical model that includes an energy management system in an evolving angiogenic tumor. The energy management model makes the counterintuitive prediction that ATP concentration in resting cells increases with increasing ATP hydrolysis, as seen in other theoretical and empirical studies. As a result, increasing ATP hydrolysis for angiogenesis can increase proliferative potential, which is the trait directly under selection. Intriguingly, this energy dynamic allows an evolutionary stable angiogenesis strategy, but this strategy is an evolutionary repeller, leading to runaway selection for extreme vascular hypo- or hyperplasia. The former case yields a tumor-on-a-tumor, or hypertumor, as predicted in other studies, and the latter case may explain vascular hyperplasia evident in certain tumor types.
The major goal of evolutionary oncology is to explain how malignant traits evolve to become cancer "hallmarks." One such hallmark---the angiogenic switch---is difficult to explain for the same reason altruism is difficult to explain. An angiogenic clone is vulnerable to "cheater" lineages that shunt energy from angiogenesis to proliferation, allowing the cheater to outcompete cooperative phenotypes in the environment built by the cooperators. Here we show that cell- or clone-level selection is sufficient to explain the angiogenic switch, but not because of direct selection on angiogenesis factor secretion---angiogenic potential evolves only as a pleiotropic afterthought. We study a multiscale mathematical model that includes an energy management system in an evolving angiogenic tumor. The energy management model makes the counterintuitive prediction that ATP concentration in resting cells increases with increasing ATP hydrolysis, as seen in other theoretical and empirical studies. As a result, increasing ATP hydrolysis for angiogenesis can increase proliferative potential, which is the trait directly under selection. Intriguingly, this energy dynamic allows an evolutionary stable angiogenesis strategy, but this strategy is an evolutionary repeller, leading to runaway selection for extreme vascular hypo- or hyperplasia. The former case yields a tumor-on-a-tumor, or hypertumor, as predicted in other studies, and the latter case may explain vascular hyperplasia evident in certain tumor types.
2012, 9(4): 877-898
doi: 10.3934/mbe.2012.9.877
+[Abstract](2387)
+[PDF](661.3KB)
Abstract:
Individuals who carry the sickle cell trait ($S$-gene) have a greatly reduced risk of experiencing symptomatic malaria infections. However, previous studies suggest that the sickle cell trait does not protect against acquiring asymptomatic malaria infections, although the proportion of symptomatic infections is up to $50\%$ in areas where malaria is endemic. To examine the differential impact of the sickle cell trait on symptomatic and asymptomatic malaria, we developed a mathematical model of malaria transmission that incorporates the evolutionary dynamics of $S$-gene frequency. Our model indicates that the fitness of sickle cell trait is likely to increase with the proportion of symptomatic malaria infections. Our model also shows that control efforts aimed at diminishing the burden of symptomatic malaria are not likely to eradicate malaria in endemic areas, due to the increase in the relative prevalence of asymptomatic infection, the reservoir of malaria. Furthermore, when the prevalence of symptomatic malaria is reduced, both the fitness and frequency of the $S$-gene may decrease. In turn, a decreased frequency of the $S$-gene may eventually increase the overall prevalence of both symptomatic and asymptomatic malaria. Therefore, the control of symptomatic malaria might result in evolutionary repercussions, despite short-term epidemiological benefits.
Individuals who carry the sickle cell trait ($S$-gene) have a greatly reduced risk of experiencing symptomatic malaria infections. However, previous studies suggest that the sickle cell trait does not protect against acquiring asymptomatic malaria infections, although the proportion of symptomatic infections is up to $50\%$ in areas where malaria is endemic. To examine the differential impact of the sickle cell trait on symptomatic and asymptomatic malaria, we developed a mathematical model of malaria transmission that incorporates the evolutionary dynamics of $S$-gene frequency. Our model indicates that the fitness of sickle cell trait is likely to increase with the proportion of symptomatic malaria infections. Our model also shows that control efforts aimed at diminishing the burden of symptomatic malaria are not likely to eradicate malaria in endemic areas, due to the increase in the relative prevalence of asymptomatic infection, the reservoir of malaria. Furthermore, when the prevalence of symptomatic malaria is reduced, both the fitness and frequency of the $S$-gene may decrease. In turn, a decreased frequency of the $S$-gene may eventually increase the overall prevalence of both symptomatic and asymptomatic malaria. Therefore, the control of symptomatic malaria might result in evolutionary repercussions, despite short-term epidemiological benefits.
2012, 9(4): 899-914
doi: 10.3934/mbe.2012.9.899
+[Abstract](2559)
+[PDF](490.0KB)
Abstract:
In this study, the treatment of Human Immunodeficiency Virus (HIV) infection is investigated through an optimal structured treatment interruption (STI) schedule of two classes of antiretroviral drugs, mainly, reverse transcriptase inhibitors and protease inhibitors. An STI treatment strategy may be beneficial in lowering the risk of HIV mutating to drug-resistant strains, and could provide patients with respite from toxic side effects of HAART. A shorter treatment period is considered compared to previous studies and the solution to the HIV STI problem is obtained via the Finite Set Control Transcription (FSCT) formulation. The FSCT formulation offers a unique approach for handling multiple independent decision variables simultaneously, and, as is shown by the results of this study, is well-suited for an effective treatment of the optimal STI problem. The results obtained in the present investigation demonstrate that immune boosting and subsequent natural suppression of the viral load are possible even when a reduced STI therapy treatment duration is in consideration.
In this study, the treatment of Human Immunodeficiency Virus (HIV) infection is investigated through an optimal structured treatment interruption (STI) schedule of two classes of antiretroviral drugs, mainly, reverse transcriptase inhibitors and protease inhibitors. An STI treatment strategy may be beneficial in lowering the risk of HIV mutating to drug-resistant strains, and could provide patients with respite from toxic side effects of HAART. A shorter treatment period is considered compared to previous studies and the solution to the HIV STI problem is obtained via the Finite Set Control Transcription (FSCT) formulation. The FSCT formulation offers a unique approach for handling multiple independent decision variables simultaneously, and, as is shown by the results of this study, is well-suited for an effective treatment of the optimal STI problem. The results obtained in the present investigation demonstrate that immune boosting and subsequent natural suppression of the viral load are possible even when a reduced STI therapy treatment duration is in consideration.
2012, 9(4): 915-935
doi: 10.3934/mbe.2012.9.915
+[Abstract](2922)
+[PDF](1759.9KB)
Abstract:
Stochastic differential equation (SDE) models are formulated for intra-host virus-cell dynamics during the early stages of viral infection, prior to activation of the immune system. The SDE models incorporate more realism into the mechanisms for viral entry and release than ordinary differential equation (ODE) models and show distinct differences from the ODE models. The variability in the SDE models depends on the concentration, with much greater variability for small concentrations than large concentrations. In addition, the SDE models show significant variability in the timing of the viral peak. The viral peak is earlier for viruses that are released from infected cells via bursting rather than via budding from the cell membrane.
Stochastic differential equation (SDE) models are formulated for intra-host virus-cell dynamics during the early stages of viral infection, prior to activation of the immune system. The SDE models incorporate more realism into the mechanisms for viral entry and release than ordinary differential equation (ODE) models and show distinct differences from the ODE models. The variability in the SDE models depends on the concentration, with much greater variability for small concentrations than large concentrations. In addition, the SDE models show significant variability in the timing of the viral peak. The viral peak is earlier for viruses that are released from infected cells via bursting rather than via budding from the cell membrane.
2012, 9(4): 937-952
doi: 10.3934/mbe.2012.9.937
+[Abstract](1942)
+[PDF](501.8KB)
Abstract:
Although a virus contains several epitopes that can be recognized by cytotoxic T lymphocytes (CTL), the immune responses against different epitopes are not uniform. Only a few CTLs (sometimes just one) will be immunodominant. Mutation of epitopes has been recognized as an important mechanism of immunodominance. Previous research has studied the influences of sporadic, discrete mutation events. In this work, we introduce a bounded noise term to account for the intrinsic stochastic nature of mutation. Monte Carlo simulations of the stochastic model show abounding complex phenomena, and patterns observed from the numerical simulations shed lights on long term trends of immunodominance.
Although a virus contains several epitopes that can be recognized by cytotoxic T lymphocytes (CTL), the immune responses against different epitopes are not uniform. Only a few CTLs (sometimes just one) will be immunodominant. Mutation of epitopes has been recognized as an important mechanism of immunodominance. Previous research has studied the influences of sporadic, discrete mutation events. In this work, we introduce a bounded noise term to account for the intrinsic stochastic nature of mutation. Monte Carlo simulations of the stochastic model show abounding complex phenomena, and patterns observed from the numerical simulations shed lights on long term trends of immunodominance.
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