Nikos Mantzaris - Academia.edu (original) (raw)
Papers by Nikos Mantzaris
Chaos, 2007
Astrocytes, a special type of glial cells, were considered to have just a supporting role in info... more Astrocytes, a special type of glial cells, were considered to have just a supporting role in information processing in the brain. However, several recent studies have shown that they can be chemically stimulated by various neurotransmitters, such as ATP, and can generate Ca2+ and ATP waves, which can propagate over many cell lengths before being blocked. Although pathological conditions, such as spreading depression and epilepsy, have been linked to abnormal wave propagation in astrocytic cellular networks, a quantitative understanding of the underlying characteristics is still lacking. Astrocytic cellular networks are inhomogeneous, in the sense that the domain they occupy contains passive regions or gaps, which are unable to support wave propagation. Thus, this work focuses on understanding the complex interplay between single-cell signal transduction, domain inhomogeneity, and the characteristics of wave propagation and blocking in astrocytic cellular networks. The single-cell signal transduction model that was employed accounts for ATP-mediated IP3 production, the subsequent Ca2+ release from the ER, and ATP release into the extracellular space. The model is excitable and thus an infinite range of wave propagation is observed if the domain of propagation is homogeneous. This is not always the case for inhomogeneous domains. To model wave propagation in inhomogeneous astrocytic networks, a reaction-diffusion framework was developed and one-gap as well as multiple-gap cases were simulated using an efficient finite-element algorithm. The minimum gap length that blocks the wave was computed as a function of excitability levels and geometric characteristics of the inhomogeneous network, such as the length of the active regions (cells). Complex transient patterns, such as wave reflection, wave trapping, and generation of echo waves, were also predicted by the model, and their relationship to the geometric characteristics of the network was evaluated. Therefore, the proposed model can help in the formulation of testable hypotheses to explain the observed abnormal wave propagation in pathological situations.
Journal of Theoretical Biology, 2006
A Monte Carlo algorithm, which can accurately simulate the dynamics of entire heterogeneous cell ... more A Monte Carlo algorithm, which can accurately simulate the dynamics of entire heterogeneous cell populations, was developed. The algorithm takes into account the random nature of cell division as well as unequal partitioning of cellular material at cell division. Moreover, it is general in the sense that it can accommodate a variety of single-cell, deterministic reaction kinetics as well as various stochastic division and partitioning mechanisms. The validity of the algorithm was assessed through comparison of its results with those of the corresponding deterministic cell population balance model in cases where stochastic behavior is expected to be quantitatively negligible. Both algorithms were applied to study: (a) linear intracellular kinetics and (b) the expression dynamics of a genetic network with positive feedback architecture, such as the lac operon. The effects of stochastic division as well as those of different division and partitioning mechanisms were assessed in these systems, while the comparison of the stochastic model with a continuum model elucidated the significance of cell population heterogeneity even in cases where only the prediction of average properties is of primary interest. r
Journal of Theoretical Biology, 2006
Astrocytes, a special type of glial cells, were considered to have supporting role in information... more Astrocytes, a special type of glial cells, were considered to have supporting role in information processing in the brain. However, several recent studies have shown that they can be chemically stimulated by neurotransmitters and use a form of signaling, in which ATP acts as an extracellular messenger. Pathological conditions, such as spreading depression, have been linked to abnormal range of wave propagation in astrocytic cellular networks. Nevertheless, the underlying intra-and inter-cellular signaling mechanisms remain unclear. Motivated by the above, we constructed a model to understand the relationship between single-cell signal transduction mechanisms and wave propagation and blocking in astrocytic networks. The model incorporates ATP-mediated IP 3 production, the subsequent Ca 2+ release from the ER through IP 3 R channels and ATP release into the extracellular space. For the latter, two hypotheses were tested: Ca 2+ -or IP 3 -dependent ATP release. In the first case, single astrocytes can exhibit excitable behavior and frequency-encoded oscillations. Homogeneous, one-dimensional astrocytic networks can propagate waves with infinite range, while in two dimensions, spiral waves can be generated. However, in the IP 3 -dependent ATP release case, the specific coupling of the driver ATP-IP 3 system with the driven Ca 2+ subsystem leads to one-and two-dimensional wave patterns with finite range of propagation. r
Chaos, 2010
Oscillatory dynamics are common in biological pathways, emerging from the coupling of positive an... more Oscillatory dynamics are common in biological pathways, emerging from the coupling of positive and negative feedback loops. Due to the small numbers of molecules typically contained in cellular volumes, stochastic effects may play an important role in system behavior. Thus, for moderate noise strengths, stochasticity has been shown to enhance signal-to-noise ratios or even induce oscillations in a class of phenomena referred to as "stochastic resonance" and "coherence resonance," respectively. Furthermore, the biological oscillators are subject to influences from the division cycle of the cell. In this paper we consider a biologically relevant oscillator and investigate the effect of intrinsic noise as well as division cycle which encompasses the processes of growth, DNA duplication, and cell division. We first construct a minimal reaction network which can oscillate in the presence of large or negligible timescale separation. We then derive corresponding deterministic and stochastic models and compare their dynamical behaviors with respect to (i) the extent of the parameter space where each model can exhibit oscillatory behavior and (ii) the oscillation characteristics, namely, the amplitude and the period. We further incorporate division cycle effects on both models and investigate the effect of growth rate on system behavior. Our results show that in the presence but not in the absence of large timescale separation, coherence resonance effects result in extending the oscillatory region and lowering the period for the stochastic model. When the division cycle is taken into account, the oscillatory region of the deterministic model is shown to extend or shrink for moderate or high growth rates, respectively. Further, under the influence of the division cycle, the stochastic model can oscillate for parameter sets for which the deterministic model does not. The division cycle is also found to be able to resonate with the oscillator, thereby enhancing oscillation robustness. The results of this study can give valuable insight into the complex interplay between oscillatory intracellular dynamics and various noise sources, stemming from gene expression, cell growth, and division.
Chemical Engineering Science, 2005
The effectiveness of liquid-phase synthesis routes for nanoparticles is largely affected by the n... more The effectiveness of liquid-phase synthesis routes for nanoparticles is largely affected by the narrowness of the particle size distribution. To study the particle size distribution dynamics, we formulated a mathematical model describing nanoparticle growth in batch reactors. The ...
Journal of Physics A-mathematical and General, 2005
... Transient and asymptotic behaviour of the binary breakage problem Nikos V Mantzaris ... Kosto... more ... Transient and asymptotic behaviour of the binary breakage problem Nikos V Mantzaris ... Kostoglou et al [12] and Kostoglou and Karabelas [13] developed solutions of the steady-state breakage equation with homogeneous breakage kernels in the case of a maximum stable size. ...
Angiogenesis, the formation of new blood vessels from preexisting vasculature, is an essential co... more Angiogenesis, the formation of new blood vessels from preexisting vasculature, is an essential component of tumor growth. Without this, solid tumors are nutrient limited and cannot grow more than 1-2 mm in diameter and the tumor mass cannot contain more than 105-106 cells. The recent discovery of angiogenic inhibitors has revolutionized the field making anti-angiogenic treatment one of the most potent therapies for cancer. Despite this progress, a fundamental understanding of the entire angiogenic process and of the role and function of angiogenic inhibitors, in particular, is still lacking. We have developed a two-dimensional mathematical model, which takes into account the complex interactions between endothelial cells, proteolytic enzymes, tumor angiogenic factors and inhibitors. The model serves as a tool in order to investigate different possible functions of the angiogenic inhibitors as well as the mechanisms leading to experimentally observed phenomena during the angiogenic process.
Biotechnology and Bioengineering, 2008
A strain of Escherichia coli was metabolically engineered to produce poly(3-hydroxybutyrate-co-3-... more A strain of Escherichia coli was metabolically engineered to produce poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) of specified composition between 5% and 18% HV. A gene encoding propionyl-CoA synthetase (prpE from S. enterica) was placed under the control of the IPTG-inducible tac promoter (PtaclacUV5) while the polyhydroxyalkanoate synthesis operon (phaBCA) from R. eutropha was expressed constitutively. A strain of E. coli harboring both plasmids was grown in defined medium and PHBV was produced with specified hydroxyvalerate (HV) molar content between 5% and 18%. The molecular weight of the copolymer was ∼700,000 across various HV contents, and average polydispersity was ∼ 1.3. The majority of the PHBV production occurred during the late exponential/stationary phase. The HV content of the copolymer generally peaked early in the incubation before falling to its final value. We found that the time profiles of PrpE activity, propionyl-CoA, and acetyl-CoA were well correlated to the HV content time profile. Despite an abundance of propionyl-CoA, incorporation of HV into the copolymer was inefficient. Therefore, both the PHA operon and conditions affecting the availability of propionyl-CoA must be chosen carefully to achieve the desired HV content. The ability to engineer copolymer composition control into an E. coli strain would be useful in cases where the feedstock composition is not adjustable. Biotechnol. Bioeng. 2008;99: 919–928. © 2007 Wiley Periodicals, Inc.
Journal of Biotechnology, 2007
We studied the distribution of expression levels amongst the cells of an Escherichia coli populat... more We studied the distribution of expression levels amongst the cells of an Escherichia coli population carrying a gene-switching network, known as the genetic toggle. We employed two green fluorescent protein (GFP) reporter proteins with different half-lives and characterized the effect of isopropyl--d-thiogalactopyranoside (IPTG) inducer concentration on fluorescence distribution characteristics. Our flow cytometric measurements indicated that there is a spread of fluorescence phenotypes of one to three orders of magnitude, due to the highly heterogeneous nature of the cell populations under investigation. Moreover, the shape of the distribution at a specific quasi-time-invariant reference state, defined for comparison purposes, strongly depended on inducer concentration. For very low and very high inducer concentrations, the distributions at the reference state are unimodal. On the contrary, for intermediate IPTG concentrations, two distinct subpopulations were formed below and above a single-cell threshold, resulting in distributions with a bimodal shape. The region of inducer concentrations where bimodality is observed is the same and independent of GFP half-life. Bimodal number density functions are not only obtained at the reference state. Transient studies revealed that even in cases where the distribution at the reference state is unimodal, the distribution becomes bimodal for a period of time required for the population to pass through the single-cell induction threshold. However, this feature was only captured by the system with the reduced half-life GFP. A simple single-cell model was used to shed light into the effect of inducer concentration and GFP half-life on the shape of the experimentally measured number density functions. The wide range of fluorescent phenotypes and the inability of the average population properties to fully characterize network behavior, indicate the importance of taking into account cell population heterogeneity when designing such a gene-switching network for biotechnological and biomedical applications.
Journal of Biotechnology, 2009
We investigated the distribution of green fluorescent protein (GFP) expression levels in a popula... more We investigated the distribution of green fluorescent protein (GFP) expression levels in a population of E. coli cells expressing an artificial genetic regulatory network, known as the "repressilator". This network originally constructed by Elowitz and Leibler in 2000 consists of three cyclically-inhibiting promoter-repressor pairs. It is because of this architecture that the network has been known to oscillate at the single-cell level under certain conditions. A series of shake flask experiments were performed and analyzed using flow cytometry to test how cell populations carrying this system could be controlled extracellularly using the inducers anhydrotetracycline (aTc) and isopropyl-beta-d-thiogalactopyranoside (IPTG). With variation of [aTc], it exhibits a novel bi-threshold behavior, such that the entire culture reaches one of three steady states at a quasi-time-invariant "reference state." Also, there is significant hysteresis. Transiently, the middle state shows damping oscillations, while the low and high states show a stable steady state. The addition of IPTG serves to fine-tune the characteristics of the aTc-only expression, lowering the average and coefficient of variation (CV) of the distributions, and possibly perturbing the network to a different state. However, in modeling this system, the multiplicity and bi-threshold behavior are not theoretically possible according to the designed interactions. In order to explain this discrepancy, we hypothesize that one or more of the repressors have a significant nonspecific interaction with a promoter that does not contain its operator site. The new modeling results incorporating these extra interactions qualitatively match our experimental findings. After constructing plasmids to test these hypotheses, we discover that at least four of these interactions exist, which can create the low and high states and multiplicity seen experimentally. This genetic architecture has flexibility in its behavior that has not been demonstrated before, and the combination of experiment and modeling enlightened our understanding of the molecular interactions driving the network's behavior, leading us to discover the significance of nonspecific interactions.
Chaos, 2007
Astrocytes, a special type of glial cells, were considered to have just a supporting role in info... more Astrocytes, a special type of glial cells, were considered to have just a supporting role in information processing in the brain. However, several recent studies have shown that they can be chemically stimulated by various neurotransmitters, such as ATP, and can generate Ca2+ and ATP waves, which can propagate over many cell lengths before being blocked. Although pathological conditions, such as spreading depression and epilepsy, have been linked to abnormal wave propagation in astrocytic cellular networks, a quantitative understanding of the underlying characteristics is still lacking. Astrocytic cellular networks are inhomogeneous, in the sense that the domain they occupy contains passive regions or gaps, which are unable to support wave propagation. Thus, this work focuses on understanding the complex interplay between single-cell signal transduction, domain inhomogeneity, and the characteristics of wave propagation and blocking in astrocytic cellular networks. The single-cell signal transduction model that was employed accounts for ATP-mediated IP3 production, the subsequent Ca2+ release from the ER, and ATP release into the extracellular space. The model is excitable and thus an infinite range of wave propagation is observed if the domain of propagation is homogeneous. This is not always the case for inhomogeneous domains. To model wave propagation in inhomogeneous astrocytic networks, a reaction-diffusion framework was developed and one-gap as well as multiple-gap cases were simulated using an efficient finite-element algorithm. The minimum gap length that blocks the wave was computed as a function of excitability levels and geometric characteristics of the inhomogeneous network, such as the length of the active regions (cells). Complex transient patterns, such as wave reflection, wave trapping, and generation of echo waves, were also predicted by the model, and their relationship to the geometric characteristics of the network was evaluated. Therefore, the proposed model can help in the formulation of testable hypotheses to explain the observed abnormal wave propagation in pathological situations.
Journal of Theoretical Biology, 2006
A Monte Carlo algorithm, which can accurately simulate the dynamics of entire heterogeneous cell ... more A Monte Carlo algorithm, which can accurately simulate the dynamics of entire heterogeneous cell populations, was developed. The algorithm takes into account the random nature of cell division as well as unequal partitioning of cellular material at cell division. Moreover, it is general in the sense that it can accommodate a variety of single-cell, deterministic reaction kinetics as well as various stochastic division and partitioning mechanisms. The validity of the algorithm was assessed through comparison of its results with those of the corresponding deterministic cell population balance model in cases where stochastic behavior is expected to be quantitatively negligible. Both algorithms were applied to study: (a) linear intracellular kinetics and (b) the expression dynamics of a genetic network with positive feedback architecture, such as the lac operon. The effects of stochastic division as well as those of different division and partitioning mechanisms were assessed in these systems, while the comparison of the stochastic model with a continuum model elucidated the significance of cell population heterogeneity even in cases where only the prediction of average properties is of primary interest. r
Journal of Theoretical Biology, 2006
Astrocytes, a special type of glial cells, were considered to have supporting role in information... more Astrocytes, a special type of glial cells, were considered to have supporting role in information processing in the brain. However, several recent studies have shown that they can be chemically stimulated by neurotransmitters and use a form of signaling, in which ATP acts as an extracellular messenger. Pathological conditions, such as spreading depression, have been linked to abnormal range of wave propagation in astrocytic cellular networks. Nevertheless, the underlying intra-and inter-cellular signaling mechanisms remain unclear. Motivated by the above, we constructed a model to understand the relationship between single-cell signal transduction mechanisms and wave propagation and blocking in astrocytic networks. The model incorporates ATP-mediated IP 3 production, the subsequent Ca 2+ release from the ER through IP 3 R channels and ATP release into the extracellular space. For the latter, two hypotheses were tested: Ca 2+ -or IP 3 -dependent ATP release. In the first case, single astrocytes can exhibit excitable behavior and frequency-encoded oscillations. Homogeneous, one-dimensional astrocytic networks can propagate waves with infinite range, while in two dimensions, spiral waves can be generated. However, in the IP 3 -dependent ATP release case, the specific coupling of the driver ATP-IP 3 system with the driven Ca 2+ subsystem leads to one-and two-dimensional wave patterns with finite range of propagation. r
Chaos, 2010
Oscillatory dynamics are common in biological pathways, emerging from the coupling of positive an... more Oscillatory dynamics are common in biological pathways, emerging from the coupling of positive and negative feedback loops. Due to the small numbers of molecules typically contained in cellular volumes, stochastic effects may play an important role in system behavior. Thus, for moderate noise strengths, stochasticity has been shown to enhance signal-to-noise ratios or even induce oscillations in a class of phenomena referred to as "stochastic resonance" and "coherence resonance," respectively. Furthermore, the biological oscillators are subject to influences from the division cycle of the cell. In this paper we consider a biologically relevant oscillator and investigate the effect of intrinsic noise as well as division cycle which encompasses the processes of growth, DNA duplication, and cell division. We first construct a minimal reaction network which can oscillate in the presence of large or negligible timescale separation. We then derive corresponding deterministic and stochastic models and compare their dynamical behaviors with respect to (i) the extent of the parameter space where each model can exhibit oscillatory behavior and (ii) the oscillation characteristics, namely, the amplitude and the period. We further incorporate division cycle effects on both models and investigate the effect of growth rate on system behavior. Our results show that in the presence but not in the absence of large timescale separation, coherence resonance effects result in extending the oscillatory region and lowering the period for the stochastic model. When the division cycle is taken into account, the oscillatory region of the deterministic model is shown to extend or shrink for moderate or high growth rates, respectively. Further, under the influence of the division cycle, the stochastic model can oscillate for parameter sets for which the deterministic model does not. The division cycle is also found to be able to resonate with the oscillator, thereby enhancing oscillation robustness. The results of this study can give valuable insight into the complex interplay between oscillatory intracellular dynamics and various noise sources, stemming from gene expression, cell growth, and division.
Chemical Engineering Science, 2005
The effectiveness of liquid-phase synthesis routes for nanoparticles is largely affected by the n... more The effectiveness of liquid-phase synthesis routes for nanoparticles is largely affected by the narrowness of the particle size distribution. To study the particle size distribution dynamics, we formulated a mathematical model describing nanoparticle growth in batch reactors. The ...
Journal of Physics A-mathematical and General, 2005
... Transient and asymptotic behaviour of the binary breakage problem Nikos V Mantzaris ... Kosto... more ... Transient and asymptotic behaviour of the binary breakage problem Nikos V Mantzaris ... Kostoglou et al [12] and Kostoglou and Karabelas [13] developed solutions of the steady-state breakage equation with homogeneous breakage kernels in the case of a maximum stable size. ...
Angiogenesis, the formation of new blood vessels from preexisting vasculature, is an essential co... more Angiogenesis, the formation of new blood vessels from preexisting vasculature, is an essential component of tumor growth. Without this, solid tumors are nutrient limited and cannot grow more than 1-2 mm in diameter and the tumor mass cannot contain more than 105-106 cells. The recent discovery of angiogenic inhibitors has revolutionized the field making anti-angiogenic treatment one of the most potent therapies for cancer. Despite this progress, a fundamental understanding of the entire angiogenic process and of the role and function of angiogenic inhibitors, in particular, is still lacking. We have developed a two-dimensional mathematical model, which takes into account the complex interactions between endothelial cells, proteolytic enzymes, tumor angiogenic factors and inhibitors. The model serves as a tool in order to investigate different possible functions of the angiogenic inhibitors as well as the mechanisms leading to experimentally observed phenomena during the angiogenic process.
Biotechnology and Bioengineering, 2008
A strain of Escherichia coli was metabolically engineered to produce poly(3-hydroxybutyrate-co-3-... more A strain of Escherichia coli was metabolically engineered to produce poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) of specified composition between 5% and 18% HV. A gene encoding propionyl-CoA synthetase (prpE from S. enterica) was placed under the control of the IPTG-inducible tac promoter (PtaclacUV5) while the polyhydroxyalkanoate synthesis operon (phaBCA) from R. eutropha was expressed constitutively. A strain of E. coli harboring both plasmids was grown in defined medium and PHBV was produced with specified hydroxyvalerate (HV) molar content between 5% and 18%. The molecular weight of the copolymer was ∼700,000 across various HV contents, and average polydispersity was ∼ 1.3. The majority of the PHBV production occurred during the late exponential/stationary phase. The HV content of the copolymer generally peaked early in the incubation before falling to its final value. We found that the time profiles of PrpE activity, propionyl-CoA, and acetyl-CoA were well correlated to the HV content time profile. Despite an abundance of propionyl-CoA, incorporation of HV into the copolymer was inefficient. Therefore, both the PHA operon and conditions affecting the availability of propionyl-CoA must be chosen carefully to achieve the desired HV content. The ability to engineer copolymer composition control into an E. coli strain would be useful in cases where the feedstock composition is not adjustable. Biotechnol. Bioeng. 2008;99: 919–928. © 2007 Wiley Periodicals, Inc.
Journal of Biotechnology, 2007
We studied the distribution of expression levels amongst the cells of an Escherichia coli populat... more We studied the distribution of expression levels amongst the cells of an Escherichia coli population carrying a gene-switching network, known as the genetic toggle. We employed two green fluorescent protein (GFP) reporter proteins with different half-lives and characterized the effect of isopropyl--d-thiogalactopyranoside (IPTG) inducer concentration on fluorescence distribution characteristics. Our flow cytometric measurements indicated that there is a spread of fluorescence phenotypes of one to three orders of magnitude, due to the highly heterogeneous nature of the cell populations under investigation. Moreover, the shape of the distribution at a specific quasi-time-invariant reference state, defined for comparison purposes, strongly depended on inducer concentration. For very low and very high inducer concentrations, the distributions at the reference state are unimodal. On the contrary, for intermediate IPTG concentrations, two distinct subpopulations were formed below and above a single-cell threshold, resulting in distributions with a bimodal shape. The region of inducer concentrations where bimodality is observed is the same and independent of GFP half-life. Bimodal number density functions are not only obtained at the reference state. Transient studies revealed that even in cases where the distribution at the reference state is unimodal, the distribution becomes bimodal for a period of time required for the population to pass through the single-cell induction threshold. However, this feature was only captured by the system with the reduced half-life GFP. A simple single-cell model was used to shed light into the effect of inducer concentration and GFP half-life on the shape of the experimentally measured number density functions. The wide range of fluorescent phenotypes and the inability of the average population properties to fully characterize network behavior, indicate the importance of taking into account cell population heterogeneity when designing such a gene-switching network for biotechnological and biomedical applications.
Journal of Biotechnology, 2009
We investigated the distribution of green fluorescent protein (GFP) expression levels in a popula... more We investigated the distribution of green fluorescent protein (GFP) expression levels in a population of E. coli cells expressing an artificial genetic regulatory network, known as the "repressilator". This network originally constructed by Elowitz and Leibler in 2000 consists of three cyclically-inhibiting promoter-repressor pairs. It is because of this architecture that the network has been known to oscillate at the single-cell level under certain conditions. A series of shake flask experiments were performed and analyzed using flow cytometry to test how cell populations carrying this system could be controlled extracellularly using the inducers anhydrotetracycline (aTc) and isopropyl-beta-d-thiogalactopyranoside (IPTG). With variation of [aTc], it exhibits a novel bi-threshold behavior, such that the entire culture reaches one of three steady states at a quasi-time-invariant "reference state." Also, there is significant hysteresis. Transiently, the middle state shows damping oscillations, while the low and high states show a stable steady state. The addition of IPTG serves to fine-tune the characteristics of the aTc-only expression, lowering the average and coefficient of variation (CV) of the distributions, and possibly perturbing the network to a different state. However, in modeling this system, the multiplicity and bi-threshold behavior are not theoretically possible according to the designed interactions. In order to explain this discrepancy, we hypothesize that one or more of the repressors have a significant nonspecific interaction with a promoter that does not contain its operator site. The new modeling results incorporating these extra interactions qualitatively match our experimental findings. After constructing plasmids to test these hypotheses, we discover that at least four of these interactions exist, which can create the low and high states and multiplicity seen experimentally. This genetic architecture has flexibility in its behavior that has not been demonstrated before, and the combination of experiment and modeling enlightened our understanding of the molecular interactions driving the network's behavior, leading us to discover the significance of nonspecific interactions.