Oleg Demin - Academia.edu (original) (raw)
Papers by Oleg Demin
Alzheimer's & Dementia, 2012
Biofizika
A kinetic model of the cytochrome bf complex was developed on the assumption that the Q-cycle ope... more A kinetic model of the cytochrome bf complex was developed on the assumption that the Q-cycle operates. The bf complex was considered as a membrane enzyme catalyzing the electron transfer from plastoquinol to plastocyanine, which is coupled with proton translocation from the chloroplast stroma to the thylakoid lumen. The dependence of the electron transfer rates on the value of the transmembrane electric potential was taken into account. The model was applied to describe the experimental data on the flash-induced turnover of cytochromes b, plastocyanine, and the kinetics of proton deposition in the thylakoid lumen. The estimation of model parameters was performed.
Biochemistry (Moscow)
It is widely believed that direct nonenzymatic semiquinone oxidation with oxygen is one of the so... more It is widely believed that direct nonenzymatic semiquinone oxidation with oxygen is one of the sources of superoxide in mitochondria. In the present work we developed a mathematical model of coupled functioning of the bc1 complex and ATP producing processes that allows one to obtain the dependence of superoxide production rate on membrane potential (DeltaPsi). Assuming that electron transfer between hemes of cytochrome b is the main electrogenic step of the Q-cycle, we found that rate of superoxide production increased dramatically with increase in DeltaPsi in the range from 170 to 200 mV. This explains experimental observation of a dramatic decrease in the superoxide production with decrease in DeltaPsi in the range from 200 to 170 mV. Generation of superoxide can be diminished with the inhibition of the electron supply to the Q-cycle, with decrease in external potassium, or increase in external inorganic phosphate level.
Biofizika
A kinetic model was developed, which describing the system of generation and consumption of the t... more A kinetic model was developed, which describing the system of generation and consumption of the transmembrane electrochemical proton potential delta mu H+ in primary photosynthetic processes. The model describes the catalytic cycles of photosystems I and II and the cytochrome b/f complex, as well as the ATP synthesis and passive leakage of H+, K+ [symbol: see text] Cl- ions through the thylakoid membrane. The dependence of the electron transfer rates on the value of transmembrane electric potential was taken into account. The model was applied to describe the experimental data on the registration of the fast phase of fluorescence induction. The model gives a realistic description of the fast phase of induction curves at different light intensities (from high to low).
Basic mechanisms of kinetic regulation of photosynthetic processes are considered. These mechanis... more Basic mechanisms of kinetic regulation of photosynthetic processes are considered. These mechanisms provide strict light-dependent regulationof electron transport in photosynthetic reaction centers and more flexible regulation at the level of interaction between pboeosystems, transmembrane fluxes of ions, and coupling with dark reactions of the Calvin cycle. A generalized mathematical model was constructed. This model consolidates the modern knowledge about photosynthetic processes in higher plants. The general principles of multilevel regulation of photosynthetic processes are discussed.
Biofizika
The basic mechanisms of kinetic regulation of photosynthetic processes are considered, which prov... more The basic mechanisms of kinetic regulation of photosynthetic processes are considered, which provide a strict light regulation of electron transfer in photosynthetic reaction centers and a more flexible regulation at the level of interaction of photosystems, transmembrane ion fluxes and coupling with dark reactions of the Calvin cycle. A generalized model was developed, which integrates the modern knowledge about photosynthetic processes of higher plants. The general principles of multilevel regulation in photosynthetic systems are discussed.
Journal of theoretical biology, Jan 8, 2015
Mathematical models have been widely used for understanding the dynamics of the hepatitis C virus... more Mathematical models have been widely used for understanding the dynamics of the hepatitis C virus (HCV). We propose a method to predict final clinical outcome for 24 HIV-HCV - coinfected patients with the help of a mathematical model based on the first two weeks of PEG-IFN therapy. Applying a pharmacokinetic-pharmacodynamic (PKPD) approach, together with mixture models, to the adapted model of viral dynamics developed by Neumann et al., we have analyzed the influence of PEG-IFN on the kinetics and interaction of target cells, infected cells and virus mRNA. It was found that PEG-IFN pharmacokinetic parameters were similar in sustained virological responders and nonresponders, while the plasma PEG-IFN concentration that decreases HCV production by 50% (EC50) and the rate of infected cell death were different. The treatment outcome depended mainly on the initial viral mRNA concentration and the rate of infected cell death. The population PKPD approach with a mixture model enabled the d...
Journal of Biopharmaceutical Statistics, 2015
1 Abstract In case of small samples, asymptotic confidence sets may be inaccurate, with their act... more 1 Abstract In case of small samples, asymptotic confidence sets may be inaccurate, with their actual coverage probability far from a nominal confidence level. In a single framework, we consider four popular asymptotic methods of confidence estimation. These methods are based on model linearization, F-test, likelihood ratio test and nonparametric bootstrapping procedure. Next, we apply each of these methods to derive three types of confidence sets: confidence intervals, confidence regions and pointwise confidence bands. Finally, to estimate the actual coverage of these confidence sets, we conduct a simulation study on three regression problems. A linear model and nonlinear Hill and Gompertz models are tested in conditions of different sample size and experimental noise. The simulation study comprises calculation of the actual coverage of confidence sets over pseudo-experimental data sets for each model. For confidence intervals, such metrics as width and simultaneous coverage are also considered. Our comparison shows that the F-test and linearization methods are the most suitable for the construction of confidence intervals, the F-test - for confidence regions and the linearization - for pointwise confidence bands.
Advances in Experimental Medicine and Biology, 2011
Reviews of the productivity of the pharmaceutical industry have concluded that the current busine... more Reviews of the productivity of the pharmaceutical industry have concluded that the current business model is unsustainable. Various remedies for this have been proposed, however, arguably these do not directly address the fundamental issue; namely, that it is the knowledge required to enable good decisions in the process of delivering a drug that is largely absent; in turn, this leads to a disconnect between our intuition of what the right drug target is and the reality of pharmacological intervention in a system such as a human disease state. As this system is highly complex, modelling will be required to elucidate emergent properties together with the data necessary to construct such models. Currently, however, both the models and data available are limited. The ultimate solution to the problem of pharmaceutical productivity may be the virtual human, however, it is likely to be many years, if at all, before this goal is realised. The current challenge is, therefore, whether systems modelling can contribute to improving productivity in the pharmaceutical industry in the interim and help to guide the optimal route to the virtual human. In this context, this chapter discusses the emergence of systems pharmacology in drug discovery from the interface of pharmacokineticpharmacodynamic modelling and systems biology. Examples of applications to the identification of optimal drug targets in given pathways, selecting drug modalities and defining biomarkers are discussed, together with future directions. N. Benson ( ) • L. Cucurull-Sanchez Modelling and simulation,
Methods of biochemical analysis, 2006
Molecular biology reports, 2002
Modular kinetic analysis reveals that the environmental pollutant 2,2',5,5'-tetrachlorobi... more Modular kinetic analysis reveals that the environmental pollutant 2,2',5,5'-tetrachlorobiphenyl (2,2',5,5'-TCB) affects a large number of steps in oxidative phosphorylation in rat liver mitochondria. 2,2',5,5'-TCB increases membrane permeability to ions, and inhibits NADH dehydrogenase, cytochrome bc1, cytochrome oxidase (all in the respiratory chain) and ATP-synthase (in the phosphorylation subsystem). Surprisingly, flux control distribution does not change. A kinetic model for oxidative phosphorylation was used to simulate these findings, and it was found that combined large changes in the processes indicated indeed left the flux control largely unchanged. In addition, computational analysis with the model indicated that the adenine nucleotide translocator might be inhibited by 2,2',5,5'-TCB.
Journal of Biophysics, 2011
The mathematical model of the operation of the first enzyme of the Escherichia coli phosphotransf... more The mathematical model of the operation of the first enzyme of the Escherichia coli phosphotransferase system, EI, is proposed. Parameters of the kinetic model describing the operation of EI under different conditions are identified on the basis of a large amount of known experimental data. The verified model is employed to predict modes of operation of EI under both in vivo physiological conditions and in vitro nonphysiological conditions. The model predicts that under in vivo physiological conditions, the rate of phosphotransfer from EI to the second protein of the phosphotransferase system HPr by the dimer is much higher than by the monomer. A hypothesis is proposed on the basis of calculations that the transfer by a monomer plays a role in the regulation of chemotaxis. At submicromolar pyruvate concentration, the model predicts nonmonotonic dependence of the phosphotransfer rate on the substrate (PEP) concentration.
Chapman & Hall/CRC Mathematical & Computational Biology, 2008
... in Systems Biology Oleg Demin and Igor Goryanin Knowledge Discovery in Proteomics Igor Jurisi... more ... in Systems Biology Oleg Demin and Igor Goryanin Knowledge Discovery in Proteomics Igor Jurisica and Dennis Wigle Modeling and ... of Anatoly Sorokin, Hongwu Ma, Galina Lebedeva, Ekaterina Mogilevskaya, Nail Gizzatkulov, Evgeniy Metelkin, Kirill Peskov, Aleksey Goltsov ...
Frontiers in Pharmacology, 2014
The Renal sodium-dependent glucose co-transporter 2 (SGLT2) is one of the most promising targets ... more The Renal sodium-dependent glucose co-transporter 2 (SGLT2) is one of the most promising targets for the treatment of type 2 diabetes. Two SGLT2 inhibitors, dapagliflozin, and canagliflozin, have already been approved for use in USA and Europe; several additional compounds are also being developed for this purpose. Based on the in vitro IC 50 values and plasma concentration of dapagliflozin measured in clinical trials, the marketed dosage of the drug was expected to almost completely inhibit SGLT2 function and reduce glucose reabsorption by 90%. However, the administration of dapagliflozin resulted in only 30-50% inhibition of reabsorption. This study was aimed at investigating the mechanism underlying the discrepancy between the expected and observed levels of glucose reabsorption. To this end, systems pharmacology models were developed to analyze the time profile of dapagliflozin, canagliflozin, ipragliflozin, empagliflozin, and tofogliflozin in the plasma and urine; their filtration and active secretion from the blood to the renal proximal tubules; reverse reabsorption; urinary excretion; and their inhibitory effect on SGLT2. The model shows that concentration levels of tofogliflozin, ipragliflozin, and empagliflozin are higher than levels of other inhibitors following administration of marketed SGLT2 inhibitors at labeled doses and non-marketed SGLT2 inhibitors at maximal doses (approved for phase 2/3 studies). All the compounds exhibited almost 100% inhibition of SGLT2. Based on the results of our model, two explanations for the observed low efficacy of SGLT2 inhibitors were supported: (1) the site of action of SGLT2 inhibitors is not in the lumen of the kidney's proximal tubules, but elsewhere (e.g., the kidneys proximal tubule cells); and (2) there are other transporters that could facilitate glucose reabsorption under the conditions of SGLT2 inhibition (e.g., other transporters of SGLT family).
Molecular Biology, 2001
ABSTRACT
FEBS Journal, 2012
The mathematical model described here has been submitted to the JWS Online Cellular Systems Model... more The mathematical model described here has been submitted to the JWS Online Cellular Systems Modelling Database and can be accessed at
Journal of Biological Systems, 1995
ABSTRACT
BMC Systems Biology, 2013
Background: Celiac disease (CD) is an autoimmune disorder that occurs in genetically predisposed ... more Background: Celiac disease (CD) is an autoimmune disorder that occurs in genetically predisposed people and is caused by a reaction to the gluten protein found in wheat, which leads to intestinal villous atrophy. Currently there is no drug for treatment of CD. The only known treatment is lifelong gluten-free diet. The main aim of this work is to develop a mathematical model of the immune response in CD patients and to predict the efficacy of a transglutaminase-2 (TG-2) inhibitor as a potential drug for treatment of CD.
BMC Systems Biology, 2012
Background: 5-lipoxygenase (5-LO) is a key enzyme in the synthesis of leukotrienes and 5-Oxo-6E,8... more Background: 5-lipoxygenase (5-LO) is a key enzyme in the synthesis of leukotrienes and 5-Oxo-6E,8Z,11Z,14Zeicosatetraenoic acid (oxoETE). These inflammatory signaling molecules play a role in the pathology of asthma and so 5-LO inhibition is a promising target for asthma therapy. The 5-LO redox inhibitor zileuton (Zyflo IR/CR W ) is currently marketed for the treatment of asthma in adults and children, but widespread use of zileuton is limited by its efficacy/safety profile, potentially related to its redox characteristics. Thus, a quantitative, mechanistic description of its functioning may be useful for development of improved anti-inflammatory targeting this mechanism.
Alzheimer's & Dementia, 2012
Biofizika
A kinetic model of the cytochrome bf complex was developed on the assumption that the Q-cycle ope... more A kinetic model of the cytochrome bf complex was developed on the assumption that the Q-cycle operates. The bf complex was considered as a membrane enzyme catalyzing the electron transfer from plastoquinol to plastocyanine, which is coupled with proton translocation from the chloroplast stroma to the thylakoid lumen. The dependence of the electron transfer rates on the value of the transmembrane electric potential was taken into account. The model was applied to describe the experimental data on the flash-induced turnover of cytochromes b, plastocyanine, and the kinetics of proton deposition in the thylakoid lumen. The estimation of model parameters was performed.
Biochemistry (Moscow)
It is widely believed that direct nonenzymatic semiquinone oxidation with oxygen is one of the so... more It is widely believed that direct nonenzymatic semiquinone oxidation with oxygen is one of the sources of superoxide in mitochondria. In the present work we developed a mathematical model of coupled functioning of the bc1 complex and ATP producing processes that allows one to obtain the dependence of superoxide production rate on membrane potential (DeltaPsi). Assuming that electron transfer between hemes of cytochrome b is the main electrogenic step of the Q-cycle, we found that rate of superoxide production increased dramatically with increase in DeltaPsi in the range from 170 to 200 mV. This explains experimental observation of a dramatic decrease in the superoxide production with decrease in DeltaPsi in the range from 200 to 170 mV. Generation of superoxide can be diminished with the inhibition of the electron supply to the Q-cycle, with decrease in external potassium, or increase in external inorganic phosphate level.
Biofizika
A kinetic model was developed, which describing the system of generation and consumption of the t... more A kinetic model was developed, which describing the system of generation and consumption of the transmembrane electrochemical proton potential delta mu H+ in primary photosynthetic processes. The model describes the catalytic cycles of photosystems I and II and the cytochrome b/f complex, as well as the ATP synthesis and passive leakage of H+, K+ [symbol: see text] Cl- ions through the thylakoid membrane. The dependence of the electron transfer rates on the value of transmembrane electric potential was taken into account. The model was applied to describe the experimental data on the registration of the fast phase of fluorescence induction. The model gives a realistic description of the fast phase of induction curves at different light intensities (from high to low).
Basic mechanisms of kinetic regulation of photosynthetic processes are considered. These mechanis... more Basic mechanisms of kinetic regulation of photosynthetic processes are considered. These mechanisms provide strict light-dependent regulationof electron transport in photosynthetic reaction centers and more flexible regulation at the level of interaction between pboeosystems, transmembrane fluxes of ions, and coupling with dark reactions of the Calvin cycle. A generalized mathematical model was constructed. This model consolidates the modern knowledge about photosynthetic processes in higher plants. The general principles of multilevel regulation of photosynthetic processes are discussed.
Biofizika
The basic mechanisms of kinetic regulation of photosynthetic processes are considered, which prov... more The basic mechanisms of kinetic regulation of photosynthetic processes are considered, which provide a strict light regulation of electron transfer in photosynthetic reaction centers and a more flexible regulation at the level of interaction of photosystems, transmembrane ion fluxes and coupling with dark reactions of the Calvin cycle. A generalized model was developed, which integrates the modern knowledge about photosynthetic processes of higher plants. The general principles of multilevel regulation in photosynthetic systems are discussed.
Journal of theoretical biology, Jan 8, 2015
Mathematical models have been widely used for understanding the dynamics of the hepatitis C virus... more Mathematical models have been widely used for understanding the dynamics of the hepatitis C virus (HCV). We propose a method to predict final clinical outcome for 24 HIV-HCV - coinfected patients with the help of a mathematical model based on the first two weeks of PEG-IFN therapy. Applying a pharmacokinetic-pharmacodynamic (PKPD) approach, together with mixture models, to the adapted model of viral dynamics developed by Neumann et al., we have analyzed the influence of PEG-IFN on the kinetics and interaction of target cells, infected cells and virus mRNA. It was found that PEG-IFN pharmacokinetic parameters were similar in sustained virological responders and nonresponders, while the plasma PEG-IFN concentration that decreases HCV production by 50% (EC50) and the rate of infected cell death were different. The treatment outcome depended mainly on the initial viral mRNA concentration and the rate of infected cell death. The population PKPD approach with a mixture model enabled the d...
Journal of Biopharmaceutical Statistics, 2015
1 Abstract In case of small samples, asymptotic confidence sets may be inaccurate, with their act... more 1 Abstract In case of small samples, asymptotic confidence sets may be inaccurate, with their actual coverage probability far from a nominal confidence level. In a single framework, we consider four popular asymptotic methods of confidence estimation. These methods are based on model linearization, F-test, likelihood ratio test and nonparametric bootstrapping procedure. Next, we apply each of these methods to derive three types of confidence sets: confidence intervals, confidence regions and pointwise confidence bands. Finally, to estimate the actual coverage of these confidence sets, we conduct a simulation study on three regression problems. A linear model and nonlinear Hill and Gompertz models are tested in conditions of different sample size and experimental noise. The simulation study comprises calculation of the actual coverage of confidence sets over pseudo-experimental data sets for each model. For confidence intervals, such metrics as width and simultaneous coverage are also considered. Our comparison shows that the F-test and linearization methods are the most suitable for the construction of confidence intervals, the F-test - for confidence regions and the linearization - for pointwise confidence bands.
Advances in Experimental Medicine and Biology, 2011
Reviews of the productivity of the pharmaceutical industry have concluded that the current busine... more Reviews of the productivity of the pharmaceutical industry have concluded that the current business model is unsustainable. Various remedies for this have been proposed, however, arguably these do not directly address the fundamental issue; namely, that it is the knowledge required to enable good decisions in the process of delivering a drug that is largely absent; in turn, this leads to a disconnect between our intuition of what the right drug target is and the reality of pharmacological intervention in a system such as a human disease state. As this system is highly complex, modelling will be required to elucidate emergent properties together with the data necessary to construct such models. Currently, however, both the models and data available are limited. The ultimate solution to the problem of pharmaceutical productivity may be the virtual human, however, it is likely to be many years, if at all, before this goal is realised. The current challenge is, therefore, whether systems modelling can contribute to improving productivity in the pharmaceutical industry in the interim and help to guide the optimal route to the virtual human. In this context, this chapter discusses the emergence of systems pharmacology in drug discovery from the interface of pharmacokineticpharmacodynamic modelling and systems biology. Examples of applications to the identification of optimal drug targets in given pathways, selecting drug modalities and defining biomarkers are discussed, together with future directions. N. Benson ( ) • L. Cucurull-Sanchez Modelling and simulation,
Methods of biochemical analysis, 2006
Molecular biology reports, 2002
Modular kinetic analysis reveals that the environmental pollutant 2,2',5,5'-tetrachlorobi... more Modular kinetic analysis reveals that the environmental pollutant 2,2',5,5'-tetrachlorobiphenyl (2,2',5,5'-TCB) affects a large number of steps in oxidative phosphorylation in rat liver mitochondria. 2,2',5,5'-TCB increases membrane permeability to ions, and inhibits NADH dehydrogenase, cytochrome bc1, cytochrome oxidase (all in the respiratory chain) and ATP-synthase (in the phosphorylation subsystem). Surprisingly, flux control distribution does not change. A kinetic model for oxidative phosphorylation was used to simulate these findings, and it was found that combined large changes in the processes indicated indeed left the flux control largely unchanged. In addition, computational analysis with the model indicated that the adenine nucleotide translocator might be inhibited by 2,2',5,5'-TCB.
Journal of Biophysics, 2011
The mathematical model of the operation of the first enzyme of the Escherichia coli phosphotransf... more The mathematical model of the operation of the first enzyme of the Escherichia coli phosphotransferase system, EI, is proposed. Parameters of the kinetic model describing the operation of EI under different conditions are identified on the basis of a large amount of known experimental data. The verified model is employed to predict modes of operation of EI under both in vivo physiological conditions and in vitro nonphysiological conditions. The model predicts that under in vivo physiological conditions, the rate of phosphotransfer from EI to the second protein of the phosphotransferase system HPr by the dimer is much higher than by the monomer. A hypothesis is proposed on the basis of calculations that the transfer by a monomer plays a role in the regulation of chemotaxis. At submicromolar pyruvate concentration, the model predicts nonmonotonic dependence of the phosphotransfer rate on the substrate (PEP) concentration.
Chapman & Hall/CRC Mathematical & Computational Biology, 2008
... in Systems Biology Oleg Demin and Igor Goryanin Knowledge Discovery in Proteomics Igor Jurisi... more ... in Systems Biology Oleg Demin and Igor Goryanin Knowledge Discovery in Proteomics Igor Jurisica and Dennis Wigle Modeling and ... of Anatoly Sorokin, Hongwu Ma, Galina Lebedeva, Ekaterina Mogilevskaya, Nail Gizzatkulov, Evgeniy Metelkin, Kirill Peskov, Aleksey Goltsov ...
Frontiers in Pharmacology, 2014
The Renal sodium-dependent glucose co-transporter 2 (SGLT2) is one of the most promising targets ... more The Renal sodium-dependent glucose co-transporter 2 (SGLT2) is one of the most promising targets for the treatment of type 2 diabetes. Two SGLT2 inhibitors, dapagliflozin, and canagliflozin, have already been approved for use in USA and Europe; several additional compounds are also being developed for this purpose. Based on the in vitro IC 50 values and plasma concentration of dapagliflozin measured in clinical trials, the marketed dosage of the drug was expected to almost completely inhibit SGLT2 function and reduce glucose reabsorption by 90%. However, the administration of dapagliflozin resulted in only 30-50% inhibition of reabsorption. This study was aimed at investigating the mechanism underlying the discrepancy between the expected and observed levels of glucose reabsorption. To this end, systems pharmacology models were developed to analyze the time profile of dapagliflozin, canagliflozin, ipragliflozin, empagliflozin, and tofogliflozin in the plasma and urine; their filtration and active secretion from the blood to the renal proximal tubules; reverse reabsorption; urinary excretion; and their inhibitory effect on SGLT2. The model shows that concentration levels of tofogliflozin, ipragliflozin, and empagliflozin are higher than levels of other inhibitors following administration of marketed SGLT2 inhibitors at labeled doses and non-marketed SGLT2 inhibitors at maximal doses (approved for phase 2/3 studies). All the compounds exhibited almost 100% inhibition of SGLT2. Based on the results of our model, two explanations for the observed low efficacy of SGLT2 inhibitors were supported: (1) the site of action of SGLT2 inhibitors is not in the lumen of the kidney's proximal tubules, but elsewhere (e.g., the kidneys proximal tubule cells); and (2) there are other transporters that could facilitate glucose reabsorption under the conditions of SGLT2 inhibition (e.g., other transporters of SGLT family).
Molecular Biology, 2001
ABSTRACT
FEBS Journal, 2012
The mathematical model described here has been submitted to the JWS Online Cellular Systems Model... more The mathematical model described here has been submitted to the JWS Online Cellular Systems Modelling Database and can be accessed at
Journal of Biological Systems, 1995
ABSTRACT
BMC Systems Biology, 2013
Background: Celiac disease (CD) is an autoimmune disorder that occurs in genetically predisposed ... more Background: Celiac disease (CD) is an autoimmune disorder that occurs in genetically predisposed people and is caused by a reaction to the gluten protein found in wheat, which leads to intestinal villous atrophy. Currently there is no drug for treatment of CD. The only known treatment is lifelong gluten-free diet. The main aim of this work is to develop a mathematical model of the immune response in CD patients and to predict the efficacy of a transglutaminase-2 (TG-2) inhibitor as a potential drug for treatment of CD.
BMC Systems Biology, 2012
Background: 5-lipoxygenase (5-LO) is a key enzyme in the synthesis of leukotrienes and 5-Oxo-6E,8... more Background: 5-lipoxygenase (5-LO) is a key enzyme in the synthesis of leukotrienes and 5-Oxo-6E,8Z,11Z,14Zeicosatetraenoic acid (oxoETE). These inflammatory signaling molecules play a role in the pathology of asthma and so 5-LO inhibition is a promising target for asthma therapy. The 5-LO redox inhibitor zileuton (Zyflo IR/CR W ) is currently marketed for the treatment of asthma in adults and children, but widespread use of zileuton is limited by its efficacy/safety profile, potentially related to its redox characteristics. Thus, a quantitative, mechanistic description of its functioning may be useful for development of improved anti-inflammatory targeting this mechanism.