Haralambos Hatzikirou | Khalifa University (original) (raw)

Papers by Haralambos Hatzikirou

Physics of Life Reviews, 2022

1Collective dynamics in multicellular systems such as biological organs and tissues plays a key r... more 1Collective dynamics in multicellular systems such as biological organs and tissues plays a key role in biological development, regeneration, and pathological conditions. Collective tissue dynamics - understood as population behaviour arising from the interplay of the constituting discrete cells - can be studied with on- and off-lattice agent-based models. However, classical on-lattice agent-based models, also known as cellular automata, fail to replicate key aspects of collective migration, which is a central instance of collective behaviour in multicellular systems.To overcome drawbacks of classical on-lattice models, we introduce an on-lattice, agent-based modelling class for collective cell migration, which we call biological lattice-gas cellular automaton (BIO-LGCA). The BIO-LGCA is characterised by synchronous time updates, and the explicit consideration of individual cell velocities. While rules in classical cellular automata are typically chosen ad hoc, rules for cell-cell a...

Entropy, 2021

The way that progenitor cell fate decisions and the associated environmental sensing are regulate... more The way that progenitor cell fate decisions and the associated environmental sensing are regulated to ensure the robustness of the spatial and temporal order in which cells are generated towards a fully differentiating tissue still remains elusive. Here, we investigate how cells regulate their sensing intensity and radius to guarantee the required thermodynamic robustness of a differentiated tissue. In particular, we are interested in finding the conditions where dedifferentiation at cell level is possible (microscopic reversibility), but tissue maintains its spatial order and differentiation integrity (macroscopic irreversibility). In order to tackle this, we exploit the recently postulated Least microEnvironmental Uncertainty Principle (LEUP) to develop a theory of stochastic thermodynamics for cell differentiation. To assess the predictive and explanatory power of our theory, we challenge it against the avian photoreceptor mosaic data. By calibrating a single parameter, the LEUP ...

While many cellular mechanisms leading to chemotherapeutic resistance have been identified, there... more While many cellular mechanisms leading to chemotherapeutic resistance have been identified, there is an increasing realization that tumor-stroma interactions also play an important role. In particular, mechanical alterations are inherent to solid cancer progression and profoundly impact cell physiology. Here, we explore the impact of compressive stress on the efficacy of chemotherapeutics in pancreatic cancer spheroids. We find that increased compressive stress leads to decreased drug efficacy. Theoretical modeling and experiments suggest that mechanical stress leads to decreased cell proliferation which in turn reduces the efficacy of chemotherapeutics that target proliferating cells. Our work highlights a mechanical-form of drug resistance, and suggests new strategies for therapy.

Mathematical Modelling of Natural Phenomena, 2015

Here, we investigate different cell density-dependent migration strategies. In particular, we con... more Here, we investigate different cell density-dependent migration strategies. In particular, we consider strategies which differ in the precise regulation of transitions between resting and motile phenotypes. We develop a lattice-gas cellular automaton (LGCA) model for each migration strategy. Using a mean-field approximation we quantify the corresponding spreading dynamics at the cell population level. Our results allow for the prediction of cell population spreading based on experimentally accessible single cell migration parameters.

Lecture Notes in Computer Science, 2014

Cellular automata are discrete mathematical models that have been proven useful as representation... more Cellular automata are discrete mathematical models that have been proven useful as representations of a wide variety of systems exhibiting emergent behavior. Detection of emergent behavior is typically computationally expensive as it relies on computer simulations. We propose to specify cellular automata using a suitable Temporal Description Logic and we show that we can formulate queries about the evolution of a cellular automaton as reasoning tasks in this logic.

Computational Complexity, 2012

Journal of theoretical biology, Jan 21, 2011

Invasion of malignant glioma is a highly complex phenomenon involving molecular and cellular proc... more Invasion of malignant glioma is a highly complex phenomenon involving molecular and cellular processes at various spatio-temporal scales, whose precise interplay is still not fully understood. In order to identify the intrinsic cellular mechanisms of glioma invasion, we study an in vitro culture of glioma cells. By means of a computational approach, based on a cellular automaton model, we compare simulation results to the experimental data and deduce cellular mechanisms from microscopic and macroscopic observables (experimental data). For the first time, it is shown that the migration/proliferation dichotomy plays a central role in the invasion of glioma cells. Interestingly, we conclude that a diverging invasive zone is a consequence of this dichotomy. Additionally, we observe that radial persistence of glioma cells in the vicinity of dense areas accelerates the invasion process. We argue that this persistence results from a cell-cell repulsion mechanism. If glioma cell behavior is...

… of complexity and …, 2008

... models, provide an alter-native modeling approach, where a micro-scale investigation is allow... more ... models, provide an alter-native modeling approach, where a micro-scale investigation is allowed ... Cells are allowed to proliferate, die or adapt, ie change their phenotype ... as proliferation (migration/proliferation dichotomy), may play an important role for the dominance of invasive ...

Nature Communications

Fibrosis is a progressive biological condition, leading to organ dysfunction in various clinical ... more Fibrosis is a progressive biological condition, leading to organ dysfunction in various clinical settings. Although fibroblasts and macrophages are known as key cellular players for fibrosis development, a comprehensive functional model that considers their interaction in the metabolic/immunologic context of fibrotic tissue has not been set up. Here we show, by transcriptome-based mathematical modeling in an in vitro system that represents macrophage-fibroblast interplay and reflects the functional effects of inflammation, hypoxia and the adaptive immune context, that irreversible fibrosis development is associated with specific combinations of metabolic and inflammatory cues. The in vitro signatures are in good alignment with transcriptomic profiles generated on laser captured glomeruli and cortical tubule-interstitial area, isolated from human transplanted kidneys with advanced stages of glomerulosclerosis and interstitial fibrosis/tubular atrophy, two clinically relevant conditio...

iScience

An epidemic model on networks is developed including lockdowns and vaccination strategies An equa... more An epidemic model on networks is developed including lockdowns and vaccination strategies An equation-free method is used to compute the microscopic infection rate First dose prioritization controls the pandemic under mild contact restrictions There is an optimum ratio of vaccinating ages >65 over the younger ones of 0.85

Philosophical Transactions of the Royal Society B: Biological Sciences, 2020

Biological processes, such as embryonic development, wound repair and cancer invasion, or bacteri... more Biological processes, such as embryonic development, wound repair and cancer invasion, or bacterial swarming and fruiting body formation, involve collective motion of cells as a coordinated group. Collective cell motion of eukaryotic cells often includes interactions that result in polar alignment of cell velocities, while bacterial patterns typically show features of apolar velocity alignment. For analysing the population-scale effects of these different alignment mechanisms, various on- and off-lattice agent-based models have been introduced. However, discriminating model-specific artefacts from general features of collective cell motion is challenging. In this work, we focus on equivalence criteria at the population level to compare on- and off-lattice models. In particular, we define prototypic off- and on-lattice models of polar and apolar alignment, and show how to obtain an on-lattice from an off-lattice model of velocity alignment. By characterizing the behaviour and dynamic...

Journal of Theoretical Biology, 2020

This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Journal of Translational Medicine, 2019

Background There continues to be a great need for better biomarkers and host-directed treatment t... more Background There continues to be a great need for better biomarkers and host-directed treatment targets for community-acquired pneumonia (CAP). Alterations in phospholipid metabolism may constitute a source of small molecule biomarkers for acute infections including CAP. Evidence from animal models of pulmonary infections and sepsis suggests that inhibiting acid sphingomyelinase (which releases ceramides from sphingomyelins) may reduce end-organ damage. Methods We measured concentrations of 105 phospholipids, 40 acylcarnitines, and 4 ceramides, as well as acid sphingomyelinase activity, in plasma from patients with CAP (n = 29, sampled on admission and 4 subsequent time points), chronic obstructive pulmonary disease exacerbation with infection (COPD, n = 13) as a clinically important disease control, and 33 age- and sex-matched controls. Results Phospholipid concentrations were greatly decreased in CAP and normalized along clinical improvement. Greatest changes were seen in phosphat...

Scientific Reports, 2017

Many diffusion processes in nature and society were found to be anomalous, in the sense of being ... more Many diffusion processes in nature and society were found to be anomalous, in the sense of being fundamentally different from conventional Brownian motion. An important example is the migration of biological cells, which exhibits non-trivial temporal decay of velocity autocorrelation functions. This means that the corresponding dynamics is characterized by memory effects that slowly decay in time. Motivated by this we construct non-Markovian lattice-gas cellular automata models for moving agents with memory. For this purpose the reorientation probabilities are derived from velocity autocorrelation functions that are given a priori; in that respect our approach is “data-driven”. Particular examples we consider are velocity correlations that decay exponentially or as power laws, where the latter functions generate anomalous diffusion. The computational efficiency of cellular automata combined with our analytical results paves the way to explore the relevance of memory and anomalous di...

Cell decision-making is the cellular process of responding to microenvironmental cues. This can b... more Cell decision-making is the cellular process of responding to microenvironmental cues. This can be regarded as the regulation of cell’s intrinsic variables to extrinsic stimuli. Currently, little is known about the principles dictating cell decision-making. Regarding cells as Bayesian decision-makers under energetic constraints, I postulate the principle of least microenvironmental uncertainty (LEUP). This is translated into a free-energy principle and I develop a statistical mechanics theory for cell decision-making. I exhibit the potential of LEUP in the case of cell migration. In particular, I calculate the dependence of cell locomotion force on the steady state distribution of adhesion receptors. Finally, the associated migration velocity allows for the reproduction of the cell anomalous diffusion, as observed in cell culture experiments.

PLoS biology, 2018

Most bacteria swim in liquid environments by rotating one or several flagella. The long external ... more Most bacteria swim in liquid environments by rotating one or several flagella. The long external filament of the flagellum is connected to a membrane-embedded basal body by a flexible universal joint, the hook, which allows the transmission of motor torque to the filament. The length of the hook is controlled on a nanometer scale by a sophisticated molecular ruler mechanism. However, why its length is stringently controlled has remained elusive. We engineered and studied a diverse set of hook-length variants of Salmonella enterica. Measurements of plate-assay motility, single-cell swimming speed, and directional persistence in quasi-2D and population-averaged swimming speed and body angular velocity in 3D revealed that the motility performance is optimal around the wild-type hook length. We conclude that too-short hooks may be too stiff to function as a junction and too-long hooks may buckle and create instability in the flagellar bundle. Accordingly, peritrichously flagellated bact...

IEEE Journal on Selected Areas in Communications, 2016

In order to cope with the wireless traffic demand explosion within the next decade, operators are... more In order to cope with the wireless traffic demand explosion within the next decade, operators are underlying their macrocellular networks with low power base stations in a more dense manner. Such networks are typically referred to as heterogeneous or ultra-dense small cell networks, and their deployment entails a number of challenges in terms of backhauling, capacity provision, and dynamics in spatio-temporally fluctuating traffic load. Self-organizing network (SON) solutions have been defined to overcome these challenges. Since self-organization occurs in a plethora of biological systems, we identify the design principles of immune system self-regulation and draw analogies with respect to ultra-dense small cell networks. In particular, we develop a mathematical model of an artificial immune system (AIS) that autonomously activates or deactivates small cells in response to the local traffic demand. The main goal of the proposed AIS-based SON approach is the enhancement of energy efficiency and improvement of cell-edge throughput. As a proof of principle, system level simulations are carried out in which the bio-inspired algorithm is evaluated for various parameter settings, such as the speed of small cell activation and the delay of deactivation. Analysis using spatio-temporally varying traffic exhibiting uncertainty through geo-location demonstrates the robustness of the AIS-based SON approach proposed.

Physics of Life Reviews, 2022

1Collective dynamics in multicellular systems such as biological organs and tissues plays a key r... more 1Collective dynamics in multicellular systems such as biological organs and tissues plays a key role in biological development, regeneration, and pathological conditions. Collective tissue dynamics - understood as population behaviour arising from the interplay of the constituting discrete cells - can be studied with on- and off-lattice agent-based models. However, classical on-lattice agent-based models, also known as cellular automata, fail to replicate key aspects of collective migration, which is a central instance of collective behaviour in multicellular systems.To overcome drawbacks of classical on-lattice models, we introduce an on-lattice, agent-based modelling class for collective cell migration, which we call biological lattice-gas cellular automaton (BIO-LGCA). The BIO-LGCA is characterised by synchronous time updates, and the explicit consideration of individual cell velocities. While rules in classical cellular automata are typically chosen ad hoc, rules for cell-cell a...

Entropy, 2021

The way that progenitor cell fate decisions and the associated environmental sensing are regulate... more The way that progenitor cell fate decisions and the associated environmental sensing are regulated to ensure the robustness of the spatial and temporal order in which cells are generated towards a fully differentiating tissue still remains elusive. Here, we investigate how cells regulate their sensing intensity and radius to guarantee the required thermodynamic robustness of a differentiated tissue. In particular, we are interested in finding the conditions where dedifferentiation at cell level is possible (microscopic reversibility), but tissue maintains its spatial order and differentiation integrity (macroscopic irreversibility). In order to tackle this, we exploit the recently postulated Least microEnvironmental Uncertainty Principle (LEUP) to develop a theory of stochastic thermodynamics for cell differentiation. To assess the predictive and explanatory power of our theory, we challenge it against the avian photoreceptor mosaic data. By calibrating a single parameter, the LEUP ...

While many cellular mechanisms leading to chemotherapeutic resistance have been identified, there... more While many cellular mechanisms leading to chemotherapeutic resistance have been identified, there is an increasing realization that tumor-stroma interactions also play an important role. In particular, mechanical alterations are inherent to solid cancer progression and profoundly impact cell physiology. Here, we explore the impact of compressive stress on the efficacy of chemotherapeutics in pancreatic cancer spheroids. We find that increased compressive stress leads to decreased drug efficacy. Theoretical modeling and experiments suggest that mechanical stress leads to decreased cell proliferation which in turn reduces the efficacy of chemotherapeutics that target proliferating cells. Our work highlights a mechanical-form of drug resistance, and suggests new strategies for therapy.

Mathematical Modelling of Natural Phenomena, 2015

Here, we investigate different cell density-dependent migration strategies. In particular, we con... more Here, we investigate different cell density-dependent migration strategies. In particular, we consider strategies which differ in the precise regulation of transitions between resting and motile phenotypes. We develop a lattice-gas cellular automaton (LGCA) model for each migration strategy. Using a mean-field approximation we quantify the corresponding spreading dynamics at the cell population level. Our results allow for the prediction of cell population spreading based on experimentally accessible single cell migration parameters.

Lecture Notes in Computer Science, 2014

Cellular automata are discrete mathematical models that have been proven useful as representation... more Cellular automata are discrete mathematical models that have been proven useful as representations of a wide variety of systems exhibiting emergent behavior. Detection of emergent behavior is typically computationally expensive as it relies on computer simulations. We propose to specify cellular automata using a suitable Temporal Description Logic and we show that we can formulate queries about the evolution of a cellular automaton as reasoning tasks in this logic.

Computational Complexity, 2012

Journal of theoretical biology, Jan 21, 2011

Invasion of malignant glioma is a highly complex phenomenon involving molecular and cellular proc... more Invasion of malignant glioma is a highly complex phenomenon involving molecular and cellular processes at various spatio-temporal scales, whose precise interplay is still not fully understood. In order to identify the intrinsic cellular mechanisms of glioma invasion, we study an in vitro culture of glioma cells. By means of a computational approach, based on a cellular automaton model, we compare simulation results to the experimental data and deduce cellular mechanisms from microscopic and macroscopic observables (experimental data). For the first time, it is shown that the migration/proliferation dichotomy plays a central role in the invasion of glioma cells. Interestingly, we conclude that a diverging invasive zone is a consequence of this dichotomy. Additionally, we observe that radial persistence of glioma cells in the vicinity of dense areas accelerates the invasion process. We argue that this persistence results from a cell-cell repulsion mechanism. If glioma cell behavior is...

… of complexity and …, 2008

... models, provide an alter-native modeling approach, where a micro-scale investigation is allow... more ... models, provide an alter-native modeling approach, where a micro-scale investigation is allowed ... Cells are allowed to proliferate, die or adapt, ie change their phenotype ... as proliferation (migration/proliferation dichotomy), may play an important role for the dominance of invasive ...

Nature Communications

Fibrosis is a progressive biological condition, leading to organ dysfunction in various clinical ... more Fibrosis is a progressive biological condition, leading to organ dysfunction in various clinical settings. Although fibroblasts and macrophages are known as key cellular players for fibrosis development, a comprehensive functional model that considers their interaction in the metabolic/immunologic context of fibrotic tissue has not been set up. Here we show, by transcriptome-based mathematical modeling in an in vitro system that represents macrophage-fibroblast interplay and reflects the functional effects of inflammation, hypoxia and the adaptive immune context, that irreversible fibrosis development is associated with specific combinations of metabolic and inflammatory cues. The in vitro signatures are in good alignment with transcriptomic profiles generated on laser captured glomeruli and cortical tubule-interstitial area, isolated from human transplanted kidneys with advanced stages of glomerulosclerosis and interstitial fibrosis/tubular atrophy, two clinically relevant conditio...

iScience

An epidemic model on networks is developed including lockdowns and vaccination strategies An equa... more An epidemic model on networks is developed including lockdowns and vaccination strategies An equation-free method is used to compute the microscopic infection rate First dose prioritization controls the pandemic under mild contact restrictions There is an optimum ratio of vaccinating ages >65 over the younger ones of 0.85

Philosophical Transactions of the Royal Society B: Biological Sciences, 2020

Biological processes, such as embryonic development, wound repair and cancer invasion, or bacteri... more Biological processes, such as embryonic development, wound repair and cancer invasion, or bacterial swarming and fruiting body formation, involve collective motion of cells as a coordinated group. Collective cell motion of eukaryotic cells often includes interactions that result in polar alignment of cell velocities, while bacterial patterns typically show features of apolar velocity alignment. For analysing the population-scale effects of these different alignment mechanisms, various on- and off-lattice agent-based models have been introduced. However, discriminating model-specific artefacts from general features of collective cell motion is challenging. In this work, we focus on equivalence criteria at the population level to compare on- and off-lattice models. In particular, we define prototypic off- and on-lattice models of polar and apolar alignment, and show how to obtain an on-lattice from an off-lattice model of velocity alignment. By characterizing the behaviour and dynamic...

Journal of Theoretical Biology, 2020

This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Journal of Translational Medicine, 2019

Background There continues to be a great need for better biomarkers and host-directed treatment t... more Background There continues to be a great need for better biomarkers and host-directed treatment targets for community-acquired pneumonia (CAP). Alterations in phospholipid metabolism may constitute a source of small molecule biomarkers for acute infections including CAP. Evidence from animal models of pulmonary infections and sepsis suggests that inhibiting acid sphingomyelinase (which releases ceramides from sphingomyelins) may reduce end-organ damage. Methods We measured concentrations of 105 phospholipids, 40 acylcarnitines, and 4 ceramides, as well as acid sphingomyelinase activity, in plasma from patients with CAP (n = 29, sampled on admission and 4 subsequent time points), chronic obstructive pulmonary disease exacerbation with infection (COPD, n = 13) as a clinically important disease control, and 33 age- and sex-matched controls. Results Phospholipid concentrations were greatly decreased in CAP and normalized along clinical improvement. Greatest changes were seen in phosphat...

Scientific Reports, 2017

Many diffusion processes in nature and society were found to be anomalous, in the sense of being ... more Many diffusion processes in nature and society were found to be anomalous, in the sense of being fundamentally different from conventional Brownian motion. An important example is the migration of biological cells, which exhibits non-trivial temporal decay of velocity autocorrelation functions. This means that the corresponding dynamics is characterized by memory effects that slowly decay in time. Motivated by this we construct non-Markovian lattice-gas cellular automata models for moving agents with memory. For this purpose the reorientation probabilities are derived from velocity autocorrelation functions that are given a priori; in that respect our approach is “data-driven”. Particular examples we consider are velocity correlations that decay exponentially or as power laws, where the latter functions generate anomalous diffusion. The computational efficiency of cellular automata combined with our analytical results paves the way to explore the relevance of memory and anomalous di...

Cell decision-making is the cellular process of responding to microenvironmental cues. This can b... more Cell decision-making is the cellular process of responding to microenvironmental cues. This can be regarded as the regulation of cell’s intrinsic variables to extrinsic stimuli. Currently, little is known about the principles dictating cell decision-making. Regarding cells as Bayesian decision-makers under energetic constraints, I postulate the principle of least microenvironmental uncertainty (LEUP). This is translated into a free-energy principle and I develop a statistical mechanics theory for cell decision-making. I exhibit the potential of LEUP in the case of cell migration. In particular, I calculate the dependence of cell locomotion force on the steady state distribution of adhesion receptors. Finally, the associated migration velocity allows for the reproduction of the cell anomalous diffusion, as observed in cell culture experiments.

PLoS biology, 2018

Most bacteria swim in liquid environments by rotating one or several flagella. The long external ... more Most bacteria swim in liquid environments by rotating one or several flagella. The long external filament of the flagellum is connected to a membrane-embedded basal body by a flexible universal joint, the hook, which allows the transmission of motor torque to the filament. The length of the hook is controlled on a nanometer scale by a sophisticated molecular ruler mechanism. However, why its length is stringently controlled has remained elusive. We engineered and studied a diverse set of hook-length variants of Salmonella enterica. Measurements of plate-assay motility, single-cell swimming speed, and directional persistence in quasi-2D and population-averaged swimming speed and body angular velocity in 3D revealed that the motility performance is optimal around the wild-type hook length. We conclude that too-short hooks may be too stiff to function as a junction and too-long hooks may buckle and create instability in the flagellar bundle. Accordingly, peritrichously flagellated bact...

IEEE Journal on Selected Areas in Communications, 2016

In order to cope with the wireless traffic demand explosion within the next decade, operators are... more In order to cope with the wireless traffic demand explosion within the next decade, operators are underlying their macrocellular networks with low power base stations in a more dense manner. Such networks are typically referred to as heterogeneous or ultra-dense small cell networks, and their deployment entails a number of challenges in terms of backhauling, capacity provision, and dynamics in spatio-temporally fluctuating traffic load. Self-organizing network (SON) solutions have been defined to overcome these challenges. Since self-organization occurs in a plethora of biological systems, we identify the design principles of immune system self-regulation and draw analogies with respect to ultra-dense small cell networks. In particular, we develop a mathematical model of an artificial immune system (AIS) that autonomously activates or deactivates small cells in response to the local traffic demand. The main goal of the proposed AIS-based SON approach is the enhancement of energy efficiency and improvement of cell-edge throughput. As a proof of principle, system level simulations are carried out in which the bio-inspired algorithm is evaluated for various parameter settings, such as the speed of small cell activation and the delay of deactivation. Analysis using spatio-temporally varying traffic exhibiting uncertainty through geo-location demonstrates the robustness of the AIS-based SON approach proposed.

—Cell decision-making is the cellular process of responding to microenvironmental cues. This can ... more —Cell decision-making is the cellular process of responding to microenvironmental cues. This can be regarded as the regulation of cell's intrinsic variables to extrinsic stimuli. Currently, little is known about the principles dictating cell decision-making. Regarding cells as Bayesian decision-makers under energetic constraints, I postulate the principle of least microenvironmental uncertainty (LEUP). This is translated into a free-energy principle and I develop a statistical mechanics theory for cell decision-making. I exhibit the potential of LEUP in the case of cell migration. In particular, I calculate the dependence of cell locomotion force on the steady state distribution of adhesion receptors. Finally, the associated migration velocity allows for the reproduction of the cell anomalous diffusion, as observed in cell culture experiments.