Browsing by Author "Kraikivski, Pavel"

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    A continuous-time stochastic Boolean model provides a quantitative description of the budding yeast cell cycle
    Laomettachit, Teeraphan; Kraikivski, Pavel; Tyson, John J. (Springer Nature, 2022-12-01)
    The cell division cycle is regulated by a complex network of interacting genes and proteins. The control system has been modeled in many ways, from qualitative Boolean switching-networks to quantitative differential equations and highly detailed stochastic simulations. Here we develop a continuous-time stochastic model using seven Boolean variables to represent the activities of major regulators of the budding yeast cell cycle plus one continuous variable representing cell growth. The Boolean variables are updated asynchronously by logical rules based on known biochemistry of the cell-cycle control system using Gillespie’s stochastic simulation algorithm. Time and cell size are updated continuously. By simulating a population of yeast cells, we calculate statistical properties of cell cycle progression that can be compared directly to experimental measurements. Perturbations of the normal sequence of events indicate that the cell cycle is 91% robust to random ‘flips’ of the Boolean variables, but 9% of the perturbations induce lethal mistakes in cell cycle progression. This simple, hybrid Boolean model gives a good account of the growth and division of budding yeast cells, suggesting that this modeling approach may be as accurate as detailed reaction-kinetic modeling with considerably less demands on estimating rate constants.
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    Crosstalk between Plk1, p53, cell cycle, and G2/M DNA damage checkpoint regulation in cancer: computational modeling and analysis
    Jung, Yongwoon; Kraikivski, Pavel; Shafiekhani, Sajad; Terhune, Scott S.; Dash, Ranjan K. (Nature Portfolio, 2021-12-09)
    Different cancer cell lines can have varying responses to the same perturbations or stressful conditions. Cancer cells that have DNA damage checkpoint-related mutations are often more sensitive to gene perturbations including altered Plk1 and p53 activities than cancer cells without these mutations. The perturbations often induce a cell cycle arrest in the former cancer, whereas they only delay the cell cycle progression in the latter cancer. To study crosstalk between Plk1, p53, and G2/M DNA damage checkpoint leading to differential cell cycle regulations, we developed a computational model by extending our recently developed model of mitotic cell cycle and including these key interactions. We have used the model to analyze the cancer cell cycle progression under various gene perturbations including Plk1-depletion conditions. We also analyzed mutations and perturbations in approximately 1800 different cell lines available in the Cancer Dependency Map and grouped lines by genes that are represented in our model. Our model successfully explained phenotypes of various cancer cell lines under different gene perturbations. Several sensitivity analysis approaches were used to identify the range of key parameter values that lead to the cell cycle arrest in cancer cells. Our resulting model can be used to predict the effect of potential treatments targeting key mitotic and DNA damage checkpoint regulators on cell cycle progression of different types of cancer cells.
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    A Dynamic Mechanistic Model of Perceptual Binding
    Kraikivski, Pavel (MDPI, 2022-04-01)
    The brain’s ability to create a unified conscious representation of an object by integrating information from multiple perception pathways is called perceptual binding. Binding is crucial for normal cognitive function. Some perceptual binding errors and disorders have been linked to certain neurological conditions, brain lesions, and conditions that give rise to illusory conjunctions. However, the mechanism of perceptual binding remains elusive. Here, I present a computational model of binding using two sets of coupled oscillatory processes that are assumed to occur in response to two different percepts. I use the model to study the dynamic behavior of coupled processes to characterize how these processes can modulate each other and reach a temporal synchrony. I identify different oscillatory dynamic regimes that depend on coupling mechanisms and parameter values. The model can also discriminate different combinations of initial inputs that are set by initial states of coupled processes. Decoding brain signals that are formed through perceptual binding is a challenging task, but my modeling results demonstrate how crosstalk between two systems of processes can possibly modulate their outputs. Therefore, my mechanistic model can help one gain a better understanding of how crosstalk between perception pathways can affect the dynamic behavior of the systems that involve perceptual binding.
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    Genetic interactions derived from high-throughput phenotyping of 6589 yeast cell cycle mutants
    Gallegos, Jenna E.; Adames, Neil R.; Rogers, Mark F.; Kraikivski, Pavel; Ibele, Aubrey; Nurzynski-Loth, Kevin; Kudlow, Eric; Murali, T. M.; Tyson, John J.; Peccoud, Jean (2020-05-06)
    Over the last 30 years, computational biologists have developed increasingly realistic mathematical models of the regulatory networks controlling the division of eukaryotic cells. These models capture data resulting from two complementary experimental approaches: low-throughput experiments aimed at extensively characterizing the functions of small numbers of genes, and large-scale genetic interaction screens that provide a systems-level perspective on the cell division process. The former is insufficient to capture the interconnectivity of the genetic control network, while the latter is fraught with irreproducibility issues. Here, we describe a hybrid approach in which the 630 genetic interactions between 36 cell-cycle genes are quantitatively estimated by high-throughput phenotyping with an unprecedented number of biological replicates. Using this approach, we identify a subset of high-confidence genetic interactions, which we use to refine a previously published mathematical model of the cell cycle. We also present a quantitative dataset of the growth rate of these mutants under six different media conditions in order to inform future cell cycle models.
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    Implications of Noise on Neural Correlates of Consciousness: A Computational Analysis of Stochastic Systems of Mutually Connected Processes
    Kraikivski, Pavel (MDPI, 2021-05-08)
    Random fluctuations in neuronal processes may contribute to variability in perception and increase the information capacity of neuronal networks. Various sources of random processes have been characterized in the nervous system on different levels. However, in the context of neural correlates of consciousness, the robustness of mechanisms of conscious perception against inherent noise in neural dynamical systems is poorly understood. In this paper, a stochastic model is developed to study the implications of noise on dynamical systems that mimic neural correlates of consciousness. We computed power spectral densities and spectral entropy values for dynamical systems that contain a number of mutually connected processes. Interestingly, we found that spectral entropy decreases linearly as the number of processes within the system doubles. Further, power spectral density frequencies shift to higher values as system size increases, revealing an increasing impact of negative feedback loops and regulations on the dynamics of larger systems. Overall, our stochastic modeling and analysis results reveal that large dynamical systems of mutually connected and negatively regulated processes are more robust against inherent noise than small systems.
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    Mathematical Modeling in Systems Biology
    Kraikivski, Pavel (MDPI, 2023-09-25)
    Mathematical modeling is a key tool used in the field of systems biology to determine the mechanisms with which the elements of biological systems interact to produce complex dynamic behavior [...]
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    Mathematical modeling of macronutrient signaling in Saccharomyces cerevisiae
    Jalihal, Amogh Prabhav (Virginia Tech, 2020-07-08)
    In eukaryotes, distinct nutrient signals are integrated in order to produce robust cellular responses to fluctuations in the environment. This process of signal integration is attributed to the crosstalk between nutrient specific signaling pathways, as well as the large degree of overlap between their regulatory targets. In the budding yeast Saccharomyces cerevisiae, these distinct pathways have been well characterized. However, the significant overlap between these pathways confounds the interpretation of the overall regulatory logic in terms of nutrient-dependent cell state determination. Here, we propose a literature-curated molecular mechanism of the integrated nutrient signaling pathway in budding yeast, focussing on carbon and nitrogen signaling. We build a computational model of this pathway to reconcile the available experimental data with our proposed molecular mechanism. We evaluate the robustness of the model fit to data with respect to the variations in the values of kinetic parameters used to calibrate the model. Finally, we use the model to make novel, experimentally testable predictions of transcription factor activities in mutant strains undergoing complex nutrient shifts. We also propose a novel framework, called BoolODE for utilizing published Boolean models to generate synthetic datasets used to benchmark the performance of algorithms performing gene regulatory network inference from single cell RNA sequencing data.
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    Mathematical Models of Death Signaling Networks
    Srinivasan, Madhumita; Clarke, Robert; Kraikivski, Pavel (MDPI, 2022-10-01)
    This review provides an overview of the progress made by computational and systems biologists in characterizing different cell death regulatory mechanisms that constitute the cell death network. We define the cell death network as a comprehensive decision-making mechanism that controls multiple death execution molecular circuits. This network involves multiple feedback and feed-forward loops and crosstalk among different cell death-regulating pathways. While substantial progress has been made in characterizing individual cell death execution pathways, the cell death decision network is poorly defined and understood. Certainly, understanding the dynamic behavior of such complex regulatory mechanisms can be only achieved by applying mathematical modeling and system-oriented approaches. Here, we provide an overview of mathematical models that have been developed to characterize different cell death mechanisms and intend to identify future research directions in this field.
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    A Mechanistic Model of Perceptual Binding Predicts That Binding Mechanism Is Robust against Noise
    Kraikivski, Pavel (MDPI, 2024-01-31)
    The concept of the brain’s own time and space is central to many models and theories that aim to explain how the brain generates consciousness. For example, the temporo-spatial theory of consciousness postulates that the brain implements its own inner time and space for conscious processing of the outside world. Furthermore, our perception and cognition of time and space can be different from actual time and space. This study presents a mechanistic model of mutually connected processes that encode phenomenal representations of space and time. The model is used to elaborate the binding mechanism between two sets of processes representing internal space and time, respectively. Further, a stochastic version of the model is developed to investigate the interplay between binding strength and noise. Spectral entropy is used to characterize noise effects on the systems of interacting processes when the binding strength between them is varied. The stochastic modeling results reveal that the spectral entropy values for strongly bound systems are similar to those for weakly bound or even decoupled systems. Thus, the analysis performed in this study allows us to conclude that the binding mechanism is noise-resilient.
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    Modeling and analysis of the macronutrient signaling network in budding yeast
    Jalihal, Amogh P.; Kraikivski, Pavel; Murali, T. M.; Tyson, John J. (American Society for Cell Biology, 2021-11-01)
    Adaptive modulation of the global cellular growth state of unicellular organisms is crucial for their survival in fluctuating nutrient environments. Because these organisms must be able to respond reliably to ever varying and unpredictable nutritional conditions, their nutrient signaling networks must have a certain inbuilt robustness. In eukaryotes, such as the budding yeast Saccharomyces cerevisiae, distinct nutrient signals are relayed by specific plasma membrane receptors to signal transduction pathways that are interconnected in complex information-processing networks, which have been well characterized. However, the complexity of the signaling network confounds the interpretation of the overall regulatory "logic"of the control system. Here, we propose a literature-curated molecular mechanism of the integrated nutrient signaling network in budding yeast, focusing on early temporal responses to carbon and nitrogen signaling. We build a computational model of this network to reconcile literature-curated quantitative experimental data with our proposed molecular mechanism. We evaluate the robustness of our estimates of the model's kinetic parameter values. We test the model by comparing predictions made in mutant strains with qualitative experimental observations made in the same strains. Finally, we use the model to predict nutrient-responsive transcription factor activities in a number of mutant strains undergoing complex nutrient shifts.