Biology subjects

Grabowski, F.

Publications and source records attributed to Grabowski, F..

6 recordsLinked to original sources

bioRxiv2025

Quantifying cancer- and drug-induced changes in Shannon information capacity of RTK signaling

Signaling pathways transmit and process information, enabling cells to respond accurately to external cues. Disease states like cancer can corrupt signal transmission, though the magnitude to which they reduce information capacity has not been quantified. Here we apply pseudo-random pulsatile optogenetic stimulation, live-cell imaging, and information theory to compare the information capacity of receptor tyrosine kinase (RTK) signaling pathways in EML4-ALK-driven lung cancer cells (STE-1) and non-transformed lung epithelial cells (BEAS-2B). The information rate through the RTK/ERK pathway in STE-1 cells was below 0.5 bit/hour but increased to 3 bit/hour after oncogene inhibition. Information was transmitted by only 50-70% of cells, whose channel capacity (maximum information rate) was estimated through in silico protocol optimization. Although oncogene inhibition increased the capacity of the RTK/ERK pathway in STE-1 cells (6 bit/hour), capacity remained lower than in BEAS-2B (11 bit/hour). The capacity of the parallel RTK/calcineurin pathway in BEAS-2B exceeded 15 bit/hour. This study highlights information capacity as a sensitive metric for identifying disease-associated dysfunction and evaluating effects of targeted interventions.

systems biology↗

bioRxiv2024

Type III interferons suppress influenza A virus infection independently of STAT activation by triggering cell death

Type III interferons (IFN-{lambda}1-{lambda}4) are known to limit influenza virus infections in vivo and are non-redundant to type I interferons (IFN- and IFN-{beta}). Here, we demonstrate that IFN-{lambda} acts through mechanisms that are beyond its ability to induce JAK/STAT signaling and promotes fast cell death in epithelial cells stimulated with poly(I:C). Studying influenza A virus (IAV) and respiratory syncytial virus (RSV) infections in vitro we notice that type I interferons, when provided prior to infection, induce higher STAT1/2 activation and a stronger accumulation of proteins coded by interferon-stimulated genes, and correspondingly suppress both IAV and RSV spread more effectively than type III interferons. The knockout of the IFN-{lambda} receptor (subunit IFNLR1), compared to the knockout of the IFN-{beta} receptor (subunit IFNAR1), only slightly influences levels of STAT1/2 phosphorylation during infection with any of the viruses; However, IFNLR1 knockout results in a greater proportion of IAV-infected cells and higher viral RNA and protein levels. We showed that the ratio of dying to infected cells is lower in IFNLR1-deficient cells compared to wild-type cells, suggesting that IFN-{lambda} promotes the rapid death of IAV-infected cells and thereby limits viral spread. This effect was not observed in RSV-infected cultures, possibly due to the RSVs ability to suppress host cell death through its nonstructural proteins. Overall, our results reveal a distinct role for IFN-{lambda} in restricting viral infections by triggering rapid death of infected epithelial cells, in contrast to type I interferons, which are the main inducers of JAK/STAT-mediated expression of ISGs, that may be used by IFN-{lambda} to trigger cell death.

immunology↗

bioRxiv2024

Information transmission in a cell monolayer: A numerical study

Motivated by the spatiotemporal waves of MAPK/ERK activity, crucial for long-range communication in regenerating tissues, we investigated stochastic homoclinic fronts propagating through channels formed by directly interacting cells. We evaluated the efficiency of long-range communication in these channels by examining the rate of information transmission. Our study identified the stochastic phenomena that reduce this rate: front propagation failure, new front spawning, and variability in the front velocity. We found that a trade-off between the frequencies of propagation failures and new front spawning determines the optimal channel width (which geometrically determines the front length). The optimal frequency of initiating new waves is determined by a trade-off between the input information rate (higher with more frequent initiation) and the fidelity of information transmission (lower with more frequent initiation). Our analysis provides insight into the relative timescales of intra- and intercellular processes necessary for successful wave propagation. Author SummaryIn biological tissues, traveling waves of cellular activity are observed in the process of wound healing when they coordinate cell replication and collective migration. These waves can carry information over long distances. However, random effects on the single-cell level can affect wave propagation and disrupt information flow. In this paper, using a numerical model we classified these stochastic events and quantified the maximum range and frequency of such waves and their capacity to carry information. We discovered that most effective transmission occurs in relatively narrow channels (formed by directly interacting cells), and that the refractory time, in which a cell is resistant to activation by neighboring cells, must be long with respect to the time needed for cell activation. The optimal time intervals between the initiated waves are of order of few refractory times (depending on channel length).

systems biology↗

bioRxiv2023

Predictive power of non-identifiable models

Resolving practical nonidentifiability of computational models typically requires either additional data or non-algorithmic model reduction, which frequently results in models containing parameters lacking direct interpretation. Here, instead of reducing models, we explore an alternative, Bayesian approach, and quantify predictive power of non-identifiable models. Considering an example biochemical signalling cascade model as well as its mechanical analog, we demonstrate that by measuring a single variable in response to a properly chosen stimulation protocol, the dimensionality of the parameter space is reduced, which allows for prediction of its trajectory in response to different stimulation protocols even if all model parameters remain unidentified. Successive measurements of remaining variables further constrain model parameters and enable more predictions. We analyse potential pitfalls of the proposed approach that can arise when the investigated model is oversimplified, incorrect, or when the training protocol is inadequate. The main advantage of the suggested iterative approach is that the predictive power of the model can be assessed and practically utilised at each step.

systems biology↗

bioRxiv2022

Antagonism between viral infection and innate immunity at the single-cell level

When infected with a virus, cells may secrete interferons (IFNs) that prompt nearby cells to prepare for upcoming infection. Reciprocally, viral proteins often interfere with IFN synthesis and IFN-induced signaling. We modeled the crosstalk between the propagating virus and the innate immune response using an agent-based stochastic approach. By analyzing immunofluorescence microscopy images we observed that the mutual antagonism between the respiratory syncytial virus (RSV) and infected A549 cells leads to dichotomous responses at the single-cell level and complex spatial patterns of cell signaling states. Our analysis indicates that RSV blocks innate responses at three levels: by inhibition of IRF3 activation, inhibition of IFN synthesis, and inhibition of STAT1/2 activation. In turn, proteins coded by IFN-stimulated (STAT1/2-activated) genes inhibit the synthesis of viral RNA and viral proteins. The striking consequence of these inhibitions is lack of coincidence of viral proteins and IFN expression within single cells. The model enables investigation of the impact of immunostimulatory defective viral particles and signaling network perturbations that could potentially facilitate containment or clearance of the viral infection.

systems biology↗

bioRxiv2018

Limits to the rate of information transmissionthrough MAPK pathway

Two important signaling pathways of NF-{kappa}B and ERK transmit merely one bit of information about the level of extracellular stimulation. It is thus unclear how such systems can coordinate complex cell responses to external cues. Here, we analyze information transmission in the MAPK/ERK pathway that features relaxation oscillations and responds to EGF by pulses of activated ERK. Based on an experimentally verified computational model of the MAPK/ERK pathway, we demonstrate that when input sequences of EGF pulses are transcoded to output sequences of ERK activity pulses, transmitted information increases nearly linearly with time. Moreover, the information channel capacity C (defined as the upper limit of information that can be transmitted over a sufficiently long time t, divided by t), is not limited by the bandwidth B = 1/{tau}, where {tau} {approx} 1 hour is the relaxation time. Specifically, when input is provided in the form of sequences of short binary EGF pulses separated by varying intervals that are multiples of {tau}/n (but are not shorter than {tau}), then for n = 2, C {approx} 1.39 bit/hour; and for n = 4, C {approx} 1.86 bit/hour. We hypothesize that the primary mode of operation of the MAPK pathway is to translate extracellular growth factor \"bursts\" into precisely timed intracellular ERK \"spikes\" of a predefined amplitude. Such pulse-interval transcoding allows to relay more information than the amplitude-amplitude transcoding considered previously for the ERK and NF-{kappa}B pathways.\n\nAuthor summaryTo coordinate their actions, cells communicate with each other by sending, receiving, and interpreting cytokine signals. Cells recognize chemical identity of signaling molecules and process quantitative and temporal properties of stimulation: amplitude, duration, or frequency. Previous studies indicated that the MAPK pathway transmits about one bit of information about the amplitude (concentration) of a stimulating cytokine, EGF. Sending more information may be enabled by temporal signal modulation. Here, we use the conceptual framework of information theory to support a hypothesis that the MAPK pathway, analyzed as a noisy information channel, reaches maximum information transmission rate when receiving sequences of EGF pulses that are transcoded to sequences of activity pulses of an effector kinase of the pathway, ERK. Since the pathway resetting time is about 1 hour, one could expect that--when sending EGF pulses of \"0\" or \"1\" amplitude every hour--the pathway is able transmit up to 1 bit per hour. We show, however, that when EGF pulses are separated by intervals that are not shorter than 1 hour and are multiples of 15 min (60, 75, 90 min, etc.), information rate can be nearly 2 bits per hour. We hypothesize that high information rate is necessary to control cell proliferation and motility.

systems biology↗