scholarly journals Anticipating critical transitions in epithelial-hybrid-mesenchymal cell-fate determination

2019 ◽  
Author(s):  
Sukanta Sarkar ◽  
Sudipta Kumar Sinha ◽  
Herbert Levine ◽  
Mohit Kumar Jolly ◽  
Partha Sharathi Dutta
Keyword(s):  
Drug Resistance ◽  
Cell Fate ◽  
Early Warning ◽  
Cancer Metastasis ◽  
Critical Slowing Down ◽  
Warning Signals ◽  
Early Warning Signals ◽  
Slowing Down ◽  
Tumor Relapse ◽  
Critical Transitions

AbstractIn the vicinity of a tipping point, critical transitions occur when small changes in an input condition causes sudden, large and often irreversible changes in the state of a system. Many natural systems ranging from ecosystems to molecular biosystems are known to exhibit critical transitions in their response to stochastic perturbations. In diseases, an early prediction of upcoming critical transitions from a healthy to a disease state by using early warning signals is of prime interest due to potential application in forecasting disease onset. Here, we analyze cell-fate transitions between different phenotypes (epithelial, hybrid epithelial/mesenchymal (E/M) and mesenchymal states) that are implicated in cancer metastasis and chemoresistance. These transitions are mediated by a mutually inhibitory feedback loop microRNA-200/ZEB driven by the levels of transcription factor SNAIL. We find that the proximity to tipping points enabling these transitions among different phenotypes can be captured by critical slowing down based early warning signals, calculated from the trajectory of ZEB mRNA level. Further, the basin stability analysis reveals the unexpectedly large basin of attraction for a hybrid E/M phenotype. Finally, we identified mechanisms that can potentially elude the transition to a hybrid E/M phenotype. Overall, our results unravel the early warning signals that can be used to anticipate upcoming epithelial-hybrid-mesenchymal transitions. With the emerging evidence about the hybrid E/M phenotype being a key driver of metastasis, drug resistance, and tumor relapse; our results suggest ways to potentially evade these transitions, reducing the fitness of cancer cells and restricting tumor aggressiveness.Significance StatementEpithelial-hybrid-mesenchymal transitions play critical roles in cancer metastasis, drug resistance, and tumor relapse. Recent studies have proposed that cells in a hybrid epithelial/mesenchymal phenotype may be more aggressive than those on either end of the spectrum. However, no biomarker to predict upcoming transitions has been identified. Here, we show that critical slowing down based early warning signals can detect sudden transitions among epithelial, hybrid E/M, and mesenchymal phenotypes. Importantly, our results highlight how stable a hybrid E/M phenotype can be, and how can a transition to this state be avoided. Thus, our study provides valuable insights into restricting cellular plasticity en route metastasis.

scholarly journals Anticipating critical transitions in epithelial–hybrid-mesenchymal cell-fate determination

2019 ◽  
Vol 116 (52) ◽  
pp. 26343-26352 ◽  
Author(s):  
Sukanta Sarkar ◽  
Sudipta Kumar Sinha ◽  
Herbert Levine ◽  
Mohit Kumar Jolly ◽  
Partha Sharathi Dutta
Keyword(s):  
Cell Fate ◽  
Early Warning ◽  
Messenger Rna ◽  
Cancer Metastasis ◽  
Basin Of Attraction ◽  
Disease Onset ◽  
Warning Signals ◽  
Early Warning Signals ◽  
Stochastic Perturbations ◽  
Critical Transitions

In the vicinity of a tipping point, critical transitions occur when small changes in an input condition cause sudden, large, and often irreversible changes in the state of a system. Many natural systems ranging from ecosystems to molecular biosystems are known to exhibit critical transitions in their response to stochastic perturbations. In diseases, an early prediction of upcoming critical transitions from a healthy to a disease state by using early-warning signals is of prime interest due to potential application in forecasting disease onset. Here, we analyze cell-fate transitions between different phenotypes (epithelial, hybrid-epithelial/mesenchymal [E/M], and mesenchymal states) that are implicated in cancer metastasis and chemoresistance. These transitions are mediated by a mutually inhibitory feedback loop—microRNA-200/ZEB—driven by the levels of transcription factor SNAIL. We find that the proximity to tipping points enabling these transitions among different phenotypes can be captured by critical slowing down-based early-warning signals, calculated from the trajectory of ZEB messenger RNA level. Further, the basin stability analysis reveals the unexpectedly large basin of attraction for a hybrid-E/M phenotype. Finally, we identified mechanisms that can potentially elude the transition to a hybrid-E/M phenotype. Overall, our results unravel the early-warning signals that can be used to anticipate upcoming epithelial–hybrid-mesenchymal transitions. With the emerging evidence about the hybrid-E/M phenotype being a key driver of metastasis, drug resistance, and tumor relapse, our results suggest ways to potentially evade these transitions, reducing the fitness of cancer cells and restricting tumor aggressiveness.

scholarly journals Anticipating Critical Transitions in Psychological Systems using Early Warning Signals: Theoretical and Practical Considerations

2020 ◽  
Author(s):  
Fabian Dablander ◽  
Anton Pichler ◽  
Arta Cika ◽  
Andrea Bacilieri
Keyword(s):  
Early Warning ◽  
Stable State ◽  
Critical Slowing Down ◽  
Future Research ◽  
Frequency Noise ◽  
Alternative Stable State ◽  
Warning Signals ◽  
Early Warning Signals ◽  
Slowing Down ◽  
Critical Transitions

Many real-world systems can exhibit sudden shifts from one stable state to another, and the theory of dynamical systems points to the existence of generic early warning signals that precede such shifts. Recently, psychologists have begun to conceptualize mental disorders such as depression as an alternative stable state, and suggested that early warning signals based on the phenomenon of critical slowing down might be useful for predicting sudden transitions into depression or other psychiatric disorders. Harnessing the potential of early warning signals requires us to understand their limitations as well as the factors influencing their performance in practice. In this paper, we (a) review limitations of early warning signals based on critical slowing down to better understand when they can and cannot occur, and (b) study the conditions under which early warning signals may anticipate critical transitions in online-monitoring settings by simulating from a bistable dynamical system, varying crucial features such as sampling frequency, noise intensity, and speed of approaching the tipping point. We find that, in sharp contrast to their reputation of being generic or model-agnostic, whether early warning signals occur or not strongly depends on the specifics of the system. We also find that they are very sensitive to noise, potentially limiting their utility in practical applications. We discuss the implications of our findings and provide suggestions and recommendations for future research.

scholarly journals Early warning signals of malaria resurgence in Kericho, Kenya

2020 ◽  
Vol 16 (3) ◽  
pp. 20190713 ◽  
Author(s):  
Mallory J. Harris ◽  
Simon I. Hay ◽  
John M. Drake
Keyword(s):  
Early Warning ◽  
Disease Transmission ◽  
Empirical Test ◽  
Disease Incidence ◽  
Critical Slowing Down ◽  
Summary Statistics ◽  
Warning Signals ◽  
Early Warning Signals ◽  
Slowing Down ◽  
Imported Case

Campaigns to eliminate infectious diseases could be greatly aided by methods for providing early warning signals of resurgence. Theory predicts that as a disease transmission system undergoes a transition from stability at the disease-free equilibrium to sustained transmission, it will exhibit characteristic behaviours known as critical slowing down, referring to the speed at which fluctuations in the number of cases are dampened, for instance the extinction of a local transmission chain after infection from an imported case. These phenomena include increases in several summary statistics, including lag-1 autocorrelation, variance and the first difference of variance. Here, we report the first empirical test of this prediction during the resurgence of malaria in Kericho, Kenya. For 10 summary statistics, we measured the approach to criticality in a rolling window to quantify the size of effect and directions. Nine of the statistics increased as predicted and variance, the first difference of variance, autocovariance, lag-1 autocorrelation and decay time returned early warning signals of critical slowing down based on permutation tests. These results show that time series of disease incidence collected through ordinary surveillance activities may exhibit characteristic signatures prior to an outbreak, a phenomenon that may be quite general among infectious disease systems.

scholarly journals Early-Warning Signals of Drought-Flood State Transition over the Dongting Lake Basin Based on the Critical Slowing Down Theory

Atmosphere ◽  
2021 ◽  
Vol 12 (8) ◽  
pp. 1082
Author(s):  
Hao Wu ◽  
Wei Hou ◽  
Dongdong Zuo ◽  
Pengcheng Yan ◽  
Yuxing Zeng
Keyword(s):  
Early Warning ◽  
State Transition ◽  
Dongting Lake ◽  
Critical Slowing Down ◽  
Lake Basin ◽  
Autocorrelation Coefficient ◽  
Warning Signals ◽  
Early Warning Signals ◽  
Technological Support ◽  
Slowing Down

In this study, the standardized precipitation index (SPI) data in Hunan Province from 1961 to 2020 is adopted. Based on the critical slowing down theory, the moving t-test is firstly used to determine the time of drought-flood state transition in the Dongting Lake basin. Afterwards, by means of the variance and autocorrelation coefficient that characterize the phenomenon of critical slowing down, the early-warning signals indicating the drought-flood state in the Dongting Lake basin are explored. The results show that an obvious drought-to-flood (flood-to-drought) event occurred around 1993 (2003) in the Dongting Lake basin in recent 60 years. The critical slowing down phenomena of the increases in the variance and autocorrelation coefficient, which are detected 5–10 years in advance, can be considered as early-warning signals indicating the drought-flood state transition. Through the studies on the drought-flood state and related early-warning signals for the Dongting Lake basin, the reliabilities of the variance and autocorrelation coefficient-based early-warning signals for abrupt changes are demonstrated. It is expected that the wide application of this method could provide important scientific and technological support for disaster prevention and mitigation in the Dongting Lake basin, and even in the middle and lower reaches of the Yangtze River.

scholarly journals Spatial Correlation as an Early Warning Signal of Regime Shifts in a Multiplex Disease-Behaviour Network

2017 ◽  
Author(s):  
Peter C. Jentsch ◽  
Madhur Anand ◽  
Chris T. Bauch
Keyword(s):  
Spatial Correlation ◽  
Early Warning ◽  
Regime Shift ◽  
Tipping Point ◽  
Regime Shifts ◽  
Critical Slowing Down ◽  
Warning Signals ◽  
Early Warning Signals ◽  
Network Layer ◽  
Slowing Down

AbstractEarly warning signals of sudden regime shifts are a widely studied phenomenon for their ability to quantify a system’s proximity to a tipping point to a new and contrasting dynamical regime. However, this effect has been little studied in the context of the complex interactions between disease dynamics and vaccinating behaviour. Our objective was to determine whether critical slowing down (CSD) occurs in a multiplex network that captures opinion propagation on one network layer and disease spread on a second network layer. We parameterized a network simulation model to represent a hypothetical self-limiting, acute, vaccine-preventable infection with shortlived natural immunity. We tested five different network types: random, lattice, small-world, scale-free, and an empirically derived network. For the first four network types, the model exhibits a regime shift as perceived vaccine risk moves beyond a tipping point from full vaccine acceptance and disease elimination to full vaccine refusal and disease endemicity. This regime shift is preceded by an increase in the spatial correlation in non-vaccinator opinions beginning well before the bifurcation point, indicating CSD. The early warning signals occur across a wide range of parameter values. However, the more gradual transition exhibited in the empirically-derived network underscores the need for further research before it can be determined whether trends in spatial correlation in real-world social networks represent critical slowing down. The potential upside of having this monitoring ability suggests that this is a worthwhile area for further research.

scholarly journals Detecting and distinguishing tipping points using spectral early warning signals

2020 ◽  
Vol 17 (170) ◽  
pp. 20200482
Author(s):  
T. M. Bury ◽  
C. T. Bauch ◽  
M. Anand
Keyword(s):  
Complex Systems ◽  
Early Warning ◽  
Dynamical Regime ◽  
Tipping Points ◽  
Warning Signals ◽  
Early Warning Signals ◽  
Density Dependent ◽  
Critical Transitions ◽  
Fold Bifurcation ◽  
Characteristic Signal

Theory and observation tell us that many complex systems exhibit tipping points—thresholds involving an abrupt and irreversible transition to a contrasting dynamical regime. Such events are commonly referred to as critical transitions. Current research seeks to develop early warning signals (EWS) of critical transitions that could help prevent undesirable events such as ecosystem collapse. However, conventional EWS do not indicate the type of transition, since they are based on the generic phenomena of critical slowing down. For instance, they may fail to distinguish the onset of oscillations (e.g. Hopf bifurcation) from a transition to a distant attractor (e.g. Fold bifurcation). Moreover, conventional EWS are less reliable in systems with density-dependent noise. Other EWS based on the power spectrum (spectral EWS) have been proposed, but they rely upon spectral reddening, which does not occur prior to critical transitions with an oscillatory component. Here, we use Ornstein–Uhlenbeck theory to derive analytic approximations for EWS prior to each type of local bifurcation, thereby creating new spectral EWS that provide greater sensitivity to transition proximity; higher robustness to density-dependent noise and bifurcation type; and clues to the type of approaching transition. We demonstrate the advantage of applying these spectral EWS in concert with conventional EWS using a population model, and show that they provide a characteristic signal prior to two different Hopf bifurcations in data from a predator–prey chemostat experiment. The ability to better infer and differentiate the nature of upcoming transitions in complex systems will help humanity manage critical transitions in the Anthropocene Era.

scholarly journals Performance of early warning signals for disease emergence: a case study on COVID-19 data

2021 ◽  
Author(s):  
Daniele Proverbio ◽  
Françoise Kemp ◽  
Stefano Magni ◽  
Jorge Gonçalves
Keyword(s):  
Early Warning ◽  
Disease Emergence ◽  
Warning Signals ◽  
Active Monitoring ◽  
Prevalence Data ◽  
Early Warning Signals ◽  
Epidemic Dynamics ◽  
Critical Transitions ◽  
Parameter Values

AbstractThe sudden emergence of infectious diseases pose threats to societies worldwide and it is notably difficult to detect. In the past few years, several early warning signals (EWS) were introduced, to alert to impending critical transitions and extend the set of indicators for risk assessment. While they were originally thought to be generic, recent works demonstrated their sensitivity to some dynamical characteristics such as system noise and rates of approach to critical parameter values. Moreover, testing on empirical data is so far limited. Hence, validating their performance remains a challenge. In this study, we analyse the performance of common EWS such as increasing variance and autocorrelation in detecting the emergence of COVID-19 outbreaks in various countries, based on prevalence data. We show that EWS are successful in detecting disease emergence provided that some basic assumptions are satisfied: a slow forcing through the transitions and not fat-tailed noise. We also show cases where EWS fail, thus providing a verification analysis of their potential and limitations. Overall, this suggests that EWS can be useful for active monitoring of epidemic dynamics, but that their performance is sensitive to surveillance procedures. Our results thus represent a further step towards the application of EWS indicators for informing public health policies.

scholarly journals Early warning signals from the periphery

2021 ◽  
Author(s):  
Manfred Füllsack ◽  
Daniel Reisinger ◽  
Marie Kapeller ◽  
Georg Jäger
Keyword(s):  
Time Series ◽  
Social Interactions ◽  
Early Warning ◽  
Focus Attention ◽  
Warning Signals ◽  
Feedback Effects ◽  
Early Warning Signals ◽  
Agent Based ◽  
Critical Transitions ◽  
Micro Level

AbstractStudies on the possibility of predicting critical transitions with statistical methods known as early warning signals (EWS) are often conducted on data generated with equation-based models (EBMs). These models base on difference or differential equations, which aggregate a system’s components in a mathematical term and therefore do not allow for a detailed analysis of interactions on micro-level. As an alternative, we suggest a simple, but highly flexible agent-based model (ABM), which, when applying EWS-analysis, gives reason to (a) consider social interaction, in particular negative feedback effects, as an essential trigger of critical transitions, and (b) to differentiate social interactions, for example in network representations, into a core and a periphery of agents and focus attention on the periphery. Results are tested against time series from a networked version of the Ising-model, which is often used as example for generating hysteretic critical transitions.

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