Neuronal activity induces symmetry breaking in neurodegenerative disease spreading.

Dynamical systems on networks typically involve several dynamical processes evolving at different timescales. For instance, in Alzheimer's disease, the spread of toxic protein throughout the brain not only disrupts neuronal activity but is also influenced by neuronal activity itself, establishing a feedback loop between the fast neuronal activity and the slow protein spreading. Motivated by the case of Alzheimer's disease, we study the multiple-timescale dynamics of a heterodimer spreading process on an adaptive network of Kuramoto oscillators. Using a minimal two-node model, we establish that heterogeneous oscillatory activity facilitates toxic outbreaks and induces symmetry breaking in the spreading patterns. We then extend the model formulation to larger networks and perform numerical simulations of the slow-fast dynamics on common network motifs and on the brain connectome. The simulations corroborate the findings from the minimal model, underscoring the significance of multiple-timescale dynamics in the modeling of neurodegenerative diseases.

Threshold dynamics of a reaction-advection-diffusion schistosomiasis epidemic model with seasonality and spatial heterogeneity.

Most water-borne disease models ignore the advection of water flows in order to simplify the mathematical analysis and numerical computation. However, advection can play an important role in determining the disease transmission dynamics. In this paper, we investigate the long-term dynamics of a periodic reaction-advection-diffusion schistosomiasis model and explore the joint impact of advection, seasonality and spatial heterogeneity on the transmission of the disease. We derive the basic reproduction number R 0 and show that the disease-free periodic solution is globally attractive when R 0 < 1 whereas there is a positive endemic periodic solution and the system is uniformly persistent in a special case when R 0 > 1 . Moreover, we find that R 0 is a decreasing function of the advection coefficients which offers insights into why schistosomiasis is more serious in regions with slow water flows.

Modelling phytoplankton-virus interactions: phytoplankton blooms and lytic virus transmission.

A dynamic reaction-diffusion model of four variables is proposed to describe the spread of lytic viruses among phytoplankton in a poorly mixed aquatic environment. The basic ecological reproductive index for phytoplankton invasion and the basic reproduction number for virus transmission are derived to characterize the phytoplankton growth and virus transmission dynamics. The theoretical and numerical results from the model show that the spread of lytic viruses effectively controls phytoplankton blooms. This validates the observations and experimental results of Emiliana huxleyi-lytic virus interactions. The studies also indicate that the lytic virus transmission cannot occur in a low-light or oligotrophic aquatic environment.

Evolution of Cooperation in Spatio-Temporal Evolutionary Games with Public Goods Feedback.

In biology, evolutionary game-theoretical models often arise in which players' strategies impact the state of the environment, driving feedback between strategy and the surroundings. In this case, cooperative interactions can be applied to studying ecological systems, animal or microorganism populations, and cells producing or actively extracting a growth resource from their environment. We consider the framework of eco-evolutionary game theory with replicator dynamics and growth-limiting public goods extracted by population members from some external source. It is known that the two sub-populations of cooperators and defectors can develop spatio-temporal patterns that enable long-term coexistence in the shared environment. To investigate this phenomenon and unveil the mechanisms that sustain cooperation, we analyze two eco-evolutionary models: a well-mixed environment and a heterogeneous model with spatial diffusion. In the latter, we integrate spatial diffusion into replicator dynamics. Our findings reveal rich strategy dynamics, including bistability and bifurcations, in the temporal system and spatial stability, as well as Turing instability, Turing-Hopf bifurcations, and chaos in the diffusion system. The results indicate that effective mechanisms to promote cooperation include increasing the player density, decreasing the relative timescale, controlling the density of initial cooperators, improving the diffusion rate of the public goods, lowering the diffusion rate of the cooperators, and enhancing the payoffs to the cooperators. We provide the conditions for the existence, stability, and occurrence of bifurcations in both systems. Our analysis can be applied to dynamic phenomena in fields as diverse as human decision-making, microorganism growth factors secretion, and group hunting.

The Michaelis-Menten Reaction at Low Substrate Concentrations: Pseudo-First-Order Kinetics and Conditions for Timescale Separation.

We demonstrate that the Michaelis-Menten reaction mechanism can be accurately approximated by a linear system when the initial substrate concentration is low. This leads to pseudo-first-order kinetics, simplifying mathematical calculations and experimental analysis. Our proof utilizes a monotonicity property of the system and Kamke's comparison theorem. This linear approximation yields a closed-form solution, enabling accurate modeling and estimation of reaction rate constants even without timescale separation. Building on prior work, we establish that the sufficient condition for the validity of this approximation is s 0 ≪ K , where K = k 2 / k 1 is the Van Slyke-Cullen constant. This condition is independent of the initial enzyme concentration. Further, we investigate timescale separation within the linear system, identifying necessary and sufficient conditions and deriving the corresponding reduced one-dimensional equations.

The Unification of Evolutionary Dynamics through the Bayesian Decay Factor in a Game on a Graph.

We unify evolutionary dynamics on graphs in strategic uncertainty through a decaying Bayesian update. Our analysis focuses on the Price theorem of selection, which governs replicator(-mutator) dynamics, based on a stratified interaction mechanism and a composite strategy update rule. Our findings suggest that the replication of a certain mutation in a strategy, leading to a shift from competition to cooperation in a well-mixed population, is equivalent to the replication of a strategy in a Bayesian-structured population without any mutation. Likewise, the replication of a strategy in a Bayesian-structured population with a certain mutation, resulting in a move from competition to cooperation, is equivalent to the replication of a strategy in a well-mixed population without any mutation. This equivalence holds when the transition rate from competition to cooperation is equal to the relative strength of selection acting on either competition or cooperation in relation to the selection differential between cooperators and competitors. Our research allows us to identify situations where cooperation is more likely, irrespective of the specific payoff levels. This approach provides new perspectives into the intended purpose of Price's equation, which was initially not designed for this type of analysis.

Evolving Improved Sampling Protocols for Dose-Response Modelling Using Genetic Algorithms with a Profile-Likelihood Metric.

Practical limitations of quality and quantity of data can limit the precision of parameter identification in mathematical models. Model-based experimental design approaches have been developed to minimise parameter uncertainty, but the majority of these approaches have relied on first-order approximations of model sensitivity at a local point in parameter space. Practical identifiability approaches such as profile-likelihood have shown potential for quantifying parameter uncertainty beyond linear approximations. This research presents a genetic algorithm approach to optimise sample timing across various parameterisations of a demonstrative PK-PD model with the goal of aiding experimental design. The optimisation relies on a chosen metric of parameter uncertainty that is based on the profile-likelihood method. Additionally, the approach considers cases where multiple parameter scenarios may require simultaneous optimisation. The genetic algorithm approach was able to locate near-optimal sampling protocols for a wide range of sample number (n = 3-20), and it reduced the parameter variance metric by 33-37% on average. The profile-likelihood metric also correlated well with an existing Monte Carlo-based metric (with a worst-case r > 0.89), while reducing computational cost by an order of magnitude. The combination of the new profile-likelihood metric and the genetic algorithm demonstrate the feasibility of considering the nonlinear nature of models in optimal experimental design at a reasonable computational cost. The outputs of such a process could allow for experimenters to either improve parameter certainty given a fixed number of samples, or reduce sample quantity while retaining the same level of parameter certainty.

Markovian Approach for Exploring Competitive Diseases with Heterogeneity-Evidence from COVID-19 and Influenza in China.

Due to the complex interactions between multiple infectious diseases, the spreading of diseases in human bodies can vary when people are exposed to multiple sources of infection at the same time. Typically, there is heterogeneity in individuals' responses to diseases, and the transmission routes of different diseases also vary. Therefore, this paper proposes an SIS disease spreading model with individual heterogeneity and transmission route heterogeneity under the simultaneous action of two competitive infectious diseases. We derive the theoretical epidemic spreading threshold using quenched mean-field theory and perform numerical analysis under the Markovian method. Numerical results confirm the reliability of the theoretical threshold and show the inhibitory effect of the proportion of fully competitive individuals on epidemic spreading. The results also show that the diversity of disease transmission routes promotes disease spreading, and this effect gradually weakens when the epidemic spreading rate is high enough. Finally, we find a negative correlation between the theoretical spreading threshold and the average degree of the network. We demonstrate the practical application of the model by comparing simulation outputs to temporal trends of two competitive infectious diseases, COVID-19 and seasonal influenza in China.

Revealing Decision-Making Strategies of Americans in Taking COVID-19 Vaccination.

Efficient coverage for newly developed vaccines requires knowing which groups of individuals will accept the vaccine immediately and which will take longer to accept or never accept. Of those who may eventually accept the vaccine, there are two main types: success-based learners, basing their decisions on others' satisfaction, and myopic rationalists, attending to their own immediate perceived benefit. We used COVID-19 vaccination data to fit a mechanistic model capturing the distinct effects of the two types on the vaccination progress. We proved the identifiability of the population proportions of each type and estimated that 47 % of Americans behaved as myopic rationalists with a high variation across the jurisdictions, from 31 % in Mississippi to 76 % in Vermont. The proportion was correlated with the vaccination coverage, proportion of votes in favor of Democrats in 2020 presidential election, and education score.

Linking Spontaneous Behavioral Changes to Disease Transmission Dynamics: Behavior Change Includes Periodic Oscillation.

Behavior change significantly influences the transmission of diseases during outbreaks. To incorporate spontaneous preventive measures, we propose a model that integrates behavior change with disease transmission. The model represents behavior change through an imitation process, wherein players exclusively adopt the behavior associated with higher payoff. We find that relying solely on spontaneous behavior change is insufficient for eradicating the disease. The dynamics of behavior change are contingent on the basic reproduction number R a corresponding to the scenario where all players adopt non-pharmaceutical interventions (NPIs). When R a < 1 , partial adherence to NPIs remains consistently feasible. We can ensure that the disease stays at a low level or maintains minor fluctuations around a lower value by increasing sensitivity to perceived infection. In cases where oscillations occur, a further reduction in the maximum prevalence of infection over a cycle can be achieved by increasing the rate of behavior change. When R a > 1 , almost all players consistently adopt NPIs if they are highly sensitive to perceived infection. Further consideration of saturated recovery leads to saddle-node homoclinic and Bogdanov-Takens bifurcations, emphasizing the adverse impact of limited medical resources on controlling the scale of infection. Finally, we parameterize our model with COVID-19 data and Tokyo subway ridership, enabling us to illustrate the disease spread co-evolving with behavior change dynamics. We further demonstrate that an increase in sensitivity to perceived infection can accelerate the peak time and reduce the peak size of infection prevalence in the initial wave.

Inferring Stochastic Rates from Heterogeneous Snapshots of Particle Positions.

Many imaging techniques for biological systems-like fixation of cells coupled with fluorescence microscopy-provide sharp spatial resolution in reporting locations of individuals at a single moment in time but also destroy the dynamics they intend to capture. These snapshot observations contain no information about individual trajectories, but still encode information about movement and demographic dynamics, especially when combined with a well-motivated biophysical model. The relationship between spatially evolving populations and single-moment representations of their collective locations is well-established with partial differential equations (PDEs) and their inverse problems. However, experimental data is commonly a set of locations whose number is insufficient to approximate a continuous-in-space PDE solution. Here, motivated by popular subcellular imaging data of gene expression, we embrace the stochastic nature of the data and investigate the mathematical foundations of parametrically inferring demographic rates from snapshots of particles undergoing birth, diffusion, and death in a nuclear or cellular domain. Toward inference, we rigorously derive a connection between individual particle paths and their presentation as a Poisson spatial process. Using this framework, we investigate the properties of the resulting inverse problem and study factors that affect quality of inference. One pervasive feature of this experimental regime is the presence of cell-to-cell heterogeneity. Rather than being a hindrance, we show that cell-to-cell geometric heterogeneity can increase the quality of inference on dynamics for certain parameter regimes. Altogether, the results serve as a basis for more detailed investigations of subcellular spatial patterns of RNA molecules and other stochastically evolving populations that can only be observed for single instants in their time evolution.

A Model of Gastric Mucosal pH Regulation: Extending Sensitivity Analysis Using Sobol' Indices to Understand Higher Moments.

Several recent theoretical studies have indicated that a relatively simple secretion control mechanism in the epithelial cells lining the stomach may be responsible for maintaining a neutral (healthy) pH adjacent to the stomach wall, even in the face of enormous electrodiffusive acid transport from the interior of the stomach. Subsequent work used Sobol' Indices (SIs) to quantify the degree to which this secretion mechanism is "self-regulating" i.e. the degree to which the wall pH is held neutral as mathematical parameters vary. However, questions remain regarding the nature of the control that specific parameters exert over the maintenance of a healthy stomach wall pH. Studying the sensitivity of higher moments of the statistical distribution of a model output can provide useful information, for example, how one parameter may skew the distribution towards or away from a physiologically advantageous regime. In this work, we prove a relationship between SIs and the higher moments and show how it can potentially reduce the cost of computing sensitivity of said moments. We define γ -indices to quantify sensitivity of variance, skewness, and kurtosis to the choice of value of a parameter, and we propose an efficient strategy that uses both SIs and γ -indices for a more comprehensive sensitivity analysis. Our analysis uncovers a control parameter which governs the "tightness of control" that the secretion mechanism exerts on wall pH. Finally, we discuss how uncertainty in this parameter can be reduced using expert information about higher moments, and speculate about the physiological advantage conferred by this control mechanism.

Morphological Stability for in silico Models of Avascular Tumors.

The landscape of computational modeling in cancer systems biology is diverse, offering a spectrum of models and frameworks, each with its own trade-offs and advantages. Ideally, models are meant to be useful in refining hypotheses, to sharpen experimental procedures and, in the longer run, even for applications in personalized medicine. One of the greatest challenges is to balance model realism and detail with experimental data to eventually produce useful data-driven models. We contribute to this quest by developing a transparent, highly parsimonious, first principle in silico model of a growing avascular tumor. We initially formulate the physiological considerations and the specific model within a stochastic cell-based framework. We next formulate a corresponding mean-field model using partial differential equations which is amenable to mathematical analysis. Despite a few notable differences between the two models, we are in this way able to successfully detail the impact of all parameters in the stability of the growth process and on the eventual tumor fate of the stochastic model. This facilitates the deduction of Bayesian priors for a given situation, but also provides important insights into the underlying mechanism of tumor growth and progression. Although the resulting model framework is relatively simple and transparent, it can still reproduce the full range of known emergent behavior. We identify a novel model instability arising from nutrient starvation and we also discuss additional insight concerning possible model additions and the effects of those. Thanks to the framework's flexibility, such additions can be readily included whenever the relevant data become available.

The robustness of phylogenetic diversity indices to extinctions.

Phylogenetic diversity indices provide a formal way to apportion evolutionary history amongst living species. Understanding the properties of these measures is key to determining their applicability in conservation biology settings. In this work, we investigate some questions posed in a recent paper by Fischer et al. (Syst Biol 72(3):606-615, 2023). In that paper, it is shown that under certain extinction scenarios, the ranking of the surviving species by their Fair Proportion index scores may be the complete reverse of their ranking beforehand. Our main results here show that this behaviour extends to a large class of phylogenetic diversity indices, including the Equal-Splits index. We also provide a necessary condition for reversals of Fair Proportion rankings to occur on phylogenetic trees whose edge lengths obey the ultrametric constraint. Specific examples of rooted phylogenetic trees displaying these behaviours are given and the impact of our results on the use of phylogenetic diversity indices more generally is discussed.

Modelling the impact of precaution on disease dynamics and its evolution.

In this paper, we introduce the notion of practically susceptible population, which is a fraction of the biologically susceptible population. Assuming that the fraction depends on the severity of the epidemic and the public's level of precaution (as a response of the public to the epidemic), we propose a general framework model with the response level evolving with the epidemic. We firstly verify the well-posedness and confirm the disease's eventual vanishing for the framework model under the assumption that the basic reproduction number R 0 < 1 . For R 0 > 1 , we study how the behavioural response evolves with epidemics and how such an evolution impacts the disease dynamics. More specifically, when the precaution level is taken to be the instantaneous best response function in literature, we show that the endemic dynamic is convergence to the endemic equilibrium; while when the precaution level is the delayed best response, the endemic dynamic can be either convergence to the endemic equilibrium, or convergence to a positive periodic solution. Our derivation offers a justification/explanation for the best response used in some literature. By replacing "adopting the best response" with "adapting toward the best response", we also explore the adaptive long-term dynamics.

Counting Phylogenetic Networks with Few Reticulation Vertices: Galled and Reticulation-Visible Networks.

We give exact and asymptotic counting results for the number of galled networks and reticulation-visible networks with few reticulation vertices. Our results are obtained with the component graph method, which was introduced by L. Zhang and his coauthors, and generating function techniques. For galled networks, we in addition use analytic combinatorics. Moreover, in an appendix, we consider maximally reticulated reticulation-visible networks and derive their number, too.

A mathematical model for HIV dynamics with multiple infections: implications for immune escape.

Multiple infections enable the recombination of different strains, which may contribute to viral diversity. How multiple infections affect the competition dynamics between the two types of strains, the wild and the immune escape mutant, remains poorly understood. This study develops a novel mathematical model that includes the two strains, two modes of viral infection, and multiple infections. For the representative double-infection case, the reproductive numbers are derived and global stabilities of equilibria are obtained via the Lyapunov direct method and theory of limiting systems. Numerical simulations indicate similar viral dynamics regardless of multiplicities of infections though the competition between the two strains would be the fiercest in the case of quadruple infections. Through sensitivity analysis, we evaluate the effect of parameters on the set-point viral loads in the presence and absence of multiple infections. The model with multiple infections predict that there exists a threshold for cytotoxic T lymphocytes (CTLs) to minimize the overall viral load. Weak or strong CTLs immune response can result in high overall viral load. If the strength of CTLs maintains at an intermediate level, the fitness cost of the mutant is likely to have a significant impact on the evolutionary dynamics of mutant viruses. We further investigate how multiple infections alter the viral dynamics during the combination antiretroviral therapy (cART). The results show that viral loads may be underestimated during cART if multiple-infection is not taken into account.

Travelling waves for a fast reaction limit of a discrete coagulation-fragmentation model with diffusion and proliferation.

We study traveling wave solutions for a reaction-diffusion model, introduced in the article Calvez et al. (Regime switching on the propagation speed of travelling waves of some size-structured myxobacteriapopulation models, 2023), describing the spread of the social bacterium Myxococcus xanthus. This model describes the spatial dynamics of two different cluster sizes: isolated bacteria and paired bacteria. Two isolated bacteria can coagulate to form a cluster of two bacteria and conversely, a pair of bacteria can fragment into two isolated bacteria. Coagulation and fragmentation are assumed to occur at a certain rate denoted by k. In this article we study theoretically the limit of fast coagulation fragmentation corresponding mathematically to the limit when the value of the parameter k tends to + ∞ . For this regime, we demonstrate the existence and uniqueness of a transition between pulled and pushed fronts for a certain critical ratio θ ⋆ between the diffusion coefficient of isolated bacteria and the diffusion coefficient of paired bacteria. When the ratio is below θ ⋆ , the critical front speed is constant and corresponds to the linear speed. Conversely, when the ratio is above the critical threshold, the critical spreading speed becomes strictly greater than the linear speed.

A hybrid transmission model for Plasmodium vivax accounting for superinfection, immunity and the hypnozoite reservoir.

Malaria is a vector-borne disease that exacts a grave toll in the Global South. The epidemiology of Plasmodium vivax, the most geographically expansive agent of human malaria, is characterised by the accrual of a reservoir of dormant parasites known as hypnozoites. Relapses, arising from hypnozoite activation events, comprise the majority of the blood-stage infection burden, with implications for the acquisition of immunity and the distribution of superinfection. Here, we construct a novel model for the transmission of P. vivax that concurrently accounts for the accrual of the hypnozoite reservoir, (blood-stage) superinfection and the acquisition of immunity. We begin by using an infinite-server queueing network model to characterise the within-host dynamics as a function of mosquito-to-human transmission intensity, extending our previous model to capture a discretised immunity level. To model transmission-blocking and antidisease immunity, we allow for geometric decay in the respective probabilities of successful human-to-mosquito transmission and symptomatic blood-stage infection as a function of this immunity level. Under a hybrid approximation-whereby probabilistic within-host distributions are cast as expected population-level proportions-we couple host and vector dynamics to recover a deterministic compartmental model in line with Ross-Macdonald theory. We then perform a steady-state analysis for this compartmental model, informed by the (analytic) distributions derived at the within-host level. To characterise transient dynamics, we derive a reduced system of integrodifferential equations, likewise informed by our within-host queueing network, allowing us to recover population-level distributions for various quantities of epidemiological interest. In capturing the interplay between hypnozoite accrual, superinfection and acquired immunity-and providing, to the best of our knowledge, the most complete population-level distributions for a range of epidemiological values-our model provides insights into important, but poorly understood, epidemiological features of P. vivax.

A mathematical model on the propagation of tau pathology in neurodegenerative diseases.

A system of partial differential equations is developed to study the spreading of tau pathology in the brain for Alzheimer's and other neurodegenerative diseases. Two cases are considered with one assuming intracellular diffusion through synaptic activities or the nanotubes that connect the adjacent cells. The other, in addition to intracellular spreading, takes into account of the secretion of the tau species which are able to diffuse, move with the interstitial fluid flow and subsequently taken up by the surrounding cells providing an alternative pathway for disease spreading. Cross membrane transport of the tau species are considered enabling us to examine the role of extracellular clearance of tau protein on the disease status. Bifurcation analysis is carried out for the steady states of the spatially homogeneous system yielding the results that fast cross-membrane transport combined with effective extracellular clearance is key to maintain the brain's healthy status. Numerical simulations of the first case exhibit solutions of travelling wave form describing the gradual outward spreading of the pathology; whereas the second case shows faster spreading with the buildup of neurofibrillary tangles quickly elevated throughout. Our investigation thus indicates that the gradual progression of the intracellular spreading case is more consistent with the clinical observations of the development of Alzheimer's disease.