BackgroundMany organisms coordinate cell growth and division through size control mechanisms: cells must reach a critical size to trigger a cell cycle event. Bacterial division is often assumed to be controlled in this way, but experimental evidence to support this assumption is still lacking. Theoretical arguments show that size control is required to maintain size homeostasis in the case of exponential growth of individual cells. Nevertheless, if the growth law deviates slightly from exponential for very small cells, homeostasis can be maintained with a simple ‘timer’ triggering division. Therefore, deciding whether division control in bacteria relies on a ‘timer’ or ‘sizer’ mechanism requires quantitative comparisons between models and data.ResultsThe timer and sizer hypotheses find a natural expression in models based on partial differential equations. Here we test these models with recent data on single-cell growth of Escherichia coli. We demonstrate that a size-independent timer mechanism for division control, though theoretically possible, is quantitatively incompatible with the data and extremely sensitive to slight variations in the growth law. In contrast, a sizer model is robust and fits the data well. In addition, we tested the effect of variability in individual growth rates and noise in septum positioning and found that size control is robust to this phenotypic noise.ConclusionsConfrontations between cell cycle models and data usually suffer from a lack of high-quality data and suitable statistical estimation techniques. Here we overcome these limitations by using high precision measurements of tens of thousands of single bacterial cells combined with recent statistical inference methods to estimate the division rate within the models. We therefore provide the first precise quantitative assessment of different cell cycle models.

We raise the issue of estimating the division rate for a growing and dividing population modelled by a piecewise deterministic Markov branching tree. Such models have broad applications, ranging from TCP/IP window size protocol to bacterial growth. Here, the individuals split into two offsprings at a division rate B(x) that depends on their size x, whereas their size grow exponentially in time, at a rate that exhibits variability. The mean empirical measure of the model satisfies a growth-fragmentation type equation, and we bridge the deterministic and probabilistic viewpoints. We then construct a nonparametric estimator of the division rate B(x) based on the observation of the population over different sampling schemes of size n on the genealogical tree. Our estimator nearly achieves the rate n −s/(2s+1) in squared-loss error asymptotically, generalizing and improving on the rate n −s/(2s+3) obtained in [13,15] through indirect observation schemes. Our method is consistently tested numerically and implemented on Escherichia coli data, which demonstrates its major interest for practical applications.

We consider a size-structured model for cell division and address the question of determining the division (birth) rate from the measured stable size distribution of the population. We propose a new regularization technique based on a filtering approach. We prove convergence of the algorithm and validate the theoretical results by implementing numerical simulations, based on classical techniques. We compare the results for direct and inverse problems, for the filtering method and for the quasi-reversibility method proposed in [1].

CFSE analysis of a proliferating cell population is a popular tool for the study of cell division and division-linked changes in cell behavior. Recently [13, 43, 45], a partial differential equation (PDE) model to describe lymphocyte dynamics in a CFSE proliferation assay was proposed. We present a significant revision of this model which improves the physiological understanding of several parameters. Namely, the parameter γ used previously as a heuristic explanation for the dilution of CFSE dye by cell division is replaced with a more physical component, cellular autofluorescence. The rate at which label decays is also quantified using a Gompertz decay process. We then demonstrate a revised method of fitting the model to the commonly used histogram representation of the data. It is shown that these improvements result in a model with a strong physiological basis which is fully capable of replicating the behavior observed in the data.

Protein polymerization consists in the aggregation of single monomers into polymers that may fragment. Fibrils assembly is a key process in amyloid diseases. Up to now, protein aggregation was commonly mathematically simulated by a polymer size-structured ordinary differential equations (ODE) system, which is infinite by definition and therefore leads to high computational costs. Moreover, this Ordinary Differential Equation-based modeling approach implies biological assumptions that may be difficult to justify in the general case. For example, whereas several ordinary differential equation models use the assumption that polymerization would occur at a constant rate independently of polymer size, it cannot be applied to certain protein aggregation mechanisms. Here, we propose a novel and efficient analytical method, capable of modelling and simulating amyloid aggregation processes. This alternative approach consists of an integro-Partial Differential Equation (PDE) model of coalescence-fragmentation type that was mathematically derived from the infinite differential system by asymptotic analysis. To illustrate the efficiency of our approach, we applied it to aggregation experiments on polyglutamine polymers that are involved in Huntington’s disease. Our model demonstrates the existence of a monomeric structural intermediate acting as a nucleus and deriving from a non polymerizing monomer (). Furthermore, we compared our model to previously published works carried out in different contexts and proved its accuracy to describe other amyloid aggregation processes.

We consider the problem of estimating the division rate of a size-structured population in a nonparametric setting. The size of the system evolves according to a transport-fragmentation equation: each individual grows with a given transport rate, and splits into two offsprings of the same size, following a binary fragmentation process with unknown division rate that depends on its size. In contrast to a deterministic inverse problem approach, as in [23,4], we take in this paper the perspective of statistical inference: our data consists in a large sample of the size of individuals, when the evolution of the system is close to its time-asymptotic behavior, so that it can be related to the eigenproblem of the considered transport-fragmentation equation (see [22] for instance). By estimating statistically each term of the eigenvalue problem and by suitably inverting a certain linear operator (see [4]), we are able to construct a more realistic estimator of the division rate that achieves the same optimal error bound as in related deterministic inverse problems. Our procedure relies on kernel methods with automatic bandwidth selection. It is inspired by model selection and recent results of Goldenschluger and Lepski [13,14].

Abstract. We study the mathematical properties of a general model of cell division structured with several internal variables. We begin with a simpler and specific model with two variables, we solve the eigenvalue problem with strong or weak assumptions, and deduce from it the long-time convergence. The main difficulty comes from natural degeneracy of birth terms that we overcome with a regularization technique. We then extend the results to the case with several parameters and recall the link between this simplified model and the one presented in [6]; an application to the non-linear problem is also given, leading to robust subpolynomial growth of the total population.

The spike trains are the main components of the information processing in the brain. To model spike trains several point processes have been investigated in the literature. And more macroscopic approaches have also been studied, using partial differential equation models. The main aim of the present article is to build a bridge between several point processes models (Poisson, Wold, Hawkes) that have been proved to statistically fit real spike trains data and age-structured partial differential equations as introduced by Pakdaman, Perthame and Salort. IntroductionIn Neuroscience, the action potentials (spikes) are the main components of the realtime information processing in the brain. Indeed, thanks to the synaptic integration, the membrane voltage of a neuron depends on the action potentials emitted by some others, whereas if this membrane potential is sufficiently high, there is production of action potentials. To access those phenomena, schematically, one can proceed in two ways: extracellularly record in vivo several neurons, at a same time, and have access to simultaneous spike trains (only the list of events corresponding to action potentials) or intracellularly record the whole membrane voltage of only one neuron at a time, being blind to the nearby neurons.Many people focus on spike trains. Those data are fundamentally random and can be modelled easily by time point processes, i.e. random countable sets of points on R + . Several point processes models have been investigated in the literature, each of them reproducing different features of the neuronal reality. The easiest model is the homogeneous Poisson process, which can only reproduce a constant firing rate for the neuron, but which, in particular, fails to reproduce refractory periods a . It is commonly admitted that this model is too poor to be realistic. Indeed, in such a model, two points or spikes can be arbitrary close as soon as their overall frequency is respected in average. Another more realistic model is the renewal process 37 , where the occurrence of a point or spike depends on the previous occurrence. More precisely, the distribution of delays between spikes (also called inter-spike intervals, ISI) is given and a distribution, which provides small weights to small delays, is able to mimic refractory periods. A deeper statistical analysis has shown that Wold processes is showing good results, with respect to goodness-of-fit test on real data sets 38 . Wold processes are point processes for which the next occurrence of a spike depends on the previous occurrence but also on the previous ISI. From another point of view, the fact that spike trains are usually non stationary can be easily modelled by inhomogeneous Poisson processes 43 . All those models do not reflect one of the main features of spike trains, which is the synaptic integration and there has been various attempts to catch such phenomenon. One of the main model is the Hawkes model, which has been introduced in 13 and which has been recently shown to fit several stationary data ...