# Publications

Metagenomics has revealed hundreds of bacterial species in almost all microbiota. In a few well-studied cases, bacterial communities have been observed to coordinate their metabolic fluxes. In principle, bacteria can divide tasks to reap the benefits of specialization, as in human economies. However, the benefits and stability of an economy of bacterial specialists are far from obvious. Here, we physically model the population dynamics of bacteria that compete for steadily supplied resources. Importantly, we explicitly model the metabolic fluxes yielding cellular biomass production under the constraint of a limited enzyme budget. We find that population dynamics generally leads to the coexistence of different metabolic types. We establish that these bacterial consortia act as cartels, whereby population dynamics pins down resource concentrations at values for which no other strategy can invade. Finally, we propose that at steady supply, cartels of competing strategies automatically yield maximum biomass, thereby achieving a collective optimum.

DNA combing allows the investigation of DNA replication on genomic single DNA molecules, but the lengths that can be analysed have been restricted to molecules of 200–500 kb. We have improved the DNA combing procedure so that DNA molecules can be analysed up to the length of entire chromosomes in fission yeast and up to 12 Mb fragments in human cells. Combing multi-Mb-scale DNA molecules revealed previously undetected origin clusters in fission yeast and shows that in human cells replication origins fire stochastically forming clusters of fired origins with an average size of 370 kb. We estimate that a single human cell forms around 3200 clusters at mid S-phase and fires approximately 100,000 origins to complete genome duplication. The procedure presented here will be adaptable to other organisms and experimental conditions.

In nature a large number of species can coexist on a small number of shared resources, however resource competition models predict that the number of species in steady coexistence cannot exceed the number of resources. Motivated by recent studies of phytoplankton, we introduce trade-offs into a resource competition model, and find that an unlimited number of species can coexist. Our model spontaneously reproduces several features of natural ecosystems including keystone species and population dynamics/abundances characteristic of neutral theory, despite an underlying non- neutral competition for resources.

Five noncoding small RNAs (sRNAs) called the Qrr1-5 sRNAs act at the heart of the Vibrio harveyi quorum-sensing cascade. The Qrr sRNAs posttranscriptionally regulate 20 mRNA targets. Here, we use a method we call RSort-Seq that is based on unbiased high-throughput screening to define the critical bases in Qrr4 that specify its function. The power of our study comes from using the screening results to pinpoint particular nucleotides for follow-up biological analyses that define function. Using this approach, we discover how Qrr4 differentially regulates two of its targets, luxO and luxR. We also show how this strategy can be used to identify intramolecular suppressor mutations. This approach can be applied to any sRNA and any mRNA target.

Bacteria regulate gene expression in response to changes in cell density in a process called quorum sensing. To synchronize their gene-expression programs, these bacteria need to glean as much information as possible about their cell density. Our study is the first to physically model the flow of information in a quorum-sensing microbial community, wherein the internal regulator of the individuals response tracks the external cell density via an endogenously generated shared signal. Combining information theory and Lagrangian formalism, we find that quorum-sensing systems can improve their information capabilities by tuning circuit feedbacks. Our analysis suggests that achieving information benefit via feedback requires dedicated systems to control gene expression noise, such as sRNA-based regulation.

The firing activity of intracellularly stimulated neurons in cortical slices has been demonstrated to be profoundly affected by the temporal structure of the injected current (Mainen & Sejnowski, 1995). This suggests that the timing features of the neural response may be controlled as much by its own biophysical characteristics as by how a neuron is wired within a circuit. Modeling studies have shown that the interplay between internal noise and the fluctuations of the driving input controls the reliability and the precision of neuronal spiking (Cecchi et al., 2000; Tiesinga, 2002; Fellous, Rudolph, Destexhe, & Sejnowski, 2003). In order to investigate this interplay, we focus on the stochastic leaky integrate-and-fire neuron and identify the Hölder exponent *H* of the integrated input as the key mathematical property dictating the regime of firing of a single-unit neuron. We have recently provided numerical evidence (Taillefumier & Magnasco, 2013) for the existence of a phase transition when *H *becomes less than the statistical Hölder exponent associated with internal gaussian white noise (*H*=1/2). Here we describe the theoretical and numerical framework devised for the study of a neuron that is periodically driven by frozen noisy inputs with exponent *H*>0. In doing so, we account for the existence of a transition between two regimes of firing when *H*=1/2, and we show that spiking times have a continuous density when the Hölder exponent satisfies *H*>1/2. The transition at *H*=1/2 formally separates rate codes, for which the neural firing probability varies smoothly, from temporal codes, for which the neuron fires at sharply defined times regardless of the intensity of internal noise.

Finding the first time a fluctuating quantity reaches a given boundary is a deceptively simple-looking problem of vast practical importance in physics, biology, chemistry, neuroscience, economics, and industrial engineering. Problems in which the bound to be traversed is itself a fluctuating function of time include widely studied problems in neural coding, such as neuronal integrators with irregular inputs and internal noise. We show that the probability *p(t)* that a Gauss–Markov process will first exceed the boundary at time t suffers a phase transition as a function of the roughness of the boundary, as measured by its Hölder exponent *H*. The critical value occurs when the roughness of the boundary equals the roughness of the process, so for diffusive processes the critical value is *H*_{c} = 1/2. For smoother boundaries, *H* > 1/2, the probability density is a continuous function of time. For rougher boundaries, *H* < 1/2, the probability is concentrated on a Cantor-like set of zero measure: the probability density becomes divergent, almost everywhere either zero or infinity. The critical point *H*_{c} = 1/2 corresponds to a widely studied case in the theory of neural coding, in which the external input integrated by a model neuron is a white-noise process, as in the case of uncorrelated but precisely balanced excitatory and inhibitory inputs. We argue that this transition corresponds to a sharp boundary between rate codes, in which the neural firing probability varies smoothly, and temporal codes, in which the neuron fires at sharply defined times regardless of the intensity of internal noise.

In vivo cortical recording reveals that indirectly driven neural assemblies can produce reliable and temporally precise spiking patterns in response to stereotyped stimulation. This suggests that despite being fundamentally noisy, the collective activity of neurons conveys information through temporal coding. Stochastic integrate-and-fire models delineate a natural theoretical framework to study the interplay of intrinsic neural noise and spike timing precision. However, there are inherent difficulties in simulating their networks' dynamics in silico with standard numerical discretization schemes. Indeed, the well-posedness of the evolution of such networks requires temporally ordering every neuronal interaction, whereas the order of interactions is highly sensitive to the random variability of spiking times. Here, we answer these issues for perfect stochastic integrate-and-fire neurons by designing an exact event-driven algorithm for the simulation of recurrent networks, with delayed Dirac-like interactions. In addition to being exact from the mathematical standpoint, our proposed method is highly efficient numerically. We envision that our algorithm is especially indicated for studying the emergence of polychronized motifs in networks evolving under spike-timing-dependent plasticity with intrinsic noise.

The study of the multidimensional stochastic processes involves complex computations in intricate functional spaces. In particular, the diffusion processes, which include the practically important Gauss-Markov processes, are ordinarily defined through the theory of stochastic integration. Here, inspired by the Lévy-Ciesielski construction of the Wiener process, we propose an alternative representation of multidimensional Gauss-Markov processes as expansions on well-chosen Schauder bases, with independent random coefficients of normal law with zero mean and unit variance. We thereby offer a natural multiresolution description of the Gauss-Markov processes as limits of finite-dimensional partial sums of the expansion, that are strongly almost-surely convergent. Moreover, such finite-dimensional random processes constitute an optimal approximation of the process, in the sense of minimizing the associated Dirichlet energy under interpolating constraints. This approach allows for a simpler treatment of problems in many applied and theoretical fields, and we provide a short overview of applications we are currently developing.

Even for simple diffusion processes, treating first-passage problems analytically proves intractable for generic barriers and existing numerical methods are inaccurate and computationally costly. Here, we present a novel numerical method that is faster and has more tightly controlled accuracy. Our algorithm is a probabilistic variant of dichotomic search for the computation of first passage times through non-negative homogeneously Hölder continuous boundaries by Gauss-Markov processes. These include the Ornstein-Uhlenbeck process underlying the ubiquitous “leaky integrate-and-fire” model of neuronal excitation. Our method evaluates discrete points in a sample path exactly, and refines this representation recursively only in regions where a passage is rigorously estimated to be probable (e.g. when close to the boundary).

The classical Haar construction of Brownian motion uses a binary tree of triangular wedge-shaped functions. This basis has compactness properties which make it especially suited for certain classes of numerical algorithms. We present a similar basis for the Ornstein-Uhlenbeck process, in which the basis elements approach asymptotically the Haar functions as the index increases, and preserve the following properties of the Haar basis: all basis elements have compact support on an open interval with dyadic rational endpoints; these intervals are nested and become smaller for larger indices of the basis element, and for any dyadic rational, only a finite number of basis elements is nonzero at that number. Thus the expansion in our basis, when evaluated at a dyadic rational, terminates in a finite number of steps. We prove the covariance formulae for our expansion and discuss its statistical interpretation.