Kinetic approaches to lactose operon induction and bimodality

The quasi-equilibrium approximation is acceptable when molecular interactions are fast enough compared to circuit dynamics, but is no longer allowed when cellular activities are governed by rare events. A typical example is the lactose operon (lac), one of the most famous paradigms of transcription regulation, for which several theories still coexist to describe its behaviors. The lac system is generally analyzed by using equilibrium constants, contradicting single-event hypotheses long suggested by Novick and Weiner (1957). Enzyme induction as an all-or-none phenomenon. Proc. Natl. Acad. Sci. USA 43, 553-566) and recently refined in the study of (Choi et al., 2008. A stochastic single-molecule event triggers phenotype switching of a bacterial cell. Science 322, 442-446). In the present report, a lac repressor (LacI)-mediated DNA immunoprecipitation experiment reveals that the natural LacI-lac DNA complex built in vivo is extremely tight and long-lived compared to the time scale of lac expression dynamics, which could functionally disconnect the abortive expression bursts and forbid using the standard modes of lac bistability. As alternatives, purely kinetic mechanisms are examined for their capacity to restrict induction through: (i) widely scattered derepression related to the arrival time variance of a predominantly backward asymmetric random walk and (ii) an induction threshold arising in a single window of derepression without recourse to nonlinear multimeric binding and Hill functions. Considering the complete disengagement of the lac repressor from the lac promoter as the probabilistic consequence of a transient stepwise mechanism, is sufficient to explain the sigmoidal lac responses as functions of time and of inducer concentration. This sigmoidal shape can be misleadingly interpreted as a phenomenon of equilibrium cooperativity classically used to explain bistability, but which has been reported to be weak in this system

On Maltsev Digraphs

This is an Open Access article, first published by E-CJ on 25 February 2015.We study digraphs preserved by a Maltsev operation: Maltsev digraphs. We show that these digraphs retract either onto a directed path or to the disjoint union of directed cycles, showing in this way that the constraint satisfaction problem for Maltsev digraphs is in logspace, L. We then generalize results from Kazda (2011) to show that a Maltsev digraph is preserved not only by a majority operation, but by a class of other operations (e.g., minority, Pixley) and obtain a O(|VG|4)-time algorithm to recognize Maltsev digraphs. We also prove analogous results for digraphs preserved by conservative Maltsev operations which we use to establish that the list homomorphism problem for Maltsev digraphs is in L. We then give a polynomial time characterisation of Maltsev digraphs admitting a conservative 2-semilattice operation. Finally, we give a simple inductive construction of directed acyclic digraphs preserved by a Maltsev operation, and relate them with series parallel digraphs.Peer reviewedFinal Published versio

Join-Idle-Queue with Service Elasticity: Large-Scale Asymptotics of a Non-monotone System

We consider the model of a token-based joint auto-scaling and load balancing strategy, proposed in a recent paper by Mukherjee, Dhara, Borst, and van Leeuwaarden (SIGMETRICS '17, arXiv:1703.08373), which offers an efficient scalable implementation and yet achieves asymptotically optimal steady-state delay performance and energy consumption as the number of servers $N\to\infty$. In the above work, the asymptotic results are obtained under the assumption that the queues have fixed-size finite buffers, and therefore the fundamental question of stability of the proposed scheme with infinite buffers was left open. In this paper, we address this fundamental stability question. The system stability under the usual subcritical load assumption is not automatic. Moreover, the stability may not even hold for all $N$. The key challenge stems from the fact that the process lacks monotonicity, which has been the powerful primary tool for establishing stability in load balancing models. We develop a novel method to prove that the subcritically loaded system is stable for large enough $N$, and establish convergence of steady-state distributions to the optimal one, as $N \to \infty$. The method goes beyond the state of the art techniques -- it uses an induction-based idea and a "weak monotonicity" property of the model; this technique is of independent interest and may have broader applicability.Comment: 30 page

Localizing the Latent Structure Canonical Uncertainty: Entropy Profiles for Hidden Markov Models

This report addresses state inference for hidden Markov models. These models rely on unobserved states, which often have a meaningful interpretation. This makes it necessary to develop diagnostic tools for quantification of state uncertainty. The entropy of the state sequence that explains an observed sequence for a given hidden Markov chain model can be considered as the canonical measure of state sequence uncertainty. This canonical measure of state sequence uncertainty is not reflected by the classic multivariate state profiles computed by the smoothing algorithm, which summarizes the possible state sequences. Here, we introduce a new type of profiles which have the following properties: (i) these profiles of conditional entropies are a decomposition of the canonical measure of state sequence uncertainty along the sequence and makes it possible to localize this uncertainty, (ii) these profiles are univariate and thus remain easily interpretable on tree structures. We show how to extend the smoothing algorithms for hidden Markov chain and tree models to compute these entropy profiles efficiently.Comment: Submitted to Journal of Machine Learning Research; No RR-7896 (2012