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  1. This paper studies the effect of perturbations on the gradient flow of a general nonlinear programming problem, where the perturbation may arise from inaccurate gradient estimation in the setting of data-driven optimization. Under suitable conditions on the objective function, the perturbed gradient flow is shown to be small-disturbance input-to-state stable (ISS), which implies that, in the presence of a small-enough perturbation, the trajectories of the perturbed gradient flow must eventually enter a small neighborhood of the optimum. This work was motivated by the question of robustness of direct methods for the linear quadratic regulator problem, and specifically the analysis of the effect of perturbations caused by gradient estimation or round-off errors in policy optimization. We show small-disturbance ISS for three of the most common optimization algorithms: standard gradient flow, natural gradient flow, and Newton gradient flow. 
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    Free, publicly-accessible full text available June 1, 2025
  2. We develop some basic principles for the design and robustness analysis of a continuous-time bilinear dynamical network, where an attacker can manipulate the strength of the interconnections/edges between some of the agents/nodes. We formulate the edge protection optimization problem of picking a limited number of attack-free edges and minimizing the impact of the attack over the bilinear dynamical network. In particular, the H2-norm of bilinear systems is known to capture robustness and performance properties analogous to its linear counterpart and provides valuable insights for identifying which edges are most sensitive to attacks. The exact optimization problem is combinatorial in the number of edges, and brute-force approaches show poor scalability. However, we show that the H2-norm as a cost function is supermodular and, therefore, allows for efficient greedy approximations of the optimal solution. We illustrate and compare the effectiveness of our theoretical findings via numerical simulation 
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  3. The emergence of and transitions between distinct phenotypes in isogenic cells can be attributed to the intricate interplay of epigenetic marks, external signals, and gene-regulatory elements. These elements include chromatin remodelers, histone modifiers, transcription factors, and regulatory RNAs. Mathematical models known as gene-regulatory networks (GRNs) are an increasingly important tool to unravel the workings of such complex networks. In such models, epigenetic factors are usually proposed to act on the chromatin regions directly involved in the expression of relevant genes. However, it has been well-established that these factors operate globally and compete with each other for targets genome-wide. Therefore, a perturbation of the activity of a regulator can redistribute epigenetic marks across the genome and modulate the levels of competing regulators. In this paper, we propose a conceptual and mathematical modeling framework that incorporates both local and global competition effects between antagonistic epigenetic regulators, in addition to local transcription factors, and show the counterintuitive consequences of such interactions. We apply our approach to recent experimental findings on the epithelial–mesenchymal transition (EMT). We show that it can explain the puzzling experimental data, as well as provide verifiable predictions. 
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  4. Abstract

    Long-term behaviors of biochemical reaction networks (BRNs) are described by steady states in deterministic models and stationary distributions in stochastic models. Unlike deterministic steady states, stationary distributions capturing inherent fluctuations of reactions are extremely difficult to derive analytically due to the curse of dimensionality. Here, we develop a method to derive analytic stationary distributions from deterministic steady states by transforming BRNs to have a special dynamic property, called complex balancing. Specifically, we merge nodes and edges of BRNs to match in- and out-flows of each node. This allows us to derive the stationary distributions of a large class of BRNs, including autophosphorylation networks of EGFR, PAK1, and Aurora B kinase and a genetic toggle switch. This reveals the unique properties of their stochastic dynamics such as robustness, sensitivity, and multi-modality. Importantly, we provide a user-friendly computational package, CASTANET, that automatically derives symbolic expressions of the stationary distributions of BRNs to understand their long-term stochasticity.

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  5. null (Ed.)
    Cell-fate networks are traditionally studied within the framework of gene regulatory networks. This paradigm considers only interactions of genes through expressed transcription factors and does not incorporate chromatin modification processes. This paper introduces a mathematical model that seamlessly combines gene regulatory networks and DNA methylation (DNAm), with the goal of quantitatively characterizing the contribution of epigenetic regulation to gene silencing. The ‘Basin of Attraction percentage’ is introduced as a metric to quantify gene silencing abilities. As a case study, a computational and theoretical analysis is carried out for a model of the pluripotent stem cell circuit as well as a simplified self-activating gene model. The results confirm that the methodology quantitatively captures the key role that DNAm plays in enhancing the stability of the silenced gene state. 
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