Diffusion models have shown remarkable potential in planning and control tasks due to their ability to represent multimodal distributions over actions and trajectories. However, ensuring safety under constraints remains a critical challenge for diffusion models. This paper proposes Constrained Diffusers, an extended framework for planning and control that incorporates distribution-level constraints into pre-trained diffusion models without retraining or architectural modifications. Inspired by constrained optimization, we apply a constrained Langevin sampling method for the reverse diffusion process that jointly optimizes the trajectory and achieves constraint satisfaction through three iterative algorithms: projected method, primal-dual method and augmented Lagrangian method. In addition, we incorporate discrete control barrier functions as constraints for constrained diffusers to guarantee safety in online implementation, following a receding-horizon control that we generate a short-horizon plan and execute only the first action before replanning. Experiments in Maze2D, locomotion, and PyBullet ball running tasks demonstrate that our proposed methods achieve constraint satisfaction with less computation time, and are competitive with existing methods in environments with static and time-varying constraints.

Ensuring safety and stability is critical when using reinforcement learning (RL) to control safety-critical systems. However, model-free RL algorithms usually suffer from low sample efficiency, and employing widely-used methods like dual ascent to solve constrained RL problems may be challenging due to their sensitivity to hyperparameters. To address these difficulties, in this work, we first propose an augmented Lagrangian-based method to maintain safety and stability through state-wise control Lyapunov function (CLF) and pre-defined control barrier function (CBFs) constraints in non-constrained Markov decision process (non-CMDP) settings. To handle tasks without pre-defined CBFs, we extend this method by training a barrier certificate jointly with the control policy, supported by theoretical guarantees to ensure monotonically improved control performance. Moreover, we investigate the issue of infeasibility arising from the presence of multiple state-wise constraints. A practical algorithm, Neural ordinary differential equations-based Lyapunov-Barrier Actor-Critic (NLBAC), is further designed by integrating the proposed method with the Soft Actor-Critic (SAC) and leveraging neural ordinary differential equations (NODEs) for system modeling. Comparisons with baselines and ablation experiments demonstrate that our algorithm achieves superior performance in terms of safety and driving the system towards the desired state with higher sample efficiency.

A powerful way of gaining insight into biological systems is by creating a nonlinear differential equation model, which usually contains many unknown parameters. Such a model is called structurally identifiable if it is possible to determine the values of its parameters from measurements of the model outputs. Structural identifiability is a prerequisite for parameter estimation, and should be assessed before exploiting a model. However, this analysis is seldom performed due to the high computational cost involved in the necessary symbolic calculations, which quickly becomes prohibitive as the problem size increases. In this paper we show how to analyse the structural identifiability of a very general class of nonlinear models by extending methods originally developed for studying observability. We present results about models whose identifiability had not been previously determined, report unidentifiabilities that had not been found before, and show how to modify those unidentifiable models to make them identifiable. This method helps prevent problems caused by lack of identifiability analysis, which can compromise the success of tasks such as experiment design, parameter estimation, and model-based optimization. The procedure is called STRIKE-GOLDD (STRuctural Identifiability taKen as Extended-Generalized Observability with Lie Derivatives and Decomposition), and it is implemented in a MATLAB toolbox which is available as open source software. The broad applicability of this approach facilitates the analysis of the increasingly complex models used in systems biology and other areas.

Large, naturally evolved biomolecular networks typically fulfil multiple functions. When modelling or redesigning such systems, functional subsystems are often analysed independently first, before subsequent integration into larger-scale computational models. In the design and analysis process, it is therefore important to quantitatively analyse and predict the dynamics of the interactions between integrated subsystems; in particular, how the incremental effect of integrating a subsystem into a network depends on the existing dynamics of that network. In this paper we present a framework for simulating the contribution of any given functional subsystem when integrated together with one or more other subsystems. This is achieved through a cascaded layering of a network into functional subsystems, where each layer is defined by an appropriate subset of the reactions. We exploit symmetries in our formulation to exhaustively quantify each subsystem's incremental effects with minimal computational effort. When combining subsystems, their isolated behaviour may be amplified, attenuated, or be subject to more complicated effects. We propose the concept of mutual dynamics to quantify such nonlinear phenomena, thereby defining the incompatibility and cooperativity between all pairs of subsystems when integrated into any larger network. We exemplify our theoretical framework by analysing diverse behaviours in three dynamic models of signalling and metabolic pathways: the effect of crosstalk mechanisms on the dynamics of parallel signal transduction pathways; reciprocal side-effects between several integral feedback mechanisms and the subsystems they stabilise; and consequences of nonlinear interactions between elementary flux modes in glycolysis for metabolic engineering strategies. Our analysis shows that it is not sufficient to just specify subsystems and analyse their pairwise interactions; the environment in which the interaction takes place must also be explicitly defined. Our framework provides a natural representation of nonlinear interaction phenomena, and will therefore be an important tool for modelling large-scale evolved or synthetic biomolecular networks.

Bacteria move towards favourable and away from toxic environments by changing their swimming pattern. This response is regulated by the chemotaxis signalling pathway, which has an important feature: it uses feedback to 'reset' (adapt) the bacterial sensing ability, which allows the bacteria to sense a range of background environmental changes. The role of this feedback has been studied extensively in the simple chemotaxis pathway of Escherichia coli. However it has been recently found that the majority of bacteria have multiple chemotaxis homologues of the E. coli proteins, resulting in more complex pathways. In this paper we investigate the configuration and role of feedback in Rhodobacter sphaeroides, a bacterium containing multiple homologues of the chemotaxis proteins found in E. coli. Multiple proteins could produce different possible feedback configurations, each having different chemotactic performance qualities and levels of robustness to variations and uncertainties in biological parameters and to intracellular noise. We develop four models corresponding to different feedback configurations. Using a series of carefully designed experiments we discriminate between these models and invalidate three of them. When these models are examined in terms of robustness to noise and parametric uncertainties, we find that the non-invalidated model is superior to the others. Moreover, it has a 'cascade control' feedback architecture which is used extensively in engineering to improve system performance, including robustness. Given that the majority of bacteria are known to have multiple chemotaxis pathways, in this paper we show that some feedback architectures allow them to have better performance than others. In particular, cascade control may be an important feature in achieving robust functionality in more complex signalling pathways and in improving their performance.

BACKGROUND: Very frequently the same biological system is described by several, sometimes competing mathematical models. This usually creates confusion around their validity, ie, which one is correct. However, this is unnecessary since validity of a model cannot be established; model validation is actually a misnomer. In principle the only statement that one can make about a system model is that it is incorrect, ie, invalid, a fact which can be established given appropriate experimental data. Nonlinear models of high dimension and with many parameters are impossible to invalidate through simulation and as such the invalidation process is often overlooked or ignored. RESULTS: We develop different approaches for showing how competing ordinary differential equation (ODE) based models of the same biological phenomenon containing nonlinearities and parametric uncertainty can be invalidated using experimental data. We first emphasize the strong interplay between system identification and model invalidation and we describe a method for obtaining a lower bound on the error between candidate model predictions and data. We then turn to model invalidation and formulate a methodology for discrete-time and continuous-time model invalidation. The methodology is algorithmic and uses Semidefinite Programming as the computational tool. It is emphasized that trying to invalidate complex nonlinear models through exhaustive simulation is not only computationally intractable but also inconclusive. CONCLUSION: Biological models derived from experimental data can never be validated. In fact, in order to understand biological function one should try to invalidate models that are incompatible with available data. This work describes a framework for invalidating both continuous and discrete-time ODE models based on convex optimization techniques. The methodology does not require any simulation of the candidate models; the algorithms presented in this paper have a worst case polynomial time complexity and can provide an exact answer to the invalidation problem.

Modeling and analysis of complex biological networks presents a number of mathematical challenges. For the models to be useful from a biological standpoint, they must be systematically compared with data. Robustness is a key to biological understanding and proper feedback to guide experiments,including both the deterministic stability and performance properties of models in the presence of parametric uncertainties and their stochastic behavior in the presence of noise. In this paper, we present mathematical and algorithmic tools to address such questions for models that may be nonlinear, hybrid,and stochastic. These tools are rooted in solid mathematical theories, primarily from robust control and dynamical systems, but with important recent developments. They also have the potential for great practical relevance, which we explore through a series of biologically motivated examples.