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We introduce Catalyst.jl, a flexible and feature-filled Julia library for modeling and high-performance simulation of chemical reaction networks (CRNs). Catalyst supports simulating stochastic chemical kinetics (jump process), chemical Langevin equation (stochastic differential equation), and reaction rate equation (ordinary differential equation) representations for CRNs. Through comprehensive benchmarks, we demonstrate that Catalyst simulation runtimes are often one to two orders of magnitude faster than other popular tools. More broadly, Catalyst acts as both a domain-specific language and an intermediate representation for symbolically encoding CRN models as Julia-native objects. This enables a pipeline of symbolically specifying, analyzing, and modifying CRNs; converting Catalyst models to symbolic representations of concrete mathematical models; and generating compiled code for numerical solvers. Leveraging ModelingToolkit.jl and Symbolics.jl, Catalyst models can be analyzed, simplified, and compiled into optimized representations for use in numerical solvers. Finally, we demonstrate Catalyst’s broad extensibility and composability by highlighting how it can compose with a variety of Julia libraries, and how existing open-source biological modeling projects have extended its intermediate representation. 

Abstract. Photosynthesis plays an important role in carbon,nitrogen, and water cycles. Ecosystem models for photosynthesis arecharacterized by many parameters that are obtained from limited in situmeasurements and applied to the same plant types. Previous site-by-sitecalibration approaches could not leverage big data and faced issues likeoverfitting or parameter non-uniqueness. Here we developed an end-to-endprogrammatically differentiable (meaning gradients of outputs to variablesused in the model can be obtained efficiently and accurately) version of thephotosynthesis process representation within the Functionally AssembledTerrestrial Ecosystem Simulator (FATES) model. As a genre ofphysics-informed machine learning (ML), differentiable models couplephysics-based formulations to neural networks (NNs) that learn parameterizations(and potentially processes) from observations, here photosynthesis rates. Wefirst demonstrated that the framework was able to correctly recover multiple assumedparameter values concurrently using synthetic training data. Then, using areal-world dataset consisting of many different plant functional types (PFTs), welearned parameters that performed substantially better and greatly reducedbiases compared to literature values. Further, the framework allowed us togain insights at a large scale. Our results showed that the carboxylationrate at 25 ∘C (Vc,max25) was more impactful than a factorrepresenting water limitation, although tuning both was helpful inaddressing biases with the default values. This framework could potentiallyenable substantial improvement in our capability to learn parameters andreduce biases for ecosystem modeling at large scales. 

Differential sensitivity analysis is indispensable in fitting parameters, understanding uncertainty, and forecasting the results of both thought and lab experiments. Although there are many methods currently available for performing differential sensitivity analysis of biological models, it can be difficult to determine which method is best suited for a particular model. In this paper, we explain a variety of differential sensitivity methods and assess their value in some typical biological models. First, we explain the mathematical basis for three numerical methods: adjoint sensitivity analysis, complex perturbation sensitivity analysis, and forward mode sensitivity analysis. We then carry out four instructive case studies. (a) The CARRGO model for tumor-immune interaction highlights the additional information that differential sensitivity analysis provides beyond traditional naive sensitivity methods, (b) the deterministic SIR model demonstrates the value of using second-order sensitivity in refining model predictions, (c) the stochastic SIR model shows how differential sensitivity can be attacked in stochastic modeling, and (d) a discrete birth-death-migration model illustrates how the complex perturbation method of differential sensitivity can be generalized to a broader range of biological models. Finally, we compare the speed, accuracy, and ease of use of these methods. We find that forward mode automatic differentiation has the quickest computational time, while the complex perturbation method is the simplest to implement and the most generalizable. 

The majority of computer algebra systems (CAS) support symbolic integration using a combination of heuristic algebraic and rule-based (integration table) methods. In this paper, we present a hybrid (symbolic-numeric) method to calculate the indefinite integrals of univariate expressions. Our method is broadly similar to the Risch-Norman algorithm. The primary motivation for this work is to add symbolic integration functionality to a modern CAS (the symbolic manipulation packages of SciML, the Scientific Machine Learning ecosystem of the Julia programming language), which is designed for numerical and machine learning applications. The symbolic part of our method is based on the combination of candidate terms generation (ansatz generation using a methodology borrowed from the Homotopy operators theory) combined with rule-based expression transformations provided by the underlying CAS. The numeric part uses sparse regression, a component of the Sparse Identification of Nonlinear Dynamics (SINDy) technique, to find the coefficients of the candidate terms. We show that this system can solve a large variety of common integration problems using only a few dozen basic integration rules. 

Process-based modelling offers interpretability and physical consistency in many domains of geosciences but struggles to leverage large datasets efficiently. Machine-learning methods, especially deep networks, have strong predictive skills yet are unable to answer specific scientific questions. In this Perspective, we explore differentiable modelling as a pathway to dissolve the perceived barrier between process-based modelling and machine learning in the geosciences and demonstrate its potential with examples from hydrological modelling. ‘Differentiable’ refers to accurately and efficiently calculating gradients with respect to model variables or parameters, enabling the discovery of high-dimensional unknown relationships. Differentiable modelling involves connecting (flexible amounts of) prior physical knowledge to neural networks, pushing the boundary of physics-informed machine learning. It offers better interpretability, generalizability, and extrapolation capabilities than purely data-driven machine learning, achieving a similar level of accuracy while requiring less training data. Additionally, the performance and efficiency of differentiable models scale well with increasing data volumes. Under data-scarce scenarios, differentiable models have outperformed machine-learning models in producing short-term dynamics and decadal-scale trends owing to the imposed physical constraints. Differentiable modelling approaches are primed to enable geoscientists to ask questions, test hypotheses, and discover unrecognized physical relationships. Future work should address computational challenges, reduce uncertainty, and verify the physical significance of outputs. 

Modern design, control, and optimization often require multiple expensive simulations of highly nonlinear stiff models. These costs can be amortized by training a cheap surrogate of the full model, which can then be used repeatedly. Here we present a general data-driven method, the continuous time echo state network (CTESN), for generating surrogates of nonlinear ordinary differential equations with dynamics at widely separated timescales. We empirically demonstrate the ability to accelerate a physically motivated scalable model of a heating system by 98x while maintaining relative error of within 0.2 %. We showcase the ability for this surrogate to accurately handle highly stiff systems which have been shown to cause training failures with common surrogate methods such as Physics-Informed Neural Networks (PINNs), Long Short Term Memory (LSTM) networks, and discrete echo state networks (ESN). We show that our model captures fast transients as well as slow dynamics, while demonstrating that fixed time step machine learning techniques are unable to adequately capture the multi-rate behavior. Together this provides compelling evidence for the ability of CTESN surrogates to predict and accelerate highly stiff dynamical systems which are unable to be directly handled by previous scientific machine learning techniques.