Almost all biological systems possess the ability to gather environmental information and modulate their behaviors to adaptively respond to changing environments. While animals excel at sensing odors, even simple bacteria can detect faint chemicals using stochastic receptors. They then navigate towards or away from the chemical source by processing this sensed information through intracellular reaction systems. In the first half of our talk, we demonstrate that the E. coli chemotactic system is optimally structured for sensing noisy signals and controlling taxis. We utilize filtering theory and optimal control theory to theoretically derive this optimal structure and compare it to the quantitatively verified biochemical model of chemotaxis. In the latter half, we discuss the limitations of traditional information theory, filtering theory, and optimal control theory in analyzing biological systems. Notably, all biological systems, especially simpler ones, have constrained computational resources like memory size and energy, which influence optimal behaviors. Conventional theories don’t directly address these resource constraints, likely because they emerged during a period when computational resources were continually expanding. To address this gap, we introduce the “memory-limited partially observable optimal control,” a new theoretical framework developed by our group, and explore its relevance to biological problems.

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ZOOM ID: 997 8258 4700 (Biomedical Mathematics Online Colloquium), (pw: 1234) + Google Map

A key goal of synthetic biology is to establish functional biochemical modules with network-independent properties. Antithetic integral feedback (AIF) is a recently developed control module in which two control species perfectly annihilate each other’s biological activity. The AIF module confers robust perfect adaptation to the steady-state average level of a controlled intracellular component when subjected to sustained perturbations. Recent work has suggested that such robustness comes at the unavoidable price of increased stochastic fluctuations around average levels. We present theoretical results that support and quantify this trade-off for the commonly analyzed AIF variant in the idealized limit with perfect annihilation. However, we also show that this trade-off is a singular limit of the control module: Even minute deviations from perfect adaptation allow systems to achieve effective noise suppression as long as cells can pay the corresponding energetic cost. We further show that a variant of the AIF control module can achieve significant noise suppression even in the idealized limit with perfect adaptation. This atypical configuration may thus be preferable in synthetic biology applications.

Typically, the mathematical description of reaction networks involves a system of parameter-dependent ordinary differential equations. Generally, one is interested in the qualitative and quantitative behavior of solutions in various parameter regions. In applications, identifying the reaction parameters is a fundamental task. Reduction of dimension is desirable from a practical perspective, and even necessary when different timescales are present. For biochemical reaction networks, a classical reduction technique assumes quasi-steady state (QSS) of certain species. From a general mathematical perspective, singular perturbation theory – involving a small parameter – is often invoked. The talk is mathematically oriented. The following points will be discussed: Singular perturbation reduction in general coordinates. (“How does one compute reductions?”) Critical parameters for singular perturbations. (“How does one find small parameters?”) Quasi-steady state and singular perturbations. (“What is applicable, what is correct?”)

In many stochastic service systems, decision-makers find themselves making a sequence of decisions, with the number of decisions being unpredictable. To enhance these decisions, it is crucial to uncover the causal impact these decisions have through careful analysis of observational data from the system. However, these decisions are not made independently, as they are shaped by previous decisions and outcomes. This phenomenon is called sequential bias and violates a key assumption in causal inference that one person’s decision does not interfere with the potential outcomes of another. To address this issue, we establish a connection between sequential bias and the subfield of causal inference known as dynamic treatment regimes. We expand these frameworks to account for the random number of decisions by modeling the decision-making process as a marked point process. Consequently, we can define and identify causal effects to quantify sequential bias. Moreover, we propose estimators and explore their properties, including double robustness and semiparametric efficiency. In a case study of 27,831 encounters with a large academic emergency department, we use our approach to demonstrate that the decision to route a patient to an area for low acuity patients has a significant impact on the care of future patients.

Background Microbial community simulations using genome scale metabolic networks (GSMs) are relevant for many application areas, such as the analysis of the human microbiome. Such simulations rely on assumptions about the culturing environment, affecting if the culture may reach a metabolically stationary state with constant microbial concentrations. They also require assumptions on decision making by the microbes: metabolic strategies can be in the interest of individual community members or of the whole community. However, the impact of such common assumptions on community simulation results has not been investigated systematically. Results Here, we investigate four combinations of assumptions, elucidate how they are applied in literature, provide novel mathematical formulations for their simulation, and show how the resulting predictions differ qualitatively. Our results stress that different assumption combinations give qualitatively different predictions on microbial coexistence by differential substrate utilization. This fundamental mechanism is critically under explored in the steady state GSM literature with its strong focus on coexistence states due to crossfeeding (division of labor). Furthermore, investigating a realistic synthetic community, where the two involved strains exhibit no growth in isolation, but grow as a community, we predict multiple modes of cooperation, even without an explicit cooperation mechanism. Conclusions Steady state GSM modelling of microbial communities relies both on assumed decision making principles and environmental assumptions. In principle, dynamic flux balance analysis addresses both. In practice, our methods that address the steady state directly may be preferable, especially if the community is expected to display multiple steady states.

Mathematical models of biological systems, including neurons, often feature components that evolve on very different timescales. Mathematical analysis of these multi-timescale systems can be greatly simplified by partitioning them into subsystems that evolve on different time scales. The subsystems are then analyzed semi-independently, using a technique called fast-slow analysis. I will briefly describe the fast-slow analysis technique and its application to neuronal bursting oscillations and basic coupled neuron modeling. After this, I will discuss fancier forms of dynamics such as canard oscillations, mixed-mode oscillations, and three-timescale dynamics. Although these examples all involve neural systems, the methods can and have been applied to other biological, chemical, and physical systems.

The Michaelis–Menten (MM) rate law has been the dominant paradigm of modeling biochemical rate processes for over a century with applications in biochemistry, biophysics, cell biology, and chemical engineering. The MM rate law and its remedied form stand on the assumption that the concentration of the complex of interacting molecules, at each moment, approaches an equilibrium much faster than the molecular concentrations change. Yet, this assumption is not always justified. Here, we relax this quasi-steady state requirement and propose the generalized MM rate law for the interactions of molecules with active concentration changes over time. Our approach for time-varying molecular concentrations, termed the effective time-delay scheme (ETS), is based on rigorously estimated time-delay effects in molecular complex formation. With particularly marked improvements in protein– protein and protein–DNA interaction modeling, the ETS provides an analytical framework to interpret and predict rich transient or rhythmic dynamics (such as autogenously-regulated cellular adaptation and circadian protein turnover), which goes beyond the quasi-steady state assumption.