Search

Controlling the stochastic dynamics of biological populations is a challenge that arises across various biological contexts. However, these dynamics are inherently nonlinear and involve a discrete state space, i.e., the number of molecules, cells, or organisms. Additionally, the possibility of extinction has a significant impact on both the dynamics and control strategies, particularly when the population size is small. These factors hamper the direct application of conventional control theories to biological systems. To address these challenges, we formulate the optimal control problem for stochastic population dynamics by utilizing a control cost function based on the Kullback-Leibler divergence. This approach naturally accounts for population-specific factors and simplifies the complex nonlinear Hamilton-Jacobi-Bellman equation into a linear form, facilitating efficient computation of optimal solutions. We demonstrate the effectiveness of our approach by applying it to the control of interacting random walkers, Moran processes, and SIR models, and observe the mode-switching phenomena in the control strategies. Our approach provides new opportunities for applying control theory to a wide range of biological problems., Comment: 12 pages, 4 figures

Despite being optimized, the information processing of biological organisms exhibits significant variability in its complexity and capability. One potential source of this diversity is the limitation of resources required for information processing. However, we lack a theoretical framework that comprehends the relationship between biological information processing and resource limitations and integrates it with decision-making conduced downstream of the information processing. In this paper, we propose a novel optimal estimation and control theory that accounts for the resource limitations inherent in biological systems. This theory explicitly formulates the memory that organisms can store and operate and obtains optimal memory dynamics using optimal control theory. This approach takes account of various resource limitations, such as memory capacity, intrinsic noise, and energy cost, and unifies state estimation and control. We apply this theory to minimal models of biological information processing and decision-making under resource limitations and find that such limitations induce discontinuous and non-monotonic phase transitions between memory-less and memory-based strategies. Therefore, this theory establishes a comprehensive framework for addressing biological information processing and decision-making under resource limitations, revealing the rich and complex behaviors that arise from resource limitations.

Biological information processing manifests a huge variety in its complexity and capability among different organisms, which presumably stems from the evolutionary optimization under limited computational resources. Starting from the simplest memory-less responsive behaviors, more complicated information processing using internal memory may have developed in the evolution as more resources become available. In this letter, we report that optimal information processing strategy can show discontinuous transitions along with the available resources, i.e., reliability of sensing and intrinsic dynamics, or the cost of memory control. In addition, we show that transition is not always progressive but can be regressed. Our result obtained under a minimal setup suggests that the capability and complexity of information processing would be an evolvable trait that can switch back and forth between different strategies and architectures in a punctuated manner.

Reinforcement Learning (RL) offers a fundamental framework for discovering optimal action strategies through interactions within unknown environments. Recent advancement have shown that the performance and applicability of RL can significantly be enhanced by exploiting a population of agents in various ways. Zeroth-Order Optimization (ZOO) leverages an agent population to estimate the gradient of the objective function, enabling robust policy refinement even in non-differentiable scenarios. As another application, Genetic Algorithms (GA) boosts the exploration of policy landscapes by mutational generation of policy diversity in an agent population and its refinement by selection. A natural question is whether we can have the best of two worlds that the agent population can have. In this work, we propose Ancestral Reinforcement Learning (ARL), which synergistically combines the robust gradient estimation of ZOO with the exploratory power of GA. The key idea in ARL is that each agent within a population infers gradient by exploiting the history of its ancestors, i.e., the ancestor population in the past, while maintaining the diversity of policies in the current population as in GA. We also theoretically reveal that the populational search in ARL implicitly induces the KL-regularization of the objective function, resulting in the enhanced exploration. Our results extend the applicability of populational algorithms for RL., Comment: 16pages, 3 figures

Collective migration is a phenomenon observed in various biological systems, where the cooperation of multiple cells leads to complex functions beyond individual capabilities, such as in immunity and development. A distinctive example is cell populations that not only ascend attractant gradient originating from targets, such as damaged tissue, but also actively modify the gradient, through their own production and degradation. While the optimality of single-cell information processing has been extensively studied, the optimality of the collective information processing that includes gradient sensing and gradient generation, remains underexplored. In this study, we formulated a cell population that produces and degrades an attractant while exploring the environment as an agent population performing distributed reinforcement learning. We demonstrated the existence of optimal couplings between gradient sensing and gradient generation, showing that the optimal gradient generation qualitatively differs depending on whether the gradient sensing is logarithmic or linear. The derived dynamics have a structure homogeneous to the Keller-Segel model, suggesting that cell populations might be learning. Additionally, we showed that the distributed information processing structure of the agent population enables a proportion of the population to robustly accumulate at the target. Our results provide a quantitative foundation for understanding the collective information processing mediated by attractants in extracellular environments.

Analyzing the motion of multiple biological agents, be it cells or individual animals, is pivotal for the understanding of complex collective behaviors. With the advent of advanced microscopy, detailed images of complex tissue formations involving multiple cell types have become more accessible in recent years. However, deciphering the underlying rules that govern cell movements is far from trivial. Here, we present a novel deep learning framework for estimating the underlying equations of motion from observed trajectories, a pivotal step in decoding such complex dynamics. Our framework integrates graph neural networks with neural differential equations, enabling effective prediction of two-body interactions based on the states of the interacting entities. We demonstrate the efficacy of our approach through two numerical experiments. First, we used simulated data from a toy model to tune the hyperparameters. Based on the obtained hyperparameters, we then applied this approach to a more complex model with non-reciprocal forces that mimic the collective dynamics of the cells of slime molds. Our results show that the proposed method can accurately estimate the functional forms of two-body interactions -- even when they are nonreciprocal -- thereby precisely replicating both individual and collective behaviors within these systems., Comment: Accepted at NeurIPS 2024. Some contents are omitted due to arXiv's storage limit. Please refer to the full paper at OpenReview (NeurIPS 2024) or https://github.com/MasahitoUWAMICHI/collectiveMotionNN

Eukaryotic cells perform chemotaxis by determining the direction of chemical gradients based on stochastic sensing of concentrations at the cell surface. To examine the efficiency of this process, previous studies have investigated the limit of estimation accuracy for gradients. However, these studies assume that the cell shape and gradient are constant, and do not consider how adaptive regulation of cell shape affects the estimation limit. Dynamics of cell shape during gradient sensing is biologically ubiquitous and can influence the estimation by altering the way the concentration is measured, and cells may strategically regulate their shape to improve estimation accuracy. To address this gap, we investigate the estimation limits in dynamic situations where cells change shape adaptively depending on the sensed signal. We approach this problem by analyzing the stationary solution of the Bayesian nonlinear filtering equation. By applying diffusion approximation to the ligand-receptor binding process and the Laplace method for the posterior expectation under a high signal-to-noise ratio regime, we obtain an analytical expression for the estimation limit. This expression indicates that estimation accuracy can be improved by elongating perpendicular to the estimated direction, which is also confirmed by numerical simulations. Our analysis provides a basis for clarifying the interplay between estimation and control in gradient sensing and sheds light on how cells optimize their shape to enhance chemotactic efficiency., Comment: 14 pages, 5 figures

Chemical reaction networks (CRNs) exhibit complex dynamics governed by their underlying network structure. In this paper, we propose a novel approach to study the dynamics of CRNs by representing them on species graphs (S-graphs). By scaling concentrations by conservation laws, we obtain a graph representation of transitions compatible with the S-graph, which allows us to treat the dynamics in CRNs as transitions between chemicals. We also define thermodynamic-like quantities on the S-graph from the introduced transitions and investigate their properties, including the relationship between specieswise forces, activities, and conventional thermodynamic quantities. Remarkably, we demonstrate that this formulation can be developed for a class of irreversible CRNs, while for reversible CRNs, it is related to conventional thermodynamic quantities associated with reactions. The behavior of these specieswise quantities is numerically validated using an oscillating system (Brusselator). Our work provides a novel methodology for studying dynamics on S-graphs, paving the way for a deeper understanding of the intricate interplay between the structure and dynamics of chemical reaction networks., Comment: 8 pages, 4 figures

Understanding deaths and life-death boundaries of cells is a fundamental challenge in biological sciences. In this study, we present a theoretical framework for investigating cell death. We conceptualize cell death as a controllability problem within dynamical systems, and compute the life-death boundary through the development of "stoichiometric rays". This method utilizes enzyme activity as control parameters, exploiting the inherent property of enzymes to enhance reaction rates without shifting equilibrium states. This approach facilitates the efficient evaluation of the global controllability of models. We demonstrate the utility of our framework using its application to a toy metabolic model, where we delineate the life-death boundary. The formulation of cell death through mathematical principles provides a foundation for the theoretical study of cellular mortality.

We delve into growing open chemical reaction systems (CRSs) characterized by autocatalytic reactions within a variable volume, which changes in response to these reactions. Understanding the thermodynamics of such systems is crucial for comprehending biological cells and constructing protocells, as it sheds light on the physical conditions necessary for their self-replication. Building on our recent work, where we developed a thermodynamic theory for growing CRSs featuring basic autocatalytic motifs with regular stoichiometric matrices, we now expand this theory to include scenarios where the stoichiometric matrix has a nontrivial left kernel space. This extension introduces conservation laws, which limit the variations in chemical species due to reactions, thereby confining the system's possible states to those compatible with its initial conditions. By considering both thermodynamic and stoichiometric constraints, we clarify the environmental and initial conditions that dictate the CRSs' fate-whether they grow, shrink, or reach equilibrium. We also find that the conserved quantities significantly influence the equilibrium state achieved by a growing CRS. These results are derived independently of specific thermodynamic potentials or reaction kinetics, therefore underscoring the fundamental impact of conservation laws on the growth of the system., Comment: 26 pages, 9 figures

We investigate the dynamics of chemical reaction networks (CRNs) with the goal of deriving an upper bound on their reaction rates. This task is challenging due to the nonlinear nature and discrete structure inherent in CRNs. To address this, we employ an information geometric approach, using the natural gradient, to develop a nonlinear system that yields an upper bound for CRN dynamics. We validate our approach through numerical simulations, demonstrating faster convergence in a specific class of CRNs. This class is characterized by the number of chemicals, the maximum value of stoichiometric coefficients of the chemical reactions, and the number of reactions. We also compare our method to a conventional approach, showing that the latter cannot provide an upper bound on reaction rates of CRNs. While our study focuses on CRNs, the ubiquity of hypergraphs in fields from natural sciences to engineering suggests that our method may find broader applications, including in information science., Comment: 11 pages

Recently, Hessian geometry - an extension of information geometry - has emerged as a framework to naturally connect the geometries appearing in the theory of chemical reaction networks (CRN) to their inherent thermodynamical and kinetic properties. This framework is used in this letter to derive multivariate thermodynamic uncertainty relations (TUR) for CRN. The matrices featured in the TUR are shown to be representations of Riemmanian metric tensors, whereby one tensor characterizes the pseudo entropy production rate and the other the current fluctuations. It is shown that the latter tensor is a restriction of the former one to a linear subspace in the flux tangent space. Therefore, in addition to clarifying the geometric origin of TUR in CRN, the Hessian geometric setup yields a characterization of the error term in the TUR as the norm of a linear subspace component of the flux vector and thus characterizes the fluxes where TUR become equalities., Comment: 3 figures, 6 pages

While visual and auditory information conveyed by wavelength of light and frequency of sound have been decoded, predicting olfactory information encoded by the combination of odorants remains challenging due to the unknown and potentially discontinuous perceptual space of smells and odorants. Herein, we develop a deep learning model called Mol-PECO (Molecular Representation by Positional Encoding of Coulomb Matrix) to predict olfactory perception from molecular structures. Mol-PECO updates the learned atom embedding by directional graph convolutional networks (GCN), which model the Laplacian eigenfunctions as positional encoding, and Coulomb matrix, which encodes atomic coordinates and charges. With a comprehensive dataset of 8,503 molecules, Mol-PECO directly achieves an area-under-the-receiver-operating-characteristic (AUROC) of 0.813 in 118 odor descriptors, superior to the machine learning of molecular fingerprints (AUROC of 0.761) and GCN of adjacency matrix (AUROC of 0.678). The learned embeddings by Mol-PECO also capture a meaningful odor space with global clustering of descriptors and local retrieval of similar odorants. Our work may promote the understanding and decoding of the olfactory sense and mechanisms., Comment: 17 pages, 8 figures

We introduce a new information-geometric structure associated with the dynamics on discrete objects such as graphs and hypergraphs. The presented setup consists of two dually flat structures built on the vertex and edge spaces, respectively. The former is the conventional duality between density and potential, e.g., the probability density and its logarithmic form induced by a convex thermodynamic function. The latter is the duality between flux and force induced by a convex and symmetric dissipation function, which drives the dynamics of the density. These two are connected topologically by the homological algebraic relation induced by the underlying discrete objects. The generalized gradient flow in this doubly dual flat structure is an extension of the gradient flows on Riemannian manifolds, which include Markov jump processes and nonlinear chemical reaction dynamics as well as the natural gradient and mirror descent. The information-geometric projections on this doubly dual flat structure lead to information-geometric extensions of the Helmholtz-Hodge decomposition and the Otto structure in $L^{2}$ Wasserstein geometry. The structure can be extended to non-gradient nonequilibrium flows, from which we also obtain the induced dually flat structure on cycle spaces. This abstract but general framework can extend the applicability of information geometry to various problems of linear and nonlinear dynamics., Comment: 92 pages, 9 figures

Memory-limited partially observable stochastic control (ML-POSC) is the stochastic optimal control problem under incomplete information and memory limitation. In order to obtain the optimal control function of ML-POSC, a system of the forward Fokker-Planck (FP) equation and the backward Hamilton-Jacobi-Bellman (HJB) equation needs to be solved. In this work, we firstly show that the system of HJB-FP equations can be interpreted via the Pontryagin's minimum principle on the probability density function space. Based on this interpretation, we then propose the forward-backward sweep method (FBSM) to ML-POSC, which has been used in the Pontryagin's minimum principle. FBSM is an algorithm to compute the forward FP equation and the backward HJB equation alternately. Although the convergence of FBSM is generally not guaranteed, it is guaranteed in ML-POSC because the coupling of HJB-FP equations is limited to the optimal control function in ML-POSC.

Decentralized stochastic control (DSC) considers the optimal control problem of a multi-agent system. However, DSC cannot be solved except in the special cases because the estimation among the agents is generally intractable. In this work, we propose memory-limited DSC (ML-DSC), in which each agent compresses the observation history into the finite-dimensional memory. Because this compression simplifies the estimation among the agents, ML-DSC can be solved in more general cases based on the mean-field control theory. We demonstrate ML-DSC in the general LQG problem. Because estimation and control are not clearly separated in the general LQG problem, the Riccati equation is modified to the decentralized Riccati equation, which improves estimation as well as control. Our numerical experiment shows that the decentralized Riccati equation is superior to the conventional Riccati equation., Comment: arXiv admin note: text overlap with arXiv:2203.10682

We derive the Hessian geometric structure of nonequilibrium chemical reaction networks (CRN) on the flux and force spaces induced by the Legendre duality of convex dissipation functions and characterize their dynamics as a generalized flow. With this structure, we can extend theories of nonequilibrium systems with quadratic dissipation functions to more general ones with nonquadratic ones, which are pivotal for studying chemical reaction networks. By applying generalized notions of orthogonality in Hessian geometry to chemical reaction networks, we obtain two generalized decompositions of the entropy production rate, each of which captures gradient-flow and minimum-dissipation aspects in nonequilibrium dynamics., Comment: 9 figures

In multicellular systems, the single-cell behaviors should be coordinated consistently with the overall population dynamics and functions. However, the interrelation between single-cell rules and the population-level goal is still elusive. In this work, we reveal that these two levels are naturally connected via a gradient flow structure of the heterogeneous cellular population and that biologically prevalent single-cell rules such as unidirectional type-switching and hierarchical order in types emerge from this structure. We also demonstrate the gradient flow structure in a standard model of the T-cell immune response. This theoretical framework works as a basis for understanding multicellular dynamics and functions.

It is known that the trajectory of an endoreversibly driven system with minimal dissipation is a geodesic on the equilibrium state space. Thereby, the state space is equipped with the Riemannian metric given by the Hessian of the free energy function, known as Fisher information metric. However, the derivations given until now require both the system and the driving reservoir to be in local equilibrium. In the present work, we rederive the framework for chemical reaction networks and thereby enhance its scope of applicability to the nonequilibrium situation. Moreover, because our results are derived without restrictive assumptions, we are able to discuss phenomena that could not been seen previously. We introduce a suitable weighted Fisher information metric on the space of chemical concentrations and show that it characterizes the dissipation caused by diffusive driving, with arbitrary diffusion rate constants. This allows us to consider driving far from equilibrium. As the main result, we show that the isometric embedding of a steady state manifold into the concentration space yields a lower bound for the dissipation when the system is driven along the manifold. We give an analytic expression for this bound and for the corresponding geodesic, and thereby are able to dissect the contributions from the driving kinetics and from thermodynamics. Finally, we discuss in detail the application to quasi-thermostatic steady states., Comment: 13 pages, 5 figures

Control problems with incomplete information and memory limitation appear in many practical situations. Although partially observable stochastic control (POSC) is a conventional theoretical framework that considers the optimal control problem with incomplete information, it cannot consider memory limitation. Furthermore, POSC cannot be solved in practice except in the special cases. In order to address these issues, we propose an alternative theoretical framework, memory-limited POSC (ML-POSC). ML-POSC directly considers memory limitation as well as incomplete information, and it can be solved in practice by employing the mathematical technique of the mean-field control theory. ML-POSC can generalize the LQG problem to include memory limitation. Because estimation and control are not clearly separated in the LQG problem with memory limitation, the Riccati equation is modified to the partially observable Riccati equation, which improves estimation as well as control. Furthermore, we demonstrate the effectiveness of ML-POSC to a non-LQG problem by comparing it with the local LQG approximation.

We consider growing open chemical reaction systems (CRSs), in which autocatalytic chemical reactions are encapsulated in a finite volume and its size can change in conjunction with the reactions. The thermodynamics of growing CRSs is indispensable for understanding biological cells and designing protocells by clarifying the physical conditions and costs for their growing states. In this work, we establish a thermodynamic theory of growing CRSs by extending the Hessian geometric structure of non-growing CRSs. The theory provides the environmental conditions to determine the fate of the growing CRSs; growth, shrinking or equilibration. We also identify thermodynamic constraints; one to restrict the possible states of the growing CRSs and the other to further limit the region where a nonequilibrium steady growing state can exist. Moreover, we evaluate the entropy production rate in the steady growing state. The growing nonequilibrium state has its origin in the extensivity of thermodynamics, which is different from the conventional nonequilibrium states with constant volume. These results are derived from general thermodynamic considerations without assuming any specific thermodynamic potentials or reaction kinetics; i.e., they are obtained based solely on the second law of thermodynamics., Comment: 22 pages, 9 figures

The theory of chemical kinetics form the basis to describe the dynamics of chemical systems. Owing to physical and thermodynamic constraints, chemical reaction systems possess various structures, which can be utilized to characterize important physical properties of the systems. In this work, we reveal the Hessian geometry which underlies chemical reaction systems and demonstrate how it originates from the interplay of stoichiometric and thermodynamic constraints. Our derivation is based on kinetics, we assume the law of mass action and characterize the equilibrium states by the detailed balance condition. The obtained geometric structure is then related to thermodynamics via the Hessian geometry appearing in a pure thermodynamic derivation. We demonstrate, based on the fact that both equilibrium and complex balanced states form toric varieties, how the Hessian geometric framework can be extended to nonequilibrium complex balanced steady states. We conclude that Hessian geometry provides a natural framework to capture the thermodynamic aspects of chemical reaction kinetics., Comment: 15 pages, 5 figures

We establish a Hessian geometric structure in chemical thermodynamics which describes chemical reaction networks (CRNs) with equilibrium states. In our setup, the ideal gas assumption and mass action kinetics are not required. The existence and uniqueness condition of the equilibrium state is derived by using the Legendre duality inherent to the Hessian structure. The entropy production during a relaxation to the equilibrium state can be evaluated by the Bregman divergence. Furthermore, the equilibrium state is characterized by four distinct minimization problems of the divergence, which are obtained from the generalized Pythagorean theorem originating in the dual flatness. For the ideal gas case, we confirm that our existence and uniqueness condition implies Birch's theorem, and that the entropy production represented by the divergence coincides with the generalized Kullback-Leibler divergence. In addition, under mass action kinetics, our general framework reproduces the local detailed balance condition., Comment: 15 pages, 5 figures

Run-and-tumble chemotaxis is one of the representative search strategies of an odor source via sensing its spatial gradient. The optimal ways of sensing and control in the run-and-tumble chemotaxis have been analyzed theoretically to elucidate the efficiency of strategies implemented in organisms. However, because of theoretical difficulties, most of attempts have been limited only to either linear or deterministic analysis even though real biological chemotactic systems involve considerable stochasticity and nonlinearity in their sensory processes and controlled responses. In this paper, by combining the theories of optimal filtering and Kullback-Leibler control of partially observed Markov decision process (POMDP), we derive the optimal and fully nonlinear strategy for controlling run-and-tumble motion depending on noisy sensing of ligand gradient. The derived optimal strategy consists of the optimal filtering dynamics to estimate the run-direction from noisy sensory input and the control function to regulate the motor output. We further show that this optimal strategy can be associated naturally with a standard biochemical model and experimental data of the Escherichia coli's chemotaxis. These results demonstrate that our theoretical framework can work as a basis for analyzing the efficiency and optimality of run-and-tumble chemotaxis., Comment: 8 pages, 4 figures

Natural selection is general and powerful concept not only to explain evolutionary processes of biological organisms but also to design engineering systems such as genetic algorithms and particle filters. There is a surge of interest, both from biology and engineering, in considering natural selection of intellectual agents that can learn individually. Learning by individual agents of better behaviors for survival may accelerate the evolutionary processes by natural selection. We have accumulating pieces of evidence that organisms can transmit its information to the next generation via epigenetic states or memes. Also, such idea is important for engineering applications. To accelerate the evolutionary process, an agent should change their strategy so that the population fitness increases the most. Equivalently, an agent should update the strategy towards a gradient of the population fitness. However, it has not yet been clarified whether and how an agent can estimate the gradient and accelerate the evolutionary process. We also lack methodology to quantify the acceleration to understand and predict the impact of learning. In this paper, we address these problems. We show that an learning agent can accelerate the evolutionary process by proposing ancestral learning, which uses the information transmitted from the ancestor (ancestral information). We next show that the ancestral information is sufficient to estimate the gradient. In particular, learning can accelerate the evolutionary process without communications between agents. Finally, to quantify the acceleration, we extend the Fisher's fundamental theorem (FF-thm) for natural selection to ancestral learning. Our extended FF-thm relates the acceleration of the evolutionary process to the variety of individual fitness of the agent. By the theorem, we can quantitatively understand when and why learning is beneficial., Comment: 19 pages, 4 figures

Decentralized partially observable Markov decision process (DEC-POMDP) models sequential decision making problems by a team of agents. Since the planning of DEC-POMDP can be interpreted as the maximum likelihood estimation for the latent variable model, DEC-POMDP can be solved by the EM algorithm. However, in EM for DEC-POMDP, the forward--backward algorithm needs to be calculated up to the infinite horizon, which impairs the computational efficiency. In this paper, we propose the Bellman EM algorithm (BEM) and the modified Bellman EM algorithm (MBEM) by introducing the forward and backward Bellman equations into EM. BEM can be more efficient than EM because BEM calculates the forward and backward Bellman equations instead of the forward--backward algorithm up to the infinite horizon. However, BEM cannot always be more efficient than EM when the size of problems is large because BEM calculates an inverse matrix. We circumvent this shortcoming in MBEM by calculating the forward and backward Bellman equations without the inverse matrix. Our numerical experiments demonstrate that the convergence of MBEM is faster than that of EM.

The chemotactic network of Escherichia coli has been studied extensively both biophysically and information-theoretically. Nevertheless, the connection between these two aspects is still elusive. In this work, we report such a connection by showing that a standard biochemical model of the chemotactic network is mathematically equivalent to an information-theoretically optimal filtering dynamics. Moreover, we demonstrate that an experimentally observed nonlinear response relation can be reproduced from the optimal dynamics. These results suggest that the biochemical network of E. coli chemotaxis is designed to optimally extract gradient information in a noisy condition.

The adaptive immune system of vertebrates can detect, respond to, and memorize diverse pathogens from past experience. While the clonal selection of T helper (Th) cells is the simple and established mechanism to better recognize new pathogens, the question that still remains unexplored is how the Th cells can acquire better ways to bias the responses of immune cells for eliminating pathogens more efficiently by translating the recognized antigen information into regulatory signals. In this work, we address this problem by associating the adaptive immune network organized by the Th cells with reinforcement learning (RL). By employing recent advancements of network-based RL, we show that the Th immune network can acquire the association between antigen patterns of and the effective responses to pathogens. Moreover, the clonal selection as well as other inter-cellular interactions are derived as a learning rule of the network. We also demonstrate that the stationary clone-size distribution after learning shares characteristic features with those observed experimentally. Our theoretical framework may contribute to revising and renewing our understanding of adaptive immunity as a learning system., Comment: 9 pages, 5 figures

Phenotypic variability in a population of cells can work as the bet-hedging of the cells under an unpredictably changing environment, the typical example of which is the bacterial persistence. To understand the strategy to control such phenomena, it is indispensable to identify the phenotype of each cell and its inheritance. Although recent advancements in microfluidic technology offer us useful lineage data, they are insufficient to directly identify the phenotypes of the cells. An alternative approach is to infer the phenotype from the lineage data by latent-variable estimation. To this end, however, we must resolve the bias problem in the inference from lineage called survivorship bias. In this work, we clarify how the survivor bias distorts statistical estimations. We then propose a latent-variable estimation algorithm without the survivorship bias from lineage trees based on an expectation-maximization (EM) algorithm, which we call Lineage EM algorithm (LEM). LEM provides a statistical method to identify the traits of the cells applicable to various kinds of lineage data., Comment: 12 pages; Supplementary Information and full-resolution figures are available at bioarxiv (https://doi.org/10.1101/488981 )

We construct a pathwise formulation for a multi-type age-structured population dynamics, which involves an age-dependent cell replication and transition of gene- or phenotypes. By employing the formulation, we derive a variational representation of the stationary population growth rate; the representation comprises a trade-off relation between growth effects and a single-cell intrinsic dynamics described by a semi-Markov process. This variational representation leads to a response relation of the stationary population growth rate, in which statistics on a retrospective history work as the response coefficients. These results contribute to predicting and controlling growing populations based on experimentally observed cell-lineage information., Comment: 16 pages, 7 figures

SuperKEKB is an asymmetric electron-positron circular collider based on nano-beam scheme at interaction region and large beam current. Large beam current makes growth rates of longitudinal coupled-bunch instabilities (LCBI) large. Especially some lowest modes near accelerating frequency are serious. On the design parameter for SuperKEKB, $\mu$ = -1, -2, -3 mode of LCBI can be destabilized. We developed new LCBI damper to suppress newly arisen LCBI modes ($\mu$ = -1, -2, -3) in SuperKEKB. The new damper will be installed in Low Level RF control system. The new LCBI damper is independent of main LLRF control components. In the test bench measurement, our new LCBI damper has good performance and satisfied required specifications. For preparation of using LCBI damper, we produced the simulation of beam oscillation damped by RF feedback. The results of this simulation shows that we need more dampers than them we prepared. We report profile of new damper and results of test bench measurement and feedback simulation in this paper., Comment: Talk presented at LLRF Workshop 2017 (LLRF2017, arXiv:1803.07677)

Mutual information and its causal variant, directed information, have been widely used to quantitatively characterize the performance of biological sensing and information transduction. However, once coupled with selection in response to decision-making, the sensing signal could have more or less evolutionary value than its mutual or directed information. In this work, we show that an individually sensed signal always has a better fitness value, on average, than its mutual or directed information. The fitness gain, which satisfies fluctuation relations (FRs), is attributed to the selection of organisms in a population that obtain a better sensing signal by chance. A new quantity, similar to the coarse-grained entropy production in information thermodynamics, is introduced to quantify the total fitness gain from individual sensing, which also satisfies FRs. Using this quantity, the optimizing fitness gain from individual sensing is shown to be related to fidelity allocations for individual environmental histories. Our results are supplemented by numerical verifications of FRs, and a discussion on how this problem is linked to information encoding and decoding., Comment: 5figures

The reliability of logical operations is indispensable for the reliable operation of computational systems. Since the down-sizing of micro-fabrication generates non-negligible noise in these systems, a new approach for designing noise-immune gates is required. In this paper, we demonstrate that noise-immune gates can be designed by combining Bayesian inference theory with the idea of computation over a noisy signal. To reveal their practical advantages, the performance of these gates is evaluated in comparison with a stochastic resonance-based gate proposed previously. This approach for computation is also demonstrated to be better than a conventional one that conducts information transmission and computation separately., Comment: 3figures + 3 supplementary figures

Adaptation in a fluctuating environment is a process of fueling environmental information to gain fitness. Living systems have gradually developed strategies for adaptation from random and passive diversification of the phenotype to more proactive decision making, in which environmental information is sensed and exploited more actively and effectively. Understanding the fundamental relation between fitness and information is therefore crucial to clarify the limits and universal properties of adaptation. In this work, we elucidate the underlying stochastic and information-thermodynamic structure in this process, by deriving causal fluctuation relations (FRs) of fitness and information. Combined with a duality between phenotypic and environmental dynamics, the FRs reveal the limit of fitness gain, the relation of time reversibility with the achievability of the limit, and the possibility and condition for gaining excess fitness due to environmental fluctuation. The loss of fitness due to causal constraints and the limited capacity of real organisms is shown to be the difference between time-forward and time-backward path probabilities of phenotypic and environmental dynamics. Furthermore, the FRs generalize the concept of evolutionary stable state (ESS) for fluctuating environment by giving the probability that the optimal strategy on average can be invaded by a suboptimal one owing to rare environmental fluctuation. These results clarify the information thermodynamic structures in adaptation and evolution., Comment: 5figures

Specific interactions between receptors and their target ligands in the presence of non-target ligands are crucial for biological processes such as T cell ligand discrimination. To discriminate between the target and non-target ligands, cells have to increase specificity by amplifying the small differences in affinity among ligands. In addition, sensitivity to ligand concentration and quick discrimination are also important to detect low amounts of target ligands and facilitate fast cellular decision making after ligand recognition. In this work, we find that ultraspecificity is naturally derived from a well-known mechanism for zero-order ultrasensitivity to concentration. We also show that this mechanism can produce an optimal balance of specificity, sensitivity, and quick discrimination. Furthermore, we show that a model for insensitivity to large number of non-terget ligands can be naturally derived from the ultraspecificity model. Zero-order ultraspecificity may provide alternative way to understand ligand discrimination from the viewpoint of the nonlinear properties of biochemical reactions.

A decrease in system size can induce qualitatively different behavior compared to the macroscopic behavior of the corresponding large-size system. The mechanisms of this transition, which is known as the small-size transition, can be attributed to either a relative increase in the noise intensity or to the discreteness of the state space due to the small system size. The former mechanism has been intensively investigated using several toy and realistic models. However, the latter has rarely been analyzed and is sometimes confused with the former, because a toy model that extracts the essence of the discreteness-induced transition mechanism is lacking. In this work, we propose a 1- and 3-body reaction system as a minimal model of the discreteness-induced transition and derive the conditions under which this transition occurs in more complex systems. This work enriches our understanding of the influence of small system size on system behavior.

We report that population dynamics in fluctuating environment accompanies mathematically equivalent structure to steady state thermodynamics. By employing the structure, population growth in fluctuating environment is decomposed into housekeeping and excess parts. The housekeeping part represents the integral of stationary growth rate for each condition during a history of the environmental change. The excess part accounts for the excess growth generated when environment is switched. Focusing on the excess growth, we obtain Clausius inequality, which gives the upper bound of the excess growth. The equality is shown to be achieved in quasistatic environmental changes. We also clarify that this bound can be evaluated by "lineage fitness" that is an experimentally observable quantity., Comment: 5 pages, 2 figures

Phenotype-switching with and without sensing environment is a ubiquitous strategy of organisms to survive in fluctuating environment. Fitness of a population of organisms with phenotype-switching may be constrained and restricted by hidden relations as the entropy production in a thermal system with and without sensing and feedback is well-characterized via fluctuation relations (FRs) . In this work, we derive such FRs of fitness together with an underlying information-theoretic structure in selection. By using path-integral formulation of a multi-phenotype population dynamics, we clarify that the optimal switching strategy is characterized as a consistency condition for time-forward and backward path probabilities. Within the formulation, the selection is regarded as passive information compression, and the loss of fitness from the optimal strategy is shown to satisfy various FRs that constrain the average and fluctuation of the loss. These results are naturally extended to the situation that organisms can use an environmental signal by actively sensing the environment. FRs of fitness gain by sensing are derived in which the multivariate mutual information among the phenotype, the environment and the signal plays the role to quantify the relevant information in the signal for fitness gain., Comment: Submitted to PRL on 25/Jul/2014; resubmitted to PRL for revision on 10/Apr/2015

Intracellular biochemical networks fluctuate dynamically due to various internal and external sources of fluctuation. Dissecting the fluctuation into biologically relevant components is important for understanding how a cell controls and harnesses noise and how information is transferred over apparently noisy intracellular networks. While substantial theoretical and experimental advancement on the decomposition of fluctuation was achieved for feedforward networks without any loop, we still lack a theoretical basis that can consistently extend such advancement to feedback networks. The main obstacle that hampers is the circulative propagation of fluctuation by feedback loops. In order to define the relevant quantity for the impact of feedback loops for fluctuation, disentanglement of the causally interlocked influence between the components is required. In addition, we also lack an approach that enables us to infer non-perturbatively the influence of the feedback to fluctuation as the dual reporter system does in the feedforward network. In this work, we resolve these problems by extending the work on the fluctuation decomposition and the dual reporter system. For a single-loop feedback network with two components, we define feedback loop gain as the feedback efficiency that is consistent with the fluctuation decomposition for feedforward networks. Then, we clarify the relation of the feedback efficiency with the fluctuation propagation in an open-looped FF network. Finally, by extending the dual reporter system, we propose a conjugate feedback and feedforward system for estimating the feedback efficiency only from the statistics of the system non-perturbatively.