Pub Date : 2025-12-27DOI: 10.1016/j.jtbi.2025.112347
Yihan Liu , David J. Warne , Matthew J. Simpson
Sensitivity analysis characterises input–output relationships for mathematical models, and has been widely applied to deterministic models across many applications in the life sciences. In contrast, sensitivity analysis for stochastic models has received less attention, with most previous work focusing on well-mixed, non-spatial problems. For explicit spatio-temporal stochastic models, such as random walk models (RWMs), sensitivity analysis has received far less attention. Here we present a new type of sensitivity analysis, called parameter-wise prediction, for two types of biologically-motivated and computationally expensive RWMs. To overcome the limitations of directly analysing stochastic simulations, we employ continuum-limit partial differential equation (PDE) descriptions as surrogate models, and we link these efficient surrogate descriptions to the RWMs using a range of biophysically-motivated measurement error models. Our approach is likelihood-based, which means that we also consider likelihood-based parameter estimation and identifiability analysis along with parameter sensitivity. The new approach is presented for two important classes of lattice-based RWM including a classical model where crowding effects are neglected, and an exclusion process model that explicitly incorporates crowding. Our workflow illustrates how different process models can be combined with different measurement error models to reveal how each parameter impacts the outcome of the expensive stochastic simulation. Open-access software to replicate all results is available on GitHub (Liu, 2025).
{"title":"Parameter-wise predictions and sensitivity analysis for random walk models in the life sciences","authors":"Yihan Liu , David J. Warne , Matthew J. Simpson","doi":"10.1016/j.jtbi.2025.112347","DOIUrl":"10.1016/j.jtbi.2025.112347","url":null,"abstract":"<div><div>Sensitivity analysis characterises input–output relationships for mathematical models, and has been widely applied to deterministic models across many applications in the life sciences. In contrast, sensitivity analysis for stochastic models has received less attention, with most previous work focusing on well-mixed, non-spatial problems. For explicit spatio-temporal stochastic models, such as random walk models (RWMs), sensitivity analysis has received far less attention. Here we present a new type of sensitivity analysis, called <em>parameter-wise prediction</em>, for two types of biologically-motivated and computationally expensive RWMs. To overcome the limitations of directly analysing stochastic simulations, we employ continuum-limit partial differential equation (PDE) descriptions as surrogate models, and we link these efficient surrogate descriptions to the RWMs using a range of biophysically-motivated <em>measurement error models</em>. Our approach is likelihood-based, which means that we also consider likelihood-based parameter estimation and identifiability analysis along with parameter sensitivity. The new approach is presented for two important classes of lattice-based RWM including a classical model where crowding effects are neglected, and an exclusion process model that explicitly incorporates crowding. Our workflow illustrates how different process models can be combined with different measurement error models to reveal how each parameter impacts the outcome of the expensive stochastic simulation. Open-access software to replicate all results is available on <span><span>GitHub</span><svg><path></path></svg></span> (Liu, 2025).</div></div>","PeriodicalId":54763,"journal":{"name":"Journal of Theoretical Biology","volume":"621 ","pages":"Article 112347"},"PeriodicalIF":2.0,"publicationDate":"2025-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145859279","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"数学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-24DOI: 10.1016/j.jtbi.2025.112346
Mazen Nakad , Aaron Potkay , Marc A. Hesse , Maurizio Mencuccini , Pierre Gentine , Ensheng Weng
The transport of photosynthates, particularly sucrose, is a key process in plant physiology, eco-hydrology, and earth system modeling. The phloem plays a central role in this transport, influencing processes ranging from plant survival during drought to ecosystem-scale carbon and water cycling. The core principle underlying our understanding of phloem transport is the pressure-flow hypothesis, in which sucrose is loaded into leaves, drawing water from the xylem through osmosis and generating pressure gradients for transport. Experimental challenges in measuring sugar fluxes and phloem turgor pressure have led to a reliance on theoretical models. However, discrepancies persist, particularly for long-distance transport, where past modeling assumptions have led to difficulties in maintaining sufficient pressure, a challenge that may be alleviated when considering unloading along the transport pathway. Criticisms of the pressure-flow hypothesis often overlook the role of local unloading along the phloem pathway, which can alleviate pressure demands by reducing sucrose concentration and viscosity. To account for their effects, this study examines the influence of local sucrose sinks on transport dynamics. Osmotically driven flows are investigated through the development of a new one-dimensional numerical model that incorporates sinks toward the stem and roots. Results show that different allocation schemes of sucrose sinks along the stem influence the speed of sucrose transport, with simulations that include local sucrose sink distributions aligning more closely with past observations than those without these sinks. Sink profiles with higher demand near the stem base are more consistent with the classical pressure-flow hypothesis, referred to as the passive Münch mechanism, promoting stable pressure gradients and efficient transport. These findings provide insight into how carbon allocation within the phloem may have evolved to optimize the efficiency of soluble compound transport.
{"title":"Spatial sucrose sink profiles shape phloem transport efficiency and xylem-phloem water exchange","authors":"Mazen Nakad , Aaron Potkay , Marc A. Hesse , Maurizio Mencuccini , Pierre Gentine , Ensheng Weng","doi":"10.1016/j.jtbi.2025.112346","DOIUrl":"10.1016/j.jtbi.2025.112346","url":null,"abstract":"<div><div>The transport of photosynthates, particularly sucrose, is a key process in plant physiology, eco-hydrology, and earth system modeling. The phloem plays a central role in this transport, influencing processes ranging from plant survival during drought to ecosystem-scale carbon and water cycling. The core principle underlying our understanding of phloem transport is the pressure-flow hypothesis, in which sucrose is loaded into leaves, drawing water from the xylem through osmosis and generating pressure gradients for transport. Experimental challenges in measuring sugar fluxes and phloem turgor pressure have led to a reliance on theoretical models. However, discrepancies persist, particularly for long-distance transport, where past modeling assumptions have led to difficulties in maintaining sufficient pressure, a challenge that may be alleviated when considering unloading along the transport pathway. Criticisms of the pressure-flow hypothesis often overlook the role of local unloading along the phloem pathway, which can alleviate pressure demands by reducing sucrose concentration and viscosity. To account for their effects, this study examines the influence of local sucrose sinks on transport dynamics. Osmotically driven flows are investigated through the development of a new one-dimensional numerical model that incorporates sinks toward the stem and roots. Results show that different allocation schemes of sucrose sinks along the stem influence the speed of sucrose transport, with simulations that include local sucrose sink distributions aligning more closely with past observations than those without these sinks. Sink profiles with higher demand near the stem base are more consistent with the classical pressure-flow hypothesis, referred to as the passive Münch mechanism, promoting stable pressure gradients and efficient transport. These findings provide insight into how carbon allocation within the phloem may have evolved to optimize the efficiency of soluble compound transport.</div></div>","PeriodicalId":54763,"journal":{"name":"Journal of Theoretical Biology","volume":"621 ","pages":"Article 112346"},"PeriodicalIF":2.0,"publicationDate":"2025-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145844270","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"数学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-23DOI: 10.1016/j.jtbi.2025.112351
Honghui Gao , Ming Chen , Yuwei Liu
A dynamic model is proposed to describe an integrated multi-trophic aquaculture (IMTA) system, including nutrients, detritus, phytoplankton, zooplankton and scavenger. The dynamic properties of the model are fully studied. Ecological reproductive indexes for the survival of phytoplankton, zooplankton, and scavenger play crucial roles in the construction of IMTA structure. Parameter values of the model are estimated based on experimental data. The study reveals that zooplankton in integrated aquaculture systems exhibit a dualistic function, potentially either enhancing or suppressing the growth of scavengers. This finding provides a mechanistic explanation for the paradoxical phenomenon observed in some marine ranching, where integrated aquaculture fails to enhance productivity, thereby challenging the conventional assumption of its universally positive effects. Furthermore, the study identifies key traits of zooplankton that promote scavengers production. Through bifurcation analysis of resource inputs, the research delineates the mechanistic basis for optimizing scavengers yield while maintaining ecosystem stability. These insights provide a theoretical foundation for enhancing the structure and sustainability of multi-trophic aquaculture systems.
{"title":"Dynamics of integrated multi-trophic aquaculture (IMTA): A modeling approach incorporating zooplankton and scavenger","authors":"Honghui Gao , Ming Chen , Yuwei Liu","doi":"10.1016/j.jtbi.2025.112351","DOIUrl":"10.1016/j.jtbi.2025.112351","url":null,"abstract":"<div><div>A dynamic model is proposed to describe an integrated multi-trophic aquaculture (IMTA) system, including nutrients, detritus, phytoplankton, zooplankton and scavenger. The dynamic properties of the model are fully studied. Ecological reproductive indexes for the survival of phytoplankton, zooplankton, and scavenger play crucial roles in the construction of IMTA structure. Parameter values of the model are estimated based on experimental data. The study reveals that zooplankton in integrated aquaculture systems exhibit a dualistic function, potentially either enhancing or suppressing the growth of scavengers. This finding provides a mechanistic explanation for the paradoxical phenomenon observed in some marine ranching, where integrated aquaculture fails to enhance productivity, thereby challenging the conventional assumption of its universally positive effects. Furthermore, the study identifies key traits of zooplankton that promote scavengers production. Through bifurcation analysis of resource inputs, the research delineates the mechanistic basis for optimizing scavengers yield while maintaining ecosystem stability. These insights provide a theoretical foundation for enhancing the structure and sustainability of multi-trophic aquaculture systems.</div></div>","PeriodicalId":54763,"journal":{"name":"Journal of Theoretical Biology","volume":"620 ","pages":"Article 112351"},"PeriodicalIF":2.0,"publicationDate":"2025-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145835351","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"数学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-21DOI: 10.1016/j.jtbi.2025.112353
Rocío Ruiz-Lozano , José Luis Calvo-Gallego , Peter Pivonka , Javier Martínez-Reina
The aetiology of osteoporosis (OP) is diverse, with ageing and the oestrogen decline after menopause being the main causes of the most prevalent type, primary OP. The concurrence of other diseases (such as chronic kidney disease or hyperparathyroidism), the use of certain medications (glucocorticoids) or an inadequate diet or a sedentary lifestyle may also cause or accelerate the appearance of OP. To counteract the sedentary lifestyle, physical exercise is often recommended as a preventive therapy or even as a complement to pharmacological treatments. In this work, we use a mathematical model of bone remodelling based on cell populations that implements bone mechanical feedback as a function of the strain level and the number of cycles of daily activities. We coupled this bone remodelling model with PK-PD models of denosumab and teriparatide to study the joint effect of drug treatments and exercise on bone density of postmenopausal women. Our results show that low-intensity exercise alone could slow down bone loss and prevent OP, particularly if started at a young age, and it could improve the efficacy of drug treatments, increasing bone density and reducing fracture risk. The incremental benefit of physical activity is greater in denosumab treatments, where the anabolic effect of exercise complements the anticatabolic effect of denosumab. However, the bone density gain and the reduction in fracture risk is greater, in absolute terms, in teriparatide treatments. In any case, disuse and sedentary lifestyle are detrimental to bone density and compromises the efficacy of drug treatments.
{"title":"Can physical activity augment drug efficacy in PMO treatments - Insights from in-silico simulations of PTH and denosumab treatments","authors":"Rocío Ruiz-Lozano , José Luis Calvo-Gallego , Peter Pivonka , Javier Martínez-Reina","doi":"10.1016/j.jtbi.2025.112353","DOIUrl":"10.1016/j.jtbi.2025.112353","url":null,"abstract":"<div><div>The aetiology of osteoporosis (OP) is diverse, with ageing and the oestrogen decline after menopause being the main causes of the most prevalent type, primary OP. The concurrence of other diseases (such as chronic kidney disease or hyperparathyroidism), the use of certain medications (glucocorticoids) or an inadequate diet or a sedentary lifestyle may also cause or accelerate the appearance of OP. To counteract the sedentary lifestyle, physical exercise is often recommended as a preventive therapy or even as a complement to pharmacological treatments. In this work, we use a mathematical model of bone remodelling based on cell populations that implements bone mechanical feedback as a function of the strain level and the number of cycles of daily activities. We coupled this bone remodelling model with PK-PD models of denosumab and teriparatide to study the joint effect of drug treatments and exercise on bone density of postmenopausal women. Our results show that low-intensity exercise alone could slow down bone loss and prevent OP, particularly if started at a young age, and it could improve the efficacy of drug treatments, increasing bone density and reducing fracture risk. The incremental benefit of physical activity is greater in denosumab treatments, where the anabolic effect of exercise complements the anticatabolic effect of denosumab. However, the bone density gain and the reduction in fracture risk is greater, in absolute terms, in teriparatide treatments. In any case, disuse and sedentary lifestyle are detrimental to bone density and compromises the efficacy of drug treatments.</div></div>","PeriodicalId":54763,"journal":{"name":"Journal of Theoretical Biology","volume":"621 ","pages":"Article 112353"},"PeriodicalIF":2.0,"publicationDate":"2025-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145821861","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"数学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-20DOI: 10.1016/j.jtbi.2025.112352
Dan Adler
The emergence of complexity and information remains a fundamental question in all scientific disciplines. This paper introduces Stability-Driven Assembly (SDA) systems, a theoretical framework that models pattern evolution through probabilistic interactions governed by differential stability. Our computational experiments demonstrate that stability differences alone can generate selection pressure, driving systems toward lower-entropy states characterized by dominant stable patterns, without requiring explicit replication mechanisms. Through controlled intervention experiments, we establish a causal relationship within the model between stability constraints and system evolution, showing how stability functions as a control parameter shaping the evolutionary landscape. The SDA framework reveals the interplay between bottom-up assembly processes and top-down selective pressures, where emergent stable patterns recursively influence future interactions. Dynamic network visualization further illuminates how stability-driven selection operates on all scales. These findings may provide the foundation for a mechanistic explanation of how complexity and information can emerge in abiotic systems. Looking ahead, we suggest that SDA could provide a useful lens for connecting stochastic dynamical systems with prebiotic chemistry, and for exploring hypotheses about how stability-driven dynamics might precede the emergence of autocatalysis, replication, and Darwinian evolution.
{"title":"Stability-driven assembly theory","authors":"Dan Adler","doi":"10.1016/j.jtbi.2025.112352","DOIUrl":"10.1016/j.jtbi.2025.112352","url":null,"abstract":"<div><div>The emergence of complexity and information remains a fundamental question in all scientific disciplines. This paper introduces Stability-Driven Assembly (SDA) systems, a theoretical framework that models pattern evolution through probabilistic interactions governed by differential stability. Our computational experiments demonstrate that stability differences alone can generate selection pressure, driving systems toward lower-entropy states characterized by dominant stable patterns, without requiring explicit replication mechanisms. Through controlled intervention experiments, we establish a causal relationship within the model between stability constraints and system evolution, showing how stability functions as a control parameter shaping the evolutionary landscape. The SDA framework reveals the interplay between bottom-up assembly processes and top-down selective pressures, where emergent stable patterns recursively influence future interactions. Dynamic network visualization further illuminates how stability-driven selection operates on all scales. These findings may provide the foundation for a mechanistic explanation of how complexity and information can emerge in abiotic systems. Looking ahead, we suggest that SDA could provide a useful lens for connecting stochastic dynamical systems with prebiotic chemistry, and for exploring hypotheses about how stability-driven dynamics might precede the emergence of autocatalysis, replication, and Darwinian evolution.</div></div>","PeriodicalId":54763,"journal":{"name":"Journal of Theoretical Biology","volume":"620 ","pages":"Article 112352"},"PeriodicalIF":2.0,"publicationDate":"2025-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145812221","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"数学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-19DOI: 10.1016/j.jtbi.2025.112333
Bethany L.F. Stevens , Silke F. van Daalen , Tirzah J. Blomquist , Kristin E. Gribble , Michael G. Neubert
Species that inhabit variable environments have complex mechanisms to precisely time their life-history transitions as conditions change. One such mechanism in rotifers is a block on sexual reproduction that extends across multiple asexual generations after emergence from diapause. It has been hypothesized that this delay is advantageous in competitive and stochastic environments. Here, we develop a model of cyclically parthenogenic rotifer populations with a novel formulation of a “mictic block” that prevents sexual reproduction by females that are not sufficiently distant, generationally, from a stem ancestor that was produced sexually. We find that mictic blocks are indeed adaptive but that the most successful phenotypes have shorter blocks than previously reported and that the success of different delay phenotypes is highly dependent on the duration of the growing season. For a fixed environmental regime, coexistence of distinct mixis phenotypes is possible, wherein a phenotype with a longer block performs better in years with an average-length growing season, and a phenotype with a shorter block and lower mixis ratio performs better in years with an “extreme” growing season, whether short or long. Our model provides an eco-evolutionary framework for the study of Brachionus rotifers, a model system for non-genetic maternal effects and the evolution of sex.
{"title":"Timing the initiation of sex: Delay mechanisms alter fitness outcomes in a rotifer population model","authors":"Bethany L.F. Stevens , Silke F. van Daalen , Tirzah J. Blomquist , Kristin E. Gribble , Michael G. Neubert","doi":"10.1016/j.jtbi.2025.112333","DOIUrl":"10.1016/j.jtbi.2025.112333","url":null,"abstract":"<div><div>Species that inhabit variable environments have complex mechanisms to precisely time their life-history transitions as conditions change. One such mechanism in rotifers is a block on sexual reproduction that extends across multiple asexual generations after emergence from diapause. It has been hypothesized that this delay is advantageous in competitive and stochastic environments. Here, we develop a model of cyclically parthenogenic rotifer populations with a novel formulation of a “mictic block” that prevents sexual reproduction by females that are not sufficiently distant, generationally, from a stem ancestor that was produced sexually. We find that mictic blocks are indeed adaptive but that the most successful phenotypes have shorter blocks than previously reported and that the success of different delay phenotypes is highly dependent on the duration of the growing season. For a fixed environmental regime, coexistence of distinct mixis phenotypes is possible, wherein a phenotype with a longer block performs better in years with an average-length growing season, and a phenotype with a shorter block and lower mixis ratio performs better in years with an “extreme” growing season, whether short or long. Our model provides an eco-evolutionary framework for the study of <em>Brachionus</em> rotifers, a model system for non-genetic maternal effects and the evolution of sex.</div></div>","PeriodicalId":54763,"journal":{"name":"Journal of Theoretical Biology","volume":"620 ","pages":"Article 112333"},"PeriodicalIF":2.0,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145806251","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"数学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-18DOI: 10.1016/j.jtbi.2025.112334
Rahnuma Islam, Bard Ermentrout, Sabrina Streipert
We introduce a discrete-time continuous-space neural model to produce diverse shell structures and pigmentation patterns observed in aquatic mollusks. The model builds on an earlier neural model for shell patterns by incorporating the inhibition as a separate population and thus eliminates the need for a “refractory” substance, yet is still able to produce many varieties of molluscan pigmentation patterns. The model utilizes a system of neural excitation and inhibition to conduct secretory activity and successfully replicates various natural shell patterns found in these organisms. Through an analysis of local stability around equilibria and an analysis of bifurcation, we establish the critical role of parameters involved in our system on the bifurcations in governing the emergence of spatial, temporal, and spatio-temporal patterns.
{"title":"A discrete-time continuous-space neural model for shell patterns in mollusks","authors":"Rahnuma Islam, Bard Ermentrout, Sabrina Streipert","doi":"10.1016/j.jtbi.2025.112334","DOIUrl":"10.1016/j.jtbi.2025.112334","url":null,"abstract":"<div><div>We introduce a discrete-time continuous-space neural model to produce diverse shell structures and pigmentation patterns observed in aquatic mollusks. The model builds on an earlier neural model for shell patterns by incorporating the inhibition as a separate population and thus eliminates the need for a “refractory” substance, yet is still able to produce many varieties of molluscan pigmentation patterns. The model utilizes a system of neural excitation and inhibition to conduct secretory activity and successfully replicates various natural shell patterns found in these organisms. Through an analysis of local stability around equilibria and an analysis of bifurcation, we establish the critical role of parameters involved in our system on the bifurcations in governing the emergence of spatial, temporal, and spatio-temporal patterns.</div></div>","PeriodicalId":54763,"journal":{"name":"Journal of Theoretical Biology","volume":"620 ","pages":"Article 112334"},"PeriodicalIF":2.0,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145800907","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"数学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-17DOI: 10.1016/j.jtbi.2025.112354
Bivash Kaity , Daniel Lobo
The development and regeneration of multicellular organisms require dynamic coordination between cellular behaviors and mechanochemical signals to achieve precise and stable tissue shapes. Plastic organisms, such as planarians, can regenerate, grow, and degrow as adults while maintaining precise whole-body and organ tissue shapes. However, the mechanisms underlying the pathways that coordinate and integrate these signals into the correct balance between cellular growth, mitosis, and apoptosis to form emergent target tissue shapes remain poorly understood. Here, we present a systematic theoretical study of the biological drivers controlling the feedback mechanisms between tissue growth and morphogen signaling. The approach is based on lattice-free, center-based simulations of cell size dynamics, mitosis, and apoptosis governed by both intercellular diffusible morphogen concentrations and mechanical stress between cells to drive their spatial organization. The results demonstrate how different morphogen properties and tissue mechanics form a feedback loop that is essential for the robust regulation of target tissue shapes. Furthermore, we show that stable tissue shapes can emerge and regenerate from self-regulated patterning processes, such as Turing systems, controlling cellular growth dynamics. A stable feedback loop can form between the emergent morphogen patterns and the dynamics of cellular growth they regulate, as the tissue dynamics define the domain in which morphogens diffuse and hence pattern. Overall, this study highlights the essential role of the feedback loop between morphogen patterning and cellular growth in the regulation of tissue dynamics for stable shape formation. Moreover, this work establishes a framework for further experiments to understand the regulatory dynamics of whole-body development and regeneration using models with high spatiotemporal resolution.
Significance
Tight coordination and interpretation of the multitude of signals at different biological scales– from intracellular signals to mechanical interactions–are essential during the development and regeneration of multicellular organisms. In this work, we investigate the leading role of the feedback between mechanochemical signaling networks and tissue shape through cellular behaviors such as growth, proliferation, and apoptosis. This study demonstrates the interdependence between tissue growth and pattern formation mechanisms in the regulation of stable tissue shapes. Overall, this research provides novel mechanistic insights into the formation of tissue shapes through the regulatory feedback interaction between cell growth and patterning dynamics.
{"title":"Emergent stable tissue shapes from the regulatory feedback between morphogens and cell growth","authors":"Bivash Kaity , Daniel Lobo","doi":"10.1016/j.jtbi.2025.112354","DOIUrl":"10.1016/j.jtbi.2025.112354","url":null,"abstract":"<div><div>The development and regeneration of multicellular organisms require dynamic coordination between cellular behaviors and mechanochemical signals to achieve precise and stable tissue shapes. Plastic organisms, such as planarians, can regenerate, grow, and degrow as adults while maintaining precise whole-body and organ tissue shapes. However, the mechanisms underlying the pathways that coordinate and integrate these signals into the correct balance between cellular growth, mitosis, and apoptosis to form emergent target tissue shapes remain poorly understood. Here, we present a systematic theoretical study of the biological drivers controlling the feedback mechanisms between tissue growth and morphogen signaling. The approach is based on lattice-free, center-based simulations of cell size dynamics, mitosis, and apoptosis governed by both intercellular diffusible morphogen concentrations and mechanical stress between cells to drive their spatial organization. The results demonstrate how different morphogen properties and tissue mechanics form a feedback loop that is essential for the robust regulation of target tissue shapes. Furthermore, we show that stable tissue shapes can emerge and regenerate from self-regulated patterning processes, such as Turing systems, controlling cellular growth dynamics. A stable feedback loop can form between the emergent morphogen patterns and the dynamics of cellular growth they regulate, as the tissue dynamics define the domain in which morphogens diffuse and hence pattern. Overall, this study highlights the essential role of the feedback loop between morphogen patterning and cellular growth in the regulation of tissue dynamics for stable shape formation. Moreover, this work establishes a framework for further experiments to understand the regulatory dynamics of whole-body development and regeneration using models with high spatiotemporal resolution.</div></div><div><h3>Significance</h3><div>Tight coordination and interpretation of the multitude of signals at different biological scales– from intracellular signals to mechanical interactions–are essential during the development and regeneration of multicellular organisms. In this work, we investigate the leading role of the feedback between mechanochemical signaling networks and tissue shape through cellular behaviors such as growth, proliferation, and apoptosis. This study demonstrates the interdependence between tissue growth and pattern formation mechanisms in the regulation of stable tissue shapes. Overall, this research provides novel mechanistic insights into the formation of tissue shapes through the regulatory feedback interaction between cell growth and patterning dynamics.</div></div>","PeriodicalId":54763,"journal":{"name":"Journal of Theoretical Biology","volume":"620 ","pages":"Article 112354"},"PeriodicalIF":2.0,"publicationDate":"2025-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145792297","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"数学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-17DOI: 10.1016/j.jtbi.2025.112350
Reinhard Blickhan , Tobias Siebert , Tom Weihmann
Hemolymph channels (lacunae) in the legs of spiders are part of their open circulatory system. They are defined as hemolymph-filled spaces between tissues within the exoskeletal tubes of the legs which are otherwise largely filled with muscles. In two of the major leg joints, the leg segments are connected via hinge joints with axes that are located at their dorsal rims.
The lacunae are used to channel hemolymph, which acts as a hydraulic fluid, to the extensor-less joints during the extension of the legs. However, due to competing optimization criteria of muscle-driven flexion and drainage of the hemolymph, fluid drag in the lacunae may hinder movement and force generation during flexion. Numerical modelling of dynamic flexions of the tibia-metatarsus joint, considering anatomical and physiological properties identified in the hunting spider Cupiennius salei, was used to investigate the trade-off between muscular force and hemolymph-drainage. The results showed that the diameters of the hemolymph channels exhibit a broad optimum for quick flexion. Within a wide range of channel diameters flexion times are hardly affected. Muscle properties, especially the time of muscle activation, strongly dampen the effect of the reduced muscle cross-section available. With small loads of 0.1g, similar to the spiders’ common prey size, the radius of the observed effective lacunae seems to enable the fastest flexions. A change in the aspect ratio of the tibia while maintaining the proportionality of its radius and the radius of the effective hemolymph channels leads to an extension of the flexion time.
{"title":"Semi-hydraulic actuation in spider legs: The transport of the hemolymph does not hamper muscle driven leg joint flexion","authors":"Reinhard Blickhan , Tobias Siebert , Tom Weihmann","doi":"10.1016/j.jtbi.2025.112350","DOIUrl":"10.1016/j.jtbi.2025.112350","url":null,"abstract":"<div><div>Hemolymph channels (lacunae) in the legs of spiders are part of their open circulatory system. They are defined as hemolymph-filled spaces between tissues within the exoskeletal tubes of the legs which are otherwise largely filled with muscles. In two of the major leg joints, the leg segments are connected via hinge joints with axes that are located at their dorsal rims.</div><div>The lacunae are used to channel hemolymph, which acts as a hydraulic fluid, to the extensor-less joints during the extension of the legs. However, due to competing optimization criteria of muscle-driven flexion and drainage of the hemolymph, fluid drag in the lacunae may hinder movement and force generation during flexion. Numerical modelling of dynamic flexions of the tibia-metatarsus joint, considering anatomical and physiological properties identified in the hunting spider <em>Cupiennius salei</em>, was used to investigate the trade-off between muscular force and hemolymph-drainage. The results showed that the diameters of the hemolymph channels exhibit a broad optimum for quick flexion. Within a wide range of channel diameters flexion times are hardly affected. Muscle properties, especially the time of muscle activation, strongly dampen the effect of the reduced muscle cross-section available. With small loads of 0.1g, similar to the spiders’ common prey size, the radius of the observed effective lacunae seems to enable the fastest flexions. A change in the aspect ratio of the tibia while maintaining the proportionality of its radius and the radius of the effective hemolymph channels leads to an extension of the flexion time.</div></div>","PeriodicalId":54763,"journal":{"name":"Journal of Theoretical Biology","volume":"620 ","pages":"Article 112350"},"PeriodicalIF":2.0,"publicationDate":"2025-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145792296","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"数学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-13DOI: 10.1016/j.jtbi.2025.112344
Ruslan M. Timchenko , Mikhail A. Panteleev
The intrinsic pathway of apoptosis mediates programmed cell death in several major scenarios, but mechanisms regulating its triggering remain unclear. We developed a kinetic mathematical model based on ordinary differential equations and the law of mass action to investigate whether bistability in the regulatory system of the intrinsic apoptotic pathway can be achieved purely on the basis of Bax protein interaction with its inhibitor Bcl-xL proteins, without BH3-only proteins. The model has two compartments, the cytosol and the outer mitochondrial membrane. The mechanisms included were translocation of Bax between the compartments, its two-stage activation through incorporation into the membrane and exposure of its BH3 domain, formation of Bax homodimers and its heterodimers with Bcl-xL, the positive feedback from activated Bax. The model exhibits explosive dynamics with saturation when the threshold stimulus is exceeded. The bistability observed in the system belongs to the “trigger” class (the system can return to the lower branch when the stimulus is removed), but exists in a relatively narrow range of parameters. A structural study of the system properties shows that it is the Bax dimerization in heterodimer with Bcl-xL, homodimerization, Bax autoactivation and Bax retrotranslocation that produces a bistable system of the “trigger” type. These results suggest that pair of Bax and Bcl-xL is sufficient for a trigger and the model developed in can be used for studies of relevant intrinsic apoptotic signaling pathways that do not involve BH3-only proteins, such as those initiated by the oxidative stress of the cell.
{"title":"Bistability in the regulatory system of the intrinsic apoptotic pathway arising from the Bax and Bcl-xL interactions","authors":"Ruslan M. Timchenko , Mikhail A. Panteleev","doi":"10.1016/j.jtbi.2025.112344","DOIUrl":"10.1016/j.jtbi.2025.112344","url":null,"abstract":"<div><div>The intrinsic pathway of apoptosis mediates programmed cell death in several major scenarios, but mechanisms regulating its triggering remain unclear. We developed a kinetic mathematical model based on ordinary differential equations and the law of mass action to investigate whether bistability in the regulatory system of the intrinsic apoptotic pathway can be achieved purely on the basis of Bax protein interaction with its inhibitor Bcl-xL proteins, without BH3-only proteins. The model has two compartments, the cytosol and the outer mitochondrial membrane. The mechanisms included were translocation of Bax between the compartments, its two-stage activation through incorporation into the membrane and exposure of its BH3 domain, formation of Bax homodimers and its heterodimers with Bcl-xL, the positive feedback from activated Bax. The model exhibits explosive dynamics with saturation when the threshold stimulus is exceeded. The bistability observed in the system belongs to the “trigger” class (the system can return to the lower branch when the stimulus is removed), but exists in a relatively narrow range of parameters. A structural study of the system properties shows that it is the Bax dimerization in heterodimer with Bcl-xL, homodimerization, Bax autoactivation and Bax retrotranslocation that produces a bistable system of the “trigger” type. These results suggest that pair of Bax and Bcl-xL is sufficient for a trigger and the model developed in can be used for studies of relevant intrinsic apoptotic signaling pathways that do not involve BH3-only proteins, such as those initiated by the oxidative stress of the cell.</div></div>","PeriodicalId":54763,"journal":{"name":"Journal of Theoretical Biology","volume":"620 ","pages":"Article 112344"},"PeriodicalIF":2.0,"publicationDate":"2025-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145764600","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"数学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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