PRX life最新文献

{"title":"Sticky enzymes: increased metabolic efficiency via substrate-dependent enzyme clustering.","authors":"Alejandro Martínez-Calvo, Jello Zhou, Yaojun Zhang, Ned S Wingreen","doi":"10.1103/99bt-4ss4","DOIUrl":"10.1103/99bt-4ss4","url":null,"abstract":"<p><p>Coclustering of subsequent enzymes in a pathway can accelerate the processing of metabolic intermediates, with benefits including increased pathway fluxes, reduced toxicity, and sensitive branch-point regulation. While the optimal organization of such clusters has been explored theoretically, little is known about how to achieve such organization inside cells. Here we propose that phase-separating enzymes can self-organize into nearly-optimally sized and spaced clusters, provided that their \"stickiness\" is regulated by local substrate availability. In a nutshell, enzyme clusters only form when and where they are needed to process substrate. We study a mathematical model that implements this scheme for simple metabolic pathways, including all thermodynamic constraints. We find that pathway fluxes can be increased by 50 to 1000-fold and toxic metabolites can be decreased by 10 to 100-fold, at realistic enzyme densities. Finally, we discuss how enzyme \"stickiness\" could be allosterically regulated. This study presents a self-organization strategy that goes beyond current paradigms for natural and engineered enzyme clusters, and thus represents a motivating challenge to the fields of synthetic biology and metabolic engineering.</p>","PeriodicalId":520261,"journal":{"name":"PRX life","volume":"3 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13251717/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148230407","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Collective Dynamics of Frustrated Biological Neuron Networks.","authors":"Guanyu Li, Ryan LeFebre, Alia Starman, Patrick Chappell, Andrew Mugler, Bo Sun","doi":"10.1103/1258-cl48","DOIUrl":"10.1103/1258-cl48","url":null,"abstract":"<p><p>To maintain normal functionality, it is necessary for a multicellular organism to generate robust responses to external temporal signals. However, the underlying mechanisms to coordinate the collective dynamics of cells remain poorly understood. Here, we study the calcium activity of biological neuron networks excited by periodic ATP stimuli. We use micropatterning to control the cells' physical connectivity. We find that whereas isolated cells become more synchronized in their calcium activity at long driving periods, connected cells become less synchronized, despite expressing more gap junctions which enable calcium exchange. To understand this result, we use a mathematical model in which a bifurcation analysis has previously shown coupling-induced desynchronization in an oscillatory network. Using parameters close to this bifurcation but in the excitable regime, we find that this desynchronization persists and can explain the experimental observations. The model further predicts that co-culturing with gap-junction-deficient cells should restore synchronization, which experiments confirm. Combining quantitative experiments, the physical and biological manipulation of cells, and mathematical modeling, our results suggest that cell-to-cell connectivity significantly affects how populations encode an external temporal signal as it slows down: Sparse networks synchronize due to longer entrainment, whereas highly connected networks can desynchronize due to dynamic frustration.</p>","PeriodicalId":520261,"journal":{"name":"PRX life","volume":"3 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12366724/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144985904","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Algebraic and Diagrammatic Methods for the Rule-Based Modeling of Multiparticle Complexes.","authors":"Rebecca J Rousseau, Justin B Kinney","doi":"10.1103/prxlife.3.023004","DOIUrl":"10.1103/prxlife.3.023004","url":null,"abstract":"<p><p>The formation, dissolution, and dynamics of multi-particle complexes is of fundamental interest in the study of stochastic chemical systems. In 1976, Masao Doi introduced a Fock space formalism for modeling classical particles. Doi's formalism, however, does not support the assembly of multiple particles into complexes. Starting in the 2000's, multiple groups developed rule-based methods for computationally simulating biochemical systems involving large macromolecular complexes. However, these methods are based on graph-rewriting rules and/or process algebras that are mathematically disconnected from the statistical physics methods generally used to analyze equilibrium and nonequilibrium systems. Here we bridge these two approaches by introducing an operator algebra for the rule-based modeling of multi-particle complexes. Our formalism is based on a Fock space that supports not only the creation and annihilation of classical particles, but also the assembly of multiple particles into complexes, as well as the disassembly of complexes into their components. Rules are specified by algebraic operators that act on particles through a manifestation of Wick's theorem. We further describe diagrammatic methods that facilitate rule specification and analytic calculations. We demonstrate our formalism on systems in and out of thermal equilibrium, and for nonequilibrium systems we present a stochastic simulation algorithm based on our formalism. The results provide a unified approach to the mathematical and computational study of stochastic chemical systems in which multi-particle complexes play an important role.</p>","PeriodicalId":520261,"journal":{"name":"PRX life","volume":"3 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13293522/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148335484","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inferring Resource Competition in Microbial Communities from Time Series.","authors":"Xiaowen Chen, Kyle Crocker, Seppe Kuehn, Aleksandra M Walczak, Thierry Mora","doi":"10.1103/8gkj-rdzy","DOIUrl":"10.1103/8gkj-rdzy","url":null,"abstract":"<p><p>The competition for resources is a defining feature of microbial communities. In many contexts, from soils to host-associated communities, highly diverse microbes are organized into metabolic groups or guilds with similar resource preferences. The resource preferences of individual taxa that give rise to these guilds are critical for understanding fluxes of resources through the community and the structure of diversity in the system. However, inferring the metabolic capabilities of individual taxa, as well as their competition with other taxa, within a community is challenging and unresolved. Here we address this gap in knowledge by leveraging dynamic measurements of abundances in communities. We show that simple correlations are often misleading in predicting resource competition. We show that spectral methods such as the cross-power spectral density and coherence that account for time-delayed effects are superior metrics for inferring the structure of resource competition in communities. We demonstrate this fact on synthetic data generated from consumer-resource models with time-dependent resource availability, where taxa are organized into groups or guilds with similar resource preferences. By applying spectral methods to oceanic plankton time-series data, we demonstrate that these methods detect interaction structures among species with similar genomic sequences. Our results indicate that analyzing temporal data across multiple timescales can reveal the underlying structure of resource competition within communities.</p>","PeriodicalId":520261,"journal":{"name":"PRX life","volume":"3 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13120769/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147794802","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Universal Niche Geometry Governs the Response of Ecosystems to Environmental Perturbations.","authors":"Akshit Goyal, Jason W Rocks, Pankaj Mehta","doi":"10.1103/prxlife.3.013010","DOIUrl":"10.1103/prxlife.3.013010","url":null,"abstract":"<p><p>How ecosystems respond to environmental perturbations is a fundamental question in ecology, made especially challenging due to the strong coupling between species and their environment. Here, we introduce a theoretical framework for calculating the steady-state response of ecosystems to environmental perturbations in generalized consumer-resource models. Our construction is applicable to a wide class of systems, including models with nonreciprocal interactions, cross-feeding, and nonlinear growth/consumption rates. Within our framework, all ecological variables are embedded into four distinct vector spaces, and ecological interactions are represented by geometric transformations between these spaces. We show that, near a steady state, such geometric transformations directly map environmental perturbations-in resource availability and mortality rates-to shifts in niche structure. We illustrate these ideas in a variety of settings including a minimal model for pH-induced toxicity in bacterial denitrification. We end by discussing the biological implications of our framework. We show that it is extremely difficult to distinguish cooperative and competitive interactions by measuring the responses of species to external perturbations.</p>","PeriodicalId":520261,"journal":{"name":"PRX life","volume":"3 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12768336/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145914447","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Confinement, Jamming, and Adhesion in Cancer Cells Dissociating from a Collectively Invading Strand.","authors":"Wei Wang, Robert A Law, Emiliano Perez Ipiña, Konstantinos Konstantopoulos, Brian A Camley","doi":"10.1103/prxlife.3.013012","DOIUrl":"10.1103/prxlife.3.013012","url":null,"abstract":"<p><p>When cells in a primary tumor work together to invade into nearby tissue, this can lead to cell dissociations-cancer cells breaking off from the invading front-leading to metastasis. What controls the dissociation of cells and whether they break off singly or in small groups? Can this be determined by cell-cell adhesion or chemotactic cues given to cells? We develop a physical model for this question, based on experiments that mimic aspects of cancer cell invasion using microfluidic devices with microchannels of different widths. Experimentally, most dissociation events (\"ruptures\") involve single cells breaking off, but we observe some ruptures of large groups (~20 cells) in wider channels. The rupture probability is nearly independent of channel width. We recapitulate the experimental results with a phase-field cell motility model by introducing three different cell states (follower, guided, and high-motility \"leader\" cells) based on their spatial position. These leader cells may explain why single-cell rupture is the universal most probable outcome. Our simulation results show that cell-channel adhesion is necessary for cells in narrow channels to invade, and strong cell-cell adhesion leads to fewer but larger ruptures. Chemotaxis also influences the rupture behavior: Strong chemotaxis strength leads to larger and faster ruptures. Finally, we study the relationship between biological jamming transitions and cell dissociations. Our results suggest unjamming is necessary but not sufficient to create ruptures.</p>","PeriodicalId":520261,"journal":{"name":"PRX life","volume":"3 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12410839/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145017112","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Protein folding as a jamming transition.","authors":"Alex T Grigas, Zhuoyi Liu, Jack A Logan, Mark D Shattuck, Corey S O'Hern","doi":"10.1103/prxlife.3.013018","DOIUrl":"10.1103/prxlife.3.013018","url":null,"abstract":"<p><p>Proteins fold to a specific functional conformation with a densely packed core that controls their stability. Despite their importance, we lack a quantitative explanation for why all protein cores, regardless of their overall fold, possess the same average packing fraction <math><mo>⟨</mo> <mi>ϕ</mi> <mo>⟩</mo> <mo>≈</mo> <mn>0.55</mn></math> . However, important developments in the physics of jamming in particulate systems can shed light on the packing of protein cores. Here, we extend the framework of jamming to describe core packing in collapsed polymers, as well as in all-atom models of folded proteins. First, we show in a spherical bead-spring polymer model (with and without bond-angle constraints) that as the hydrophobic interactions increase relative to thermal fluctuations, a jamming-like transition occurs when the core packing fraction exceeds <math> <msub><mrow><mi>ϕ</mi></mrow> <mrow><mi>c</mi></mrow> </msub> </math> with the same power-law scaling behavior for the potential energy <math> <msub><mrow><mi>V</mi></mrow> <mrow><mi>r</mi></mrow> </msub> </math> , excess contact number <math><mi>Δ</mi> <mi>N</mi></math> , and characteristic frequency of the vibrational density of states <math> <msup><mrow><mi>ω</mi></mrow> <mrow><mo>*</mo></mrow> </msup> </math> versus <math><mi>Δ</mi> <mi>ϕ</mi> <mo>=</mo> <mi>ϕ</mi> <mo>-</mo> <msub><mrow><mi>ϕ</mi></mrow> <mrow><mi>c</mi></mrow> </msub> </math> as that for jammed particulate systems. Then, we develop an all-atom model for proteins and find that, above <math> <msub><mrow><mi>ϕ</mi></mrow> <mrow><mi>c</mi></mrow> </msub> <mo>~</mo> <mn>0.55</mn></math> , protein cores undergo a jamming-like transition, but with anomalous power-law scaling for <math> <msub><mrow><mi>V</mi></mrow> <mrow><mi>r</mi></mrow> </msub> </math> , <math><mi>Δ</mi> <mi>N</mi></math> , and <math> <msup><mrow><mi>ω</mi></mrow> <mrow><mo>*</mo></mrow> </msup> </math> versus <math><mi>Δ</mi> <mi>ϕ</mi></math> . The all-atom protein model remains close to the native protein structure during jamming and accurately refolds from partially unfolded states.</p>","PeriodicalId":520261,"journal":{"name":"PRX life","volume":"3 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12573692/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145433301","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Conformational Entropy of Intrinsically Disordered Proteins Bars Intruders from Biomolecular Condensates.","authors":"Vladimir Grigorev, Ned S Wingreen, Yaojun Zhang","doi":"10.1103/prxlife.3.013011","DOIUrl":"10.1103/prxlife.3.013011","url":null,"abstract":"<p><p>It was recently discovered that eukaryotic cells are host to a multiplicity of biomolecular condensates. These condensates typically contain protein and/or RNA components with intrinsically disordered regions (IDRs). While IDRs have been proposed and demonstrated to play many roles in condensate biology, we suggest here an additional crucial role of IDRs, which is to exclude unwanted \"intruders\" from condensates. This exclusion effect arises from the large conformational entropy of IDRs; i.e., there is a high free-energy cost to occupying space that would otherwise be available to the IDRs. By combining polymer theory with sticker-spacer simulations, we show that the relevant insertion free energy increases with the concentration of IDRs in the condensate as well as with intruder size, attaining a linear scaling with surface area for large intruders. We find that at realistic IDR concentrations, particles as small as the size of an average protein (4 nm in diameter) can be 97% excluded from condensates. To overcome this entropic barrier, molecules must interact favorably with condensate components to be recruited as clients. Application of the developed size-exclusion theory to biological condensates suggests that condensate IDRs may play a generic exclusionary role across organisms and types of condensates.</p>","PeriodicalId":520261,"journal":{"name":"PRX life","volume":"3 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13246162/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148214232","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hair Cells in the Cochlea Must Tune Resonant Modes to the Edge of Instability without Destabilizing Collective Modes.","authors":"Asheesh S Momi, Michael C Abbott, Julian Rubinfien, Benjamin B Machta, Isabella R Graf","doi":"10.1103/prxlife.3.013001","DOIUrl":"10.1103/prxlife.3.013001","url":null,"abstract":"<p><p>Sound produces surface waves along the cochlea's basilar membrane. To achieve the ear's astonishing frequency resolution and sensitivity to faint sounds, dissipation in the cochlea must be canceled via active processes in hair cells, effectively bringing the cochlea to the edge of instability. But how can the cochlea be globally tuned to the edge of instability with only local feedback? To address this question, we use a discretized version of a standard model of basilar membrane dynamics but with an explicit contribution from active processes in hair cells. Surprisingly, we find the basilar membrane supports two qualitatively distinct sets of modes: a continuum of <i>localized</i> modes and a small number of collective <i>extended</i> modes. Localized modes sharply peak at their resonant position and are largely uncoupled. As a result, they can be amplified almost independently from each other by local hair cells via feedback reminiscent of self-organized criticality. However, this amplification can destabilize the collective extended modes; avoiding such instabilities places limits on possible molecular mechanisms for active feedback in hair cells. Our work illuminates how and under what conditions individual hair cells can collectively create a critical cochlea.</p>","PeriodicalId":520261,"journal":{"name":"PRX life","volume":"3 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12252909/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144629290","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Coupled Dynamics in Phenotype and Tissue Spaces Shape the Three-Dimensional Cancer Invasion.","authors":"Austin Naylor, Maximilian Libmann, Izabel Raab, Wouter-Jan Rappel, Bo Sun","doi":"10.1103/prxlife.2.043022","DOIUrl":"10.1103/prxlife.2.043022","url":null,"abstract":"<p><p>The metastasis of solid tumors hinges on cancer cells navigating through complex three-dimensional tissue environments, characterized by mechanical heterogeneity and biological diversity. This process is closely linked to the dynamic migration behavior exhibited by cancer cells, which dictates the invasiveness of tumors. In our study, we investigate tumor spheroids composed of breast cancer cells embedded in three-dimensional (3D) collagen matrices. Through a combination of quantitative experiments, artificial-intelligence-driven image processing, and mathematical modeling, we uncover rapid transitions in cell phenotypes and phenotype-dependent motility among disseminating cells originating from tumor spheroids. Persistent invasion leads to continuous remodeling of the extracellular matrix surrounding the spheroids, altering the landscape of migration phenotypes. Consequently, filopodial cells emerge as the predominant phenotype across diverse extracellular matrix conditions. Our findings unveil the complex mesoscale dynamics of invading tumor spheroids, shedding light on the complex interplay between migration phenotype plasticity, microenvironment remodeling, and cell motility within 3D extracellular matrices.</p>","PeriodicalId":520261,"journal":{"name":"PRX life","volume":"2 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12369984/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144985824","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}