PRX lifePub Date : 2025-07-01Epub Date: 2025-07-02DOI: 10.1103/1258-cl48
Guanyu Li, Ryan LeFebre, Alia Starman, Patrick Chappell, Andrew Mugler, Bo Sun
{"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}
PRX lifePub Date : 2025-01-01Epub Date: 2025-02-25DOI: 10.1103/prxlife.3.013012
Wei Wang, Robert A Law, Emiliano Perez Ipiña, Konstantinos Konstantopoulos, Brian A Camley
{"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}
PRX lifePub Date : 2025-01-01Epub Date: 2025-01-02DOI: 10.1103/prxlife.3.013001
Asheesh S Momi, Michael C Abbott, Julian Rubinfien, Benjamin B Machta, Isabella R Graf
{"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}
PRX lifePub Date : 2024-12-01Epub Date: 2024-12-24DOI: 10.1103/prxlife.2.043022
Austin Naylor, Maximilian Libmann, Izabel Raab, Wouter-Jan Rappel, Bo Sun
{"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}
PRX lifePub Date : 2024-12-01Epub Date: 2024-11-05DOI: 10.1103/prxlife.2.043009
Weikang Wang, Ke Ni, Dante Poe, Jianhua Xing
{"title":"Transiently increased coordination in gene regulation during cell phenotypic transitions.","authors":"Weikang Wang, Ke Ni, Dante Poe, Jianhua Xing","doi":"10.1103/prxlife.2.043009","DOIUrl":"10.1103/prxlife.2.043009","url":null,"abstract":"<p><p>Phenotype transitions occur in many biological processes such as differentiation and reprogramming. A fundamental question is how cells coordinate switching of gene expression clusters. By analyzing single-cell RNA sequencing data within the framework of transition path theory, we studied the genome-wide expression program switching in five different cell transition processes. For each process we reconstructed a reaction coordinate describing the transition progression, and inferred the gene regulatory network along this reaction coordinate. In all processes we observed a common pattern: the overall effective number and strength of regulation between different communities increase first and then decrease. This change is accompanied by similar changes in gene regulatory network frustration-defined as the overall conflict between the regulation received by genes and their expression states. Complementing previous studies suggesting that biological networks are modularized to contain perturbation effects locally, our analyses on the five cell transition processes likely reveal a general principle: during a cell phenotypic transition, intercommunity interactions increase to concertedly coordinate global gene expression reprogramming and canalize to specific cell phenotype, as Waddington visioned.</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/PMC12204605/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144532665","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}
PRX lifePub Date : 2024-11-01Epub Date: 2024-11-19DOI: 10.1103/prxlife.2.043013
Foster Birnbaum, Saachi Jain, Aleksander Madry, Amy E Keating
{"title":"Jointly Embedding Protein Structures and Sequences through Residue Level Alignment.","authors":"Foster Birnbaum, Saachi Jain, Aleksander Madry, Amy E Keating","doi":"10.1103/prxlife.2.043013","DOIUrl":"10.1103/prxlife.2.043013","url":null,"abstract":"<p><p>The relationships between protein sequences, structures, and functions are determined by complex codes that scientists aim to decipher. While structures contain key information about proteins' biochemical functions, they are often experimentally difficult to obtain. In contrast, protein sequences are abundant but are a step removed from function. In this paper, we propose residue level alignment (RLA)-a self-supervised objective for aligning sequence and structure embedding spaces. By situating sequence and structure encoders within the same latent space, RLA enriches the sequence encoder with spatial information. Moreover, our framework enables us to measure the similarity between a sequence and structure by comparing their RLA embeddings. We show how RLA similarity scores can be used for binder design by selecting true binders from sets of designed binders. RLA scores are informative even when they are calculated given only the backbone structure of the binder and no binder sequence information, which simulates the information available in many early-stage binder design libraries. RLA performs similarly to benchmark methods and is orders of magnitude faster, making it a valuable new screening tool for binder design pipelines.</p>","PeriodicalId":520261,"journal":{"name":"PRX life","volume":"2 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12490763/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145234871","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}
PRX lifePub Date : 2024-11-01Epub Date: 2024-11-12DOI: 10.1103/prxlife.2.043011
Kiri Choi, Will Rosenbluth, Isabella R Graf, Nirag Kadakia, Thierry Emonet
{"title":"Bifurcation enhances temporal information encoding in the olfactory periphery.","authors":"Kiri Choi, Will Rosenbluth, Isabella R Graf, Nirag Kadakia, Thierry Emonet","doi":"10.1103/prxlife.2.043011","DOIUrl":"10.1103/prxlife.2.043011","url":null,"abstract":"<p><p>Living systems continually respond to signals from the surrounding environment. Survival requires that their responses adapt quickly and robustly to the changes in the environment. One particularly challenging example is olfactory navigation in turbulent plumes, where animals experience highly intermittent odor signals while odor concentration varies over many length- and timescales. Here, we show theoretically that <i>Drosophila</i> olfactory receptor neurons (ORNs) can exploit proximity to a bifurcation point of their firing dynamics to reliably extract information about the timing and intensity of fluctuations in the odor signal, which have been shown to be critical for odor-guided navigation. Close to the bifurcation, the system is intrinsically invariant to signal variance, and information about the timing, duration, and intensity of odor fluctuations is transferred efficiently. Importantly, we find that proximity to the bifurcation is maintained by mean adaptation alone and therefore does not require any additional feedback mechanism or fine-tuning. Using a biophysical model with calcium-based feedback, we demonstrate that this mechanism can explain the measured adaptation characteristics of <i>Drosophila</i> ORNs.</p>","PeriodicalId":520261,"journal":{"name":"PRX life","volume":"2 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12320936/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144786389","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}
PRX lifePub Date : 2024-10-01Epub Date: 2024-10-21DOI: 10.1103/prxlife.2.043004
Christian Cupo, Cole Allan, Vikram Ailiani, Karen E Kasza
{"title":"Signatures of structural disorder in the developing <i>Drosophila</i> germband epithelium.","authors":"Christian Cupo, Cole Allan, Vikram Ailiani, Karen E Kasza","doi":"10.1103/prxlife.2.043004","DOIUrl":"10.1103/prxlife.2.043004","url":null,"abstract":"<p><p>Epithelial cells generate functional tissues in developing embryos through collective movements and shape changes. In some morphogenetic events, a tissue dramatically reorganizes its internal structure - often generating high degrees of structural disorder - to accomplish changes in tissue shape. However, the origins of structural disorder in epithelia and what roles it might play in morphogenesis are poorly understood. We study this question in the <i>Drosophila</i> germband epithelium, which undergoes dramatic changes in internal structure as cell rearrangements drive elongation of the embryo body axis. Using two order parameters that quantify volumetric and shear disorder, we show that structural disorder increases during body axis elongation and is strongly linked with specific developmental processes. Both disorder metrics begin to increase around the onset of axis elongation, but then plateau at values that are maintained throughout the process. Notably, the disorder plateau values for volumetric disorder are similar to those for random cell packings, suggesting this may reflect a limit on tissue behavior. In mutant embryos with disrupted external stresses from the ventral furrow, both disorder metrics reach wild-type maximum disorder values with a delay, correlating with delays in cell rearrangements. In contrast, in mutants with disrupted internal stresses and cell rearrangements, volumetric disorder is reduced compared to wild type and shear disorder depends on specific external stress patterns. Together, these findings demonstrate that internal and external stresses both contribute to epithelial tissue disorder and suggest that the maximum values of disorder in a developing tissue reflect physical or biological limits on morphogenesis.</p>","PeriodicalId":520261,"journal":{"name":"PRX life","volume":"2 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12356154/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144877807","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}
PRX lifePub Date : 2024-10-01Epub Date: 2024-12-02DOI: 10.1103/prxlife.2.043016
Bo Liu, Shanshan Qin, Venkatesh Murthy, Yuhai Tu
{"title":"One nose but two nostrils: Learn to align with sparse connections between two olfactory cortices.","authors":"Bo Liu, Shanshan Qin, Venkatesh Murthy, Yuhai Tu","doi":"10.1103/prxlife.2.043016","DOIUrl":"10.1103/prxlife.2.043016","url":null,"abstract":"<p><p>The integration of neural representations in the two hemispheres is an important problem in neuroscience. Recent experiments revealed that odor responses in cortical neurons driven by separate stimulation of the two nostrils are highly correlated. This bilateral alignment points to structured inter-hemispheric connections, but detailed mechanism remains unclear. Here, we hypothesized that continuous exposure to environmental odors shapes these projections and modeled it as online learning with local Hebbian rule. We found that Hebbian learning with sparse connections achieves bilateral alignment, exhibiting a linear trade-off between speed and accuracy. We identified an inverse scaling relationship between the number of cortical neurons and the inter-hemispheric projection density required for desired alignment accuracy, i.e., more cortical neurons allow sparser inter-hemispheric projections. We next compared the alignment performance of local Hebbian rule and the global stochastic-gradient-descent (SGD) learning for artificial neural networks. We found that although SGD leads to the same alignment accuracy with modestly sparser connectivity, the same inverse scaling relation holds. We showed that their similar performance originates from the fact that the update vectors of the two learning rules align significantly throughout the learning process. This insight may inspire efficient sparse local learning algorithms for more complex problems.</p>","PeriodicalId":520261,"journal":{"name":"PRX life","volume":"2 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12494114/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145234889","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}
PRX lifePub Date : 2024-10-01Epub Date: 2024-12-20DOI: 10.1103/prxlife.2.043020
Pedrom Zadeh, Brian A Camley
{"title":"Inferring Nonlinear Dynamics of Cell Migration.","authors":"Pedrom Zadeh, Brian A Camley","doi":"10.1103/prxlife.2.043020","DOIUrl":"10.1103/prxlife.2.043020","url":null,"abstract":"<p><p>The motility of eukaryotic cells is strongly influenced by their environment, with confined cells often developing qualitatively different motility patterns from those migrating on simple two-dimensional substrates. Recent experiments, coupled with data-driven methods to extract a cell's equation of motion, showed that cancerous MDA-MB-231 cells persistently hop in a limit cycle when placed on two-state adhesive micropatterns (two large squares connected by a narrow bridge), while they remain stationary on average in rectangular confinements. In contrast, healthy MCF10A cells migrating on the two-state micropattern are bistable, i.e., they settle into either basin on average with only noise-induced hops between the two states. We can capture all these behaviors with a single computational phase field model of a crawling cell, under the assumption that contact with nonadhesive substrate inhibits the cell front. Our model predicts that larger and softer cells are more likely to persistently hop, while smaller and stiffer cells are more likely to be bistable. Other key factors controlling cell migration are the frequency of protrusions and their magnitude of noise. Our results show that relatively simple assumptions about how cells sense their geometry can explain a wide variety of different cell behaviors, and show the power of data-driven approaches to characterize both experiment and simulation.</p>","PeriodicalId":520261,"journal":{"name":"PRX life","volume":"2 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12392504/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144985871","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}