PLoS Computational Biology最新文献

{"title":"DelaySSA: stochastic simulation of biochemical systems and gene regulatory networks with or without time delays.","authors":"Ziyan Jin, Xinyi Zhou, Zhaoyuan Fang","doi":"10.1371/journal.pcbi.1012919","DOIUrl":"https://doi.org/10.1371/journal.pcbi.1012919","url":null,"abstract":"<p><p>Stochastic Simulation Algorithm (SSA) is crucial for modeling biochemical reactions and gene regulatory networks. Traditional SSA is characterized by Markovian property and cannot naturally model systems with time delays. Several algorithms have already been designed to handle delayed reactions, yet few easy-to-use implementations exist. To address these challenges, we have developed DelaySSA, an R package that implements currently available algorithms for SSA with or without delays. Meanwhile, we also provided Matlab and Python versions to support wider applications. We demonstrated its accuracy and validity by simulating two classical models: the Bursty model and Refractory model. We then tested its capability to simulate the RNA Velocity model, where it successfully reproduced both the up- and down-regulation stages in the phase portrait. Finally, we extended its application to simulate a gene regulatory network of lung cancer adeno-to-squamous transition (AST) and qualitatively analyzed its bistability behavior by approximating the Waddington's landscape. Modeling the therapeutic intervention of a SOX2 degrader as a delayed degradation reaction, AST is effectively blocked and reprogrammed back to the adenocarcinoma state, providing a useful clue for targeting drug-resistant AST in the future. Taken together, DelaySSA is a powerful and easy-to-use software suite, facilitating accurate modeling of various kinds of biological systems and broadening the scope of stochastic simulations in systems biology.</p>","PeriodicalId":20241,"journal":{"name":"PLoS Computational Biology","volume":"21 4","pages":"e1012919"},"PeriodicalIF":3.8,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143811930","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cell size and selection for stress-induced cell fusion in unicellular eukaryotes.","authors":"Xiaoyuan Liu, Jonathan W Pitchford, George W A Constable","doi":"10.1371/journal.pcbi.1012418","DOIUrl":"https://doi.org/10.1371/journal.pcbi.1012418","url":null,"abstract":"<p><p>In unicellular organisms, sexual reproduction typically begins with the fusion of two cells (plasmogamy) followed by the fusion of their two haploid nuclei (karyogamy) and finally meiosis. Most work on the evolution of sexual reproduction focuses on the benefits of the genetic recombination that takes place during meiosis. However, the selection pressures that may have driven the early evolution of binary cell fusion, which sets the stage for the evolution of karyogamy by bringing nuclei together in the same cell, have seen less attention. In this paper we develop a model for the coevolution of cell size and binary cell fusion rate. The model assumes that larger cells experience a survival advantage from their larger cytoplasmic volume. We find that under favourable environmental conditions, populations can evolve to produce larger cells that undergo obligate binary cell fission. However, under challenging environmental conditions, populations can evolve to subsequently produce smaller cells under binary cell fission that nevertheless retain a survival advantage by fusing with other cells. The model thus parsimoniously recaptures the empirical observation that sexual reproduction is typically triggered by adverse environmental conditions in many unicellular eukaryotes and draws conceptual links to the literature on the evolution of multicellularity.</p>","PeriodicalId":20241,"journal":{"name":"PLoS Computational Biology","volume":"21 4","pages":"e1012418"},"PeriodicalIF":3.8,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143811929","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The impact of climate change on ecology of tick associated with tick-borne diseases.","authors":"Heejin Choi, Chang Hyeong Lee","doi":"10.1371/journal.pcbi.1012903","DOIUrl":"https://doi.org/10.1371/journal.pcbi.1012903","url":null,"abstract":"<p><p>Infectious diseases have caused significant economic and human losses worldwide. Growing concerns exist regarding climate change potentially exacerbating the spread of these diseases, particularly those transmitted by vectors such as ticks and mosquitoes. Tick-borne diseases, such as Severe Fever with Thrombocytopenia Syndrome (SFTS), can be particularly detrimental to elderly and immunocompromised individuals. This study utilizes a mathematical modeling approach to predict changes in tick populations under climate change scenarios, incorporating tick ecology and climate-sensitive parameters. Sensitivity analysis is performed to investigate the factors influencing tick population dynamics. The study further explores effective tick control strategies and their cost-effectiveness in the context of climate change. The findings indicate that the efficacy of tick population reduction varies greatly depending on the timing of control measure implementation and the effectiveness of the control strategies exhibits a strong dependence on the duration of implementation. Furthermore, as climate change intensifies, tick populations are projected to increase, leading to a rise in control costs and SFTS cases. In light of these findings, identifying and implementing appropriate control measures to manage tick populations under climate change will be increasingly crucial.</p>","PeriodicalId":20241,"journal":{"name":"PLoS Computational Biology","volume":"21 4","pages":"e1012903"},"PeriodicalIF":3.8,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143811958","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Federated epidemic surveillance.","authors":"Ruiqi Lyu, Roni Rosenfeld, Bryan Wilder","doi":"10.1371/journal.pcbi.1012907","DOIUrl":"https://doi.org/10.1371/journal.pcbi.1012907","url":null,"abstract":"<p><p>Epidemic surveillance is a challenging task, especially when crucial data is fragmented across institutions and data custodians are unable or unwilling to share it. This study aims to explore the feasibility of a simple federated surveillance approach. We conduct hypothesis tests on count data behind each custodian's firewall and then combine p-values from these tests using techniques from meta-analysis. We propose a hypothesis testing framework to identify surges in epidemic-related data streams and conduct experiments on real and semi-synthetic data to assess the power of different p-value combination methods to detect surges without needing to combine or share the underlying counts. Our findings show that relatively simple combination methods achieve a high degree of fidelity and suggest that infectious disease outbreaks can be detected without needing to share or even aggregate data across institutions.</p>","PeriodicalId":20241,"journal":{"name":"PLoS Computational Biology","volume":"21 4","pages":"e1012907"},"PeriodicalIF":3.8,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143811957","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A burst-dependent thalamocortical substrate for perceptual awareness.","authors":"Christopher J Whyte, Eli J Müller, Jaan Aru, Matthew Larkum, Yohan John, Brandon R Munn, James M Shine","doi":"10.1371/journal.pcbi.1012951","DOIUrl":"https://doi.org/10.1371/journal.pcbi.1012951","url":null,"abstract":"<p><p>Contemporary models of perceptual awareness lack tractable neurobiological constraints. Inspired by recent cellular recordings in a mouse model of tactile threshold detection, we constructed a biophysical model of perceptual awareness that incorporated essential features of thalamocortical anatomy and cellular physiology. Our model reproduced, and mechanistically explains, the key in vivo neural and behavioural signatures of perceptual awareness in the mouse model, as well as the response to a set of causal perturbations. We generalised the same model (with identical parameters) to a more complex task - visual rivalry - and found that the same thalamic-mediated mechanism of perceptual awareness determined perceptual dominance. This led to the generation of a set of novel, and directly testable, electrophysiological predictions. Analyses of the model based on dynamical systems theory show that perceptual awareness in simulations of both threshold detection and visual rivalry arises from the emergent systems-level dynamics of thalamocortical loops.</p>","PeriodicalId":20241,"journal":{"name":"PLoS Computational Biology","volume":"21 4","pages":"e1012951"},"PeriodicalIF":3.8,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143803986","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Flux-sum coupling analysis of metabolic network models.","authors":"Mihriban Seyis, Zahra Razaghi-Moghadam, Zoran Nikoloski","doi":"10.1371/journal.pcbi.1012972","DOIUrl":"https://doi.org/10.1371/journal.pcbi.1012972","url":null,"abstract":"<p><p>Metabolites acting as substrates and regulators of all biochemical reactions play an important role in maintaining the functionality of cellular metabolism. Despite advances in the constraint-based framework for metabolic modeling at a genome-scale, we lack reliable proxies for metabolite concentrations that can be efficiently determined and that allows us to investigate the relationship between concentrations of metabolites in specified metabolic states in the absence of measurements. Here, we introduce a constraint-based approach, the flux-sum coupling analysis (FSCA), which facilitates the study of the interdependencies between metabolite concentrations by determining coupling relationships based on the flux-sum of metabolites. Application of FSCA on metabolic models of Escherichia coli, Saccharomyces cerevisiae, and Arabidopsis thaliana showed that the three coupling relations are present in all models and pinpointed similarities in coupled metabolite pairs. Using the available concentration measurements of E. coli metabolites, we demonstrated that the coupling relationships identified by FSCA can capture the qualitative associations between metabolite concentrations and that flux-sum is a reliable proxy for metabolite concentration. Therefore, FSCA provides a novel tool for exploring and understanding the intricate interdependencies between the concentration of metabolites, advancing the understanding of metabolic regulation, and improving flux-centered systems biology approaches.</p>","PeriodicalId":20241,"journal":{"name":"PLoS Computational Biology","volume":"21 4","pages":"e1012972"},"PeriodicalIF":3.8,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143804015","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The multiscale self-similarity of the weighted human brain connectome.","authors":"Laia Barjuan, Muhua Zheng, M Ángeles Serrano","doi":"10.1371/journal.pcbi.1012848","DOIUrl":"https://doi.org/10.1371/journal.pcbi.1012848","url":null,"abstract":"<p><p>Anatomical connectivity between different brain regions can be mapped to a network representation, the connectome, where the intensities of the links, the weights, influence resilience and functional processes. Yet, many features associated with these weights are not fully understood, particularly their multiscale organization. In this paper, we elucidate the architecture of weights, including weak ties, in multiscale human brain connectomes reconstructed from empirical data. Our findings reveal multiscale self-similarity, including the ordering of weak ties, in every individual connectome and group representative. This phenomenon is captured by a renormalization technique based on a geometric network model that replicates the observed structure of connectomes across all length scales, using the same connectivity law and weighting function for both weak and strong ties. The observed symmetry represents a signature of criticality in the weighted connectivity of the human brain and raises important questions for future research, such as the existence of symmetry breaking at some scale or whether it is preserved in cases of neurodegeneration or psychiatric disorder.</p>","PeriodicalId":20241,"journal":{"name":"PLoS Computational Biology","volume":"21 4","pages":"e1012848"},"PeriodicalIF":3.8,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143804088","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nanometer scale difference in myofilament lattice structure of muscle alters muscle function in a spatially explicit model.","authors":"Travis Carver Tune, Simon Sponberg","doi":"10.1371/journal.pcbi.1012862","DOIUrl":"10.1371/journal.pcbi.1012862","url":null,"abstract":"<p><p>Crossbridge binding, state transitions, and force in active muscle is dependent on the radial spacing between the myosin-containing thick filament and the actin-containing thin filament in the filament lattice. This radial spacing has been previously shown through spatially explicit modeling and experimental efforts to greatly affect quasi-static, isometric, force production in muscle. It has recently been suggested that this radial spacing might also be able to drive differences in mechanical function, or net work, under dynamic oscillations like those which occur in muscles in vivo. However, previous spatially explicit models either had no radial spacing dependence, meaning the radial spacing could not be investigated, or did include radial spacing dependence but could not reproduce in vivo net work during dynamic oscillations and only investigated isometric contractions. Here we show the first spatially explicit model to include radial crossbridge dependence which can produce mechanical function similar to real muscle. Using this spatially explicit model of a half sarcomere, we show that when oscillated at strain amplitudes and frequencies like those in the main flight muscles of the hawkmoth Manduca sexta, mechanical function (net work) does depend on the lattice spacing. In addition, since the trajectory of lattice spacing changes during dynamic oscillation can vary from organism to organism, we can prescribe a trajectory of lattice spacing changes in the spatially explicit half sarcomere model and investigate the extent to which the time course of lattice spacing changes can affect mechanical function. We simulated a half sarcomere undergoing dynamic oscillations and prescribed the Poisson's ratio of the lattice to be either 0 (constant lattice spacing) or 0.5 (isovolumetric lattice spacing changes). We also simulated net work using lattice spacing data taken from M. sexta which has a variable Poisson's ratio. Our simulation results indicate that the lattice spacing can change the mechanical function of muscle, and that in some cases a 1 nm difference can switch the net work of the half sarcomere model from positive (motor-like) to negative (brake-like).</p>","PeriodicalId":20241,"journal":{"name":"PLoS Computational Biology","volume":"21 4","pages":"e1012862"},"PeriodicalIF":3.8,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11975381/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143804021","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Analysis of targeted and whole genome sequencing of PacBio HiFi reads for a comprehensive genotyping of gene-proximal and phenotype-associated Variable Number Tandem Repeats.","authors":"Sara Javadzadeh, Aaron Adamson, Jonghun Park, Se-Young Jo, Yuan-Chun Ding, Mehrdad Bakhtiari, Vikas Bansal, Susan L Neuhausen, Vineet Bafna","doi":"10.1371/journal.pcbi.1012885","DOIUrl":"10.1371/journal.pcbi.1012885","url":null,"abstract":"<p><p>Variable Number Tandem repeats (VNTRs) refer to repeating motifs of size greater than five bp. VNTRs are an important source of genetic variation, and have been associated with multiple Mendelian and complex phenotypes. However, the highly repetitive structures require reads to span the region for accurate genotyping. Pacific Biosciences HiFi sequencing spans large regions and is highly accurate but relatively expensive. Therefore, targeted sequencing approaches coupled with long-read sequencing have been proposed to improve efficiency and throughput. In this paper, we systematically explored the trade-off between targeted and whole genome HiFi sequencing for genotyping VNTRs. We curated a set of 10 , 787 gene-proximal (G-)VNTRs, and 48 phenotype-associated (P-)VNTRs of interest. Illumina reads only spanned 46% of the G-VNTRs and 71% of P-VNTRs, motivating the use of HiFi sequencing. We performed targeted sequencing with hybridization by designing custom probes for 9,999 VNTRs and sequenced 8 samples using HiFi and Illumina sequencing, followed by adVNTR genotyping. We compared these results against HiFi whole genome sequencing (WGS) data from 28 samples in the Human Pangenome Reference Consortium (HPRC). With the targeted approach only 4,091 (41%) G-VNTRs and only 4 (8%) of P-VNTRs were spanned with at least 15 reads. A smaller subset of 3,579 (36%) G-VNTRs had higher median coverage of at least 63 spanning reads. The spanning behavior was consistent across all 8 samples. Among 5,638 VNTRs with low-coverage ( < 15), 67% were located within GC-rich regions ( > 60%). In contrast, the 40X WGS HiFi dataset spanned 98% of all VNTRs and 49 (98%) of P-VNTRs with at least 15 spanning reads, albeit with lower coverage. Spanning reads were sufficient for accurate genotyping in both cases. Our findings demonstrate that targeted sequencing provides consistently high coverage for a small subset of low-GC VNTRs, but WGS is more effective for broad and sufficient sampling of a large number of VNTRs.</p>","PeriodicalId":20241,"journal":{"name":"PLoS Computational Biology","volume":"21 4","pages":"e1012885"},"PeriodicalIF":3.8,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11975116/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143804005","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neural energy coding patterns of dopaminergic neural microcircuit and its impairment in major depressive disorder: A computational study.","authors":"Yuanxi Li, Bing Zhang, Jinqi Liu, Rubin Wang","doi":"10.1371/journal.pcbi.1012961","DOIUrl":"https://doi.org/10.1371/journal.pcbi.1012961","url":null,"abstract":"<p><p>Numerous experiments have found that the behavioral characteristics of major depressive disorder (MDD) animals are usually associated with abnormal neural activity patterns and brain energy metabolism. However, the relationship among the behavioral characteristics, neural activity patterns and brain energy metabolism remains unknown. In this paper, we computationally investigated this relationship, especially studied how neural energy coding patterns changed in MDD brains, in the VTA-NAc-mPFC dopaminergic pathway of the reward system based on our biological neural network model and neural energy calculation model. Interestingly, our results suggested that the neural energy consumption of the whole VTA-NAc-mPFC microcircuit in MDD group was significantly reduced, which was mainly attributed to the decreasing neural energy consumption in the mPFC region. This observation theoretically supported the view of low-level energy consumption in MDD. We also investigated the neural energy consumption patterns of various neuronal types in our VTA-NAc-mPFC microcircuit under the influence of different dopamine concentrations, and found that there were some specific impairments in MDD, which provided some potential biomarkers for MDD diagnosis. More specifically, we found that the actual neural energy consumption of medium spiny neurons (MSNs) in the NAc region was increased in the MDD group, whereas pyramidal neurons in the mPFC region exhibited higher actual neural energy consumption in the NC group. Additionally, in both neuron types, the actual neural energy required to generate an action potential was higher in the MDD group, suggesting that, given the same energy budget, these neurons in the MDD group tended to generate fewer action potentials. To further explore the relationship between neural coding patterns and neural energy coding patterns in the VTA-NAc-mPFC microcircuit, we in addition calculated P-V correlation for each neuronal types, defined as the Pearson's correlation coefficient between membrane potential and neural power. The results showed that the membrane potential and neural power were not perfectly correlated (P-V correlations were ranged from 0.6 to 0.9), and dopamine concentration inputs affected the P-V correlations of the MSN, pyramidal neurons and CB interneurons in the mPFC region. It suggested that the joint application of the neural coding theory and neural energy coding theory will be superior to the application of any single theory, and this joint application could help discovery new mechanisms in neurocircuits of MDD. Overall, our study not only uncovered the neural energy coding patterns for the VTA-NAc-mPFC neural microcircuit, but also presented a novel pipeline for the study of MDD based on the neural coding theory and neural energy coding theory.</p>","PeriodicalId":20241,"journal":{"name":"PLoS Computational Biology","volume":"21 4","pages":"e1012961"},"PeriodicalIF":3.8,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143804034","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}