NPJ Systems Biology and Applications最新文献

Flux sampling and graph neural networks for improved gene essentiality prediction in mammalian genome-scale metabolic models. 在哺乳动物基因组尺度代谢模型中改进基因本质性预测的通量采样和图神经网络。

IF 3.5 2区生物学

NPJ Systems Biology and Applications Pub Date : 2026-05-08 DOI: 10.1038/s41540-026-00738-8

Kieren Sharma, Lucia Marucci, Zahraa S Abdallah

{"title":"Flux sampling and graph neural networks for improved gene essentiality prediction in mammalian genome-scale metabolic models.","authors":"Kieren Sharma, Lucia Marucci, Zahraa S Abdallah","doi":"10.1038/s41540-026-00738-8","DOIUrl":"https://doi.org/10.1038/s41540-026-00738-8","url":null,"abstract":"Gene essentiality, the requirement of a gene for survival or proliferation, is central to understanding cellular processes and identifying drug targets. Experimental determination requires large growth screens that are time-consuming and expensive, motivating in silico approaches. Existing methods predominantly use flux balance analysis (FBA), a constraint-based optimisation framework that requires a predefined cellular objective function. This can introduce observer bias, because the objective often reflects the researcher's assumptions rather than the cell's biological goals. Here, we present FluxGAT, a graph neural network (GNN) that predicts gene essentiality from graphical representations of flux sampling data. Flux sampling removes the need for an explicit objective and instead characterises feasible steady-state fluxes. FluxGAT combines this information with metabolic network topology to learn flux-informed node representations and classify reactions as essential or non-essential. We apply FluxGAT to the iCHO2291 genome-scale model of Chinese hamster ovary cells and Mouse1, a generic mouse model with independent essentiality labels. In both systems, FluxGAT improves sensitivity over FBA while maintaining high precision and specificity, and recovers more experimentally essential genes, especially where FBA predicts very few essentials. These results show that flux-informed GNNs can provide more general gene essentiality predictions across mammalian genome-scale models without hand-crafted objective functions.","PeriodicalId":19345,"journal":{"name":"NPJ Systems Biology and Applications","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147856769","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}

引用次数: 0

A rule-based simulation model illuminates the role of asymmetric mitochondrial fission on beta-cell health. 一个基于规则的模拟模型阐明了不对称线粒体裂变对β细胞健康的作用。

IF 3.5 2区生物学

NPJ Systems Biology and Applications Pub Date : 2026-05-05 DOI: 10.1038/s41540-026-00732-0

Philipp Henning, Julia Schultz, Simone Baltrusch, Adelinde M Uhrmacher

{"title":"A rule-based simulation model illuminates the role of asymmetric mitochondrial fission on beta-cell health.","authors":"Philipp Henning, Julia Schultz, Simone Baltrusch, Adelinde M Uhrmacher","doi":"10.1038/s41540-026-00732-0","DOIUrl":"https://doi.org/10.1038/s41540-026-00732-0","url":null,"abstract":"Mitochondrial dynamics play a critical role in the development of aging-related diseases such as type 2 diabetes mellitus. To investigate how mitochondrial dynamics influence cellular behavior in pancreatic beta-cells, we developed a rule-based, multi-level simulation model of insulin secretion. The pancreatic beta-cell model encompasses metabolic pathways (glycolysis and oxidative phosphorylation), compartmental processes (mitochondrial fusion and fission), and cellular processes (insulin secretion), allowing for the investigation of their interplay. The rule-based simulation model captures the high plasticity of these organelles and integrates and builds upon insights from various experimental studies and previous simulation models. Its rule-based specification facilitates the exploration of new hypotheses, the integration of new knowledge and data, and the successive extension of the model. The results of our simulation experiments underscore the importance of peripheral, sorted mitochondrial fission in maintaining mitochondrial health. Downregulation of the fission-associated anchor proteins Fis1 and MFF impacts mitochondrial structure and function differently, highlighting their distinct roles in maintaining mitochondrial health and cellular biogenesis, respectively. With respect to insulin secretion, Drp1 suppression shows that beta-cells become unresponsive to glucose, whereas Fis1 downregulation only attenuates the cellular response. The simulation model and simulation results corroborate experimental findings and contribute to a deeper understanding of the mechanisms involved in mitochondrial dynamics of pancreatic beta-cells and their relation to metabolic dysregulation in type 2 diabetes mellitus.","PeriodicalId":19345,"journal":{"name":"NPJ Systems Biology and Applications","volume":"12 1","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13144372/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147841001","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}

引用次数: 0

Spatiotemporal instability of influenza seasonality during viral co-circulation. 病毒共循环期间流感季节性的时空不稳定性。

IF 3.5 2区生物学

NPJ Systems Biology and Applications Pub Date : 2026-05-04 DOI: 10.1038/s41540-026-00729-9

Hong Liu, Xuanfeng Li, Ning Sun, Jingjing Tian, Ming Xu, Chitin Hon

{"title":"Spatiotemporal instability of influenza seasonality during viral co-circulation.","authors":"Hong Liu, Xuanfeng Li, Ning Sun, Jingjing Tian, Ming Xu, Chitin Hon","doi":"10.1038/s41540-026-00729-9","DOIUrl":"https://doi.org/10.1038/s41540-026-00729-9","url":null,"abstract":"Co-circulation of multiple influenza subtypes poses a major challenge to global public health. However, its specific impact on non-stationary epidemic sequences and coupling relationships with environmental drivers remains poorly understood. By integrating STL, Adaptive Fourier Decomposition, Continuous Wavelet Transform, and Wavelet Coherence, we analyzed 323 weekly influenza surveillance time series from China (2011-2025). The study identifies a fundamental regime shift during co-circulation periods, transitioning from ordered single-dominant transmission to a chaotic state. This instability is characterized by significant dominant periodicity dispersion, amplified seasonality shifts, and high-intensity anomalies in residual components, with overall seasonal strength dropping by 28%. Crucially, we uncover a marked north-south mechanistic divergence: northern regions exhibited \"Environmental Locking,\" remaining strongly constrained by climates during co-circulation; conversely, southern regions demonstrated \"Environmental Decoupling\" (H3N2 phase consistency with soil moisture plummeted from R=0.45 to 0.07), where viral ecological competition overshadowed environmental drivers. Influenza co-circulation acts as a systemic perturbation reshaping transmission dynamics. Our findings highlight the necessity for context-adaptive strategies: northern regions can maintain reliance on meteorological warnings, while southern regions must dynamically shift focus toward real-time virological surveillance during co-circulation to capture rapid ecological shifts.","PeriodicalId":19345,"journal":{"name":"NPJ Systems Biology and Applications","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147840965","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}

引用次数: 0

Genetic basis of temporal variation in phenology in a woody perennial plant. 多年生木本植物物候变化的遗传基础。

IF 3.5 2区生物学

NPJ Systems Biology and Applications Pub Date : 2026-05-04 DOI: 10.1038/s41540-026-00691-6

Yang Liu

{"title":"Genetic basis of temporal variation in phenology in a woody perennial plant.","authors":"Yang Liu","doi":"10.1038/s41540-026-00691-6","DOIUrl":"https://doi.org/10.1038/s41540-026-00691-6","url":null,"abstract":"The form of phenotypic plasticity in traits that are repeatedly and potentially reversibly expressed multiple times throughout an individual's lifetime is labile plasticity. Yet, little is known about selection on, and genetic variation and inheritance in, such plasticity. Herein I embedded dynamic growth phenology traits into empirical understanding of the variability, inheritance, and predictability of their labile plasticity using a Populus common-garden experiment. I found no single nucleotide polymorphisms (SNPs) peak associated at P < 1e-4 with labile plasticity in phenological traits, overlapping in its two populations and no such plasticity-associated SNPs identified across study traits in single populations. Higher plasticity and more plasticity SNPs were identified in the population from climatically harsher conditions. While 6% of phenology peak-associated SNPs underwent adaptive selection, 95% of the identified plasticity SNPs were also peak associated with a given phenology, but none of them were found under selection. Plasticity SNP-containing genes highlighted environmental responsiveness functions for phenology plasticity. Projections for labile plasticity in phenology consistently showed that plasticity or trait peak-associated SNPs generated a higher predictive accuracy than non-associative counterparts. Altogether, the study elucidates the idiosyncratic characteristics of labile plasticity in growth phenology and deepens our understanding of its genetic modulation and evolution.","PeriodicalId":19345,"journal":{"name":"NPJ Systems Biology and Applications","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147840866","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}

引用次数: 0

Learning patient-specific spatial biomarker dynamics via operator learning for Alzheimer's disease progression. 通过算子学习了解阿尔茨海默病进展的患者特异性空间生物标志物动态。

IF 3.5 2区生物学

NPJ Systems Biology and Applications Pub Date : 2026-05-04 DOI: 10.1038/s41540-026-00719-x

Jindong Wang, Yutong Mao, Xiao Liu, Wenrui Hao

{"title":"Learning patient-specific spatial biomarker dynamics via operator learning for Alzheimer's disease progression.","authors":"Jindong Wang, Yutong Mao, Xiao Liu, Wenrui Hao","doi":"10.1038/s41540-026-00719-x","DOIUrl":"https://doi.org/10.1038/s41540-026-00719-x","url":null,"abstract":"Alzheimer's disease (AD) is a complex, multifactorial neurodegenerative disorder with substantial heterogeneity in progression and treatment response. Despite recent therapeutic advances, predictive models capable of accurately forecasting individualized future biomarker states remain limited. Here, we present a machine learning-based operator learning framework for personalized modeling of AD progression, integrating longitudinal multimodal imaging, biomarker, and clinical data. Unlike conventional models with prespecified dynamics, our approach directly learns patient-specific disease operators governing the spatiotemporal evolution of amyloid, tau, and neurodegeneration biomarkers. Using Laplacian eigenfunction bases, we construct geometry-aware neural operators capable of capturing complex brain dynamics. Embedded within a digital twin paradigm, the framework enables individualized predictions, simulation of therapeutic interventions, and in silico clinical trials. Applied to AD clinical data, our method achieves high prediction accuracy exceeding 90% across multiple biomarkers, substantially outperforming existing approaches. This work offers a scalable, interpretable platform for precision modeling and personalized therapeutic optimization in neurodegenerative diseases.","PeriodicalId":19345,"journal":{"name":"NPJ Systems Biology and Applications","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147841014","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}

引用次数: 0

Design principles for robust multistability in coupled feedforward-feedback regulatory circuits. 耦合前馈-反馈调节电路鲁棒多稳定性设计原则。

IF 3.5 2区生物学

NPJ Systems Biology and Applications Pub Date : 2026-05-02 DOI: 10.1038/s41540-026-00731-1

Hong Qi, Zhi-Yu Zhao, Yu-Song Yin, Xiang Li, Chen Jia, Lei Zhang

{"title":"Design principles for robust multistability in coupled feedforward-feedback regulatory circuits.","authors":"Hong Qi, Zhi-Yu Zhao, Yu-Song Yin, Xiang Li, Chen Jia, Lei Zhang","doi":"10.1038/s41540-026-00731-1","DOIUrl":"https://doi.org/10.1038/s41540-026-00731-1","url":null,"abstract":"Feedforward loops (FFLs) and feedback loops (FBLs) are ubiquitous network motifs that mediate signal filtering, pulse generation, and state switching; yet, how coupling FBLs to FFLs produces robust multistability-a key mechanism for cellular decision-making-remains unclear. Here, we systematically investigate coupled FFL-FBL architectures by focusing on two prevalent FFL types, each with AND or OR logic, yielding four distinct frameworks. For each framework, we enumerate all 36 = 729 possible circuits, corresponding to three possible states (activation, inhibition, or absence) for each of six feedback edges, formulate each circuit as a system of ordinary differential equations, and quantify robustness as the proportion of 100,000 randomly sampled parameter sets exhibiting multistability. Our results reveal two key principles. First, positive self-activation is a primary driver of multistability, but the identity of the critical node(s) depends on the FFL type and logic. Second, coherent FFLs support multistability more readily than incoherent ones, whereas the choice between AND and OR logic has a comparatively weaker effect. Notably, we identify representative high-performing circuits within each framework and find that a small set of circuit designs remain robustly multistable across all four frameworks. These findings advance the theoretical understanding of motif design and provide practical guidelines for engineering synthetic multistable circuits.","PeriodicalId":19345,"journal":{"name":"NPJ Systems Biology and Applications","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147818467","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}

引用次数: 0

Sometimes extracellular recordings fail for good reasons. 有时细胞外记录失败是有原因的。

IF 3.5 2区生物学

NPJ Systems Biology and Applications Pub Date : 2026-05-02 DOI: 10.1038/s41540-026-00730-2

Karoline Horgmo Jæger, Aslak Tveito

{"title":"Sometimes extracellular recordings fail for good reasons.","authors":"Karoline Horgmo Jæger, Aslak Tveito","doi":"10.1038/s41540-026-00730-2","DOIUrl":"https://doi.org/10.1038/s41540-026-00730-2","url":null,"abstract":"Excitable cells are commonly studied via the extracellular potentials (EPs) they generate, which underlie signals in electroencephalography (EEG), electrocardiography (ECG), and multielectrode array (MEA) recordings. However, some excitable systems produce little or no detectable EPs, for reasons that remain poorly understood. Here we show mathematically that homogeneous excitable cells and tissues - with spatially uniform ion channel distributions and no external stimulation - are extracellularly silent during spatially uniform, non-propagating action potentials (i.e., in the absence of a traveling wavefront). Specifically, an isolated, autonomous cell with uniform membrane properties generates zero EP, independent of shape, kinetics, or model complexity. The result extends to coupled cells provided the tissue remains fully homogeneous. EPs emerge only from spatial inhomogeneities, propagating electrical waves, or applied currents. We demonstrate the physiological relevance of this principle in Purkinje neurons, where clustering of sodium channels enables ephaptic synchronization, while uniform cells remain asynchronous and undetectable extracellularly. We further show that connected human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and pancreatic β-cells exhibit EPs in proportion to cellular or tissue-level heterogeneity.","PeriodicalId":19345,"journal":{"name":"NPJ Systems Biology and Applications","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147818490","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}

引用次数: 0

Association-sensory spatiotemporal hierarchy and functional gradient-regularised recurrent neural network with implications for schizophrenia. 联想-感觉时空层次和功能梯度-正则化递归神经网络对精神分裂症的影响。

IF 3.5 2区生物学

NPJ Systems Biology and Applications Pub Date : 2026-04-30 DOI: 10.1038/s41540-026-00727-x

Subati Abulikemu, Puria Radmard, Michail Mamalakis, John Suckling

{"title":"Association-sensory spatiotemporal hierarchy and functional gradient-regularised recurrent neural network with implications for schizophrenia.","authors":"Subati Abulikemu, Puria Radmard, Michail Mamalakis, John Suckling","doi":"10.1038/s41540-026-00727-x","DOIUrl":"https://doi.org/10.1038/s41540-026-00727-x","url":null,"abstract":"The human neocortex is functionally organised at its highest level along a continuous sensory-to-association (AS) hierarchy. This study investigates two questions-how this hierarchy is structurally altered in schizophrenia, and what these alterations imply for neural dynamics and cognitive computation. Using a large fMRI dataset (N = 355), we extracted individual AS gradients via spectral analysis of brain connectivity and quantified hierarchical organisation by the gradient range. Schizophrenia showed a compressed AS hierarchy, indicating reduced functional differentiation. Estimating neural timescale (autocorrelation decay constant) with the Ornstein-Uhlenbeck process, we observed that the most specialised, locally cohesive regions at the gradient extremes exhibit longer timescales, an empirical spatiotemporal mapping that is attenuated in schizophrenia. To probe the computational consequences of this compression, we used the gradients to regularise subject-specific recurrent neural networks (RNNs) trained on working memory tasks. Networks endowed with greater gradient range learned more efficiently, plateaued at lower task loss, and maintained stronger alignment to the prescribed AS hierarchical geometry. Fixed-point linearisation showed that high-range networks settled into more stable neural states during memory delay, evidenced by lower energy and smaller maximal Jacobian eigenvalues. This gradient-regularised RNN framework thereby links large-scale cortical architecture with fixed point stability, providing a computational hypothesis that AS gradient de-differentiation can destabilise neural computations in schizophrenia, convergently supported by empirical timescale flattening along AS gradient and model-based evidence of less stable fixed points.","PeriodicalId":19345,"journal":{"name":"NPJ Systems Biology and Applications","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147777154","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}

引用次数: 0

Integrating AI, mechanistic modelling and network approaches in systems biology for translational research. 整合人工智能，机制建模和网络方法在系统生物学转化研究。

IF 3.5 2区生物学

NPJ Systems Biology and Applications Pub Date : 2026-04-29 DOI: 10.1038/s41540-026-00726-y

Xin Lai, Jing Tang

引用次数: 0

Rewiring miR-22/SNAI1 via CRISPR-based edge editing destabilizes the epithelial phenotype. 通过基于crispr的边缘编辑重新连接miR-22/SNAI1会破坏上皮表型的稳定性。

IF 3.5 2区生物学

NPJ Systems Biology and Applications Pub Date : 2026-04-29 DOI: 10.1038/s41540-026-00720-4

John T Nguyen, Lijia Huang, Herbert Levine, Mingyang Lu, Leonidas Bleris

{"title":"Rewiring miR-22/SNAI1 via CRISPR-based edge editing destabilizes the epithelial phenotype.","authors":"John T Nguyen, Lijia Huang, Herbert Levine, Mingyang Lu, Leonidas Bleris","doi":"10.1038/s41540-026-00720-4","DOIUrl":"https://doi.org/10.1038/s41540-026-00720-4","url":null,"abstract":"Epithelial-to-Mesenchymal Transition (EMT) is a critical biological process by which cells acquire enhanced migratory and invasive properties. A key signaling pathway involved in EMT phenotypes includes transforming growth factor β (TGFβ) and transcription factors (TFs) such as SNAIL, ZEB, and TWIST. Additionally, microRNAs (miRNAs) - small, non-coding molecules that regulate gene expression by targeting mRNA transcripts - directly regulate genes central to the EMT process. Notably, miR-22 has been identified as a significant regulator of EMT through direct inhibition of EMT drivers like SNAI1 and indirect regulation of upstream genes. In this study, we performed CRISPR-based network rewiring by selectively removing an edge-the connection between two nodes-to investigate its impact on EMT dynamics. Specifically, we disrupted the connection between miR-22 and SNAI1 without affecting other interactions involving miR-22 or SNAI1 and examined the resulting effects on EMT. We demonstrate that the removal of the miR-22 target site from the SNAI1 gene renders cells more sensitive to TGFβ-mediated EMT. This finding highlights the unique advantage of edge-specific perturbation by ablating the direct regulatory connection between miR-22 and SNAI1. We demonstrate that all measured downstream effects on EMT can be attributed to this single interaction, independent of miR-22's influence on other targets or indirect pathways. More generally, our results underscore the importance of CRISPR-mediated edge ablation for exploring the interactions that govern biological networks and highlight an underexplored opportunity to develop edge-based therapeutic modalities.","PeriodicalId":19345,"journal":{"name":"NPJ Systems Biology and Applications","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147777284","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}

引用次数: 0