- by Bavisetty, V. S. N., Wheeler, M., Kadelka, C.Waddington's epigenetic landscape has served as biology's central metaphor for cellular differentiation for over half a century, depicting mature cell types as balls resting in stable valley floors. Boolean networks — introduced by Kauffman in 1969 to model gene regulatory dynamics — provide a mathematical formalization of this landscape, where attractors represent phenotypes and basins of attraction correspond to developmental valleys. Traditional stability measures quantify robustness by perturbing arbitrary states, yet biological systems typically reside at attractors rather than in […]
- by Vu, D. T., Sibran, W., Metousis, A., Vandewynckel, L., Eraslan, B., Goveas, L., Itang, E. C., Deldycke, C., Figueroa Garcia, A., Lefebvre, R., Mueller Reif, J. B., Virreira Winter, S., Chartier-Harlin, M.-C., Taymans, J.-M., Mann, M., Karayel, O.Pathogenic mutations in Leucine-rich repeat kinase 2 (LRRK2) are the predominant genetic cause of Parkinson's disease (PD) and often increase kinase activity, making LRRK2 inhibitors promising treatment options. Although LRRK2 kinase inhibitors are advancing clinically, non-invasive readouts of LRRK2-linked pathway modulation remain limited. Profiling urinary proteomes from 1,215 individuals across three cohorts and integrating whole-genome sequencing from >500 participants to map genotype-proteome associations, we identified 177 urinary proteins associated with pathogenic LRRK2, enriched for lysosomal/glycosphingolipid, immune, and membrane-trafficking pathways. Machine […]
- by Clark, P., Timpen, L. E., Heberle, A., Prugger, M., van Eunen, K., Rehbein, U., Thedieck, K., Shanley, D. P.Parameterisation of dynamic biochemical network models is a challenging aspect of systems biology. Especially when the parameter space is large and data is semi quantitive but comparable across different experimental conditions. Here, we present a set of command line tools utilising Pycotools (COPASI) that leverages the power of high-performance computing to facilitate parameter estimation of large models with many unknown parameters. In particular, we expand upon the abilities of Pycotools to address two particular issues. Firstly, the difficulty of constraining […]
- by Gholami, S., Korosec, C., Su, Q., Betti, M., Conway, J. M., Moyles, I., Watmough, J., Heffernan, J. M.Understanding how viruses replicate and spread within a host is fundamental to predicting disease progression, timing, and dosage of effective therapeutic and prophylactic interventions. A target-cell limited approach is often used to model within-host viral kinetics to characterize disease infection dynamics. The standard target-cell limited model, the TEIV model, has been instrumental for understanding SARS-CoV-2 within-host viral kinetics, however, its core assumptions of instantaneous viral budding and exponentially distributed cell lifetimes oversimplify fundamental biological processes, potentially limiting predictive power. In […]
- by Degefu, Y. N., Bujnowska, M., Baumann, D. G., Fallahi-Sichani, M.Cell state plasticity drives metastasis and therapy resistance in cancers. In melanoma, these behaviors map onto a melanocytic-to-mesenchymal-like continuum regulated by AP-1 transcription factors. However, how the AP-1 network encodes a limited set of discrete states, why their distributions vary across tumors, and what drives phenotypically consequential AP-1 state transitions remain unclear. We develop a mechanistic ODE model of the AP-1 network capturing their dimerization-controlled, co-regulated, competitive interactions. Calibrated to heterogeneous single-cell data across genetically diverse melanoma populations and combined […]
- by Partipilo, M., Favoino, G., Puiggene, O., Rocha, C., Meiners, C., Gurdo, N., Donati, S., Volke, D. C., Nikel, P. I.Redox homeostasis is central to microbial physiology and stress adaptation, yet the functional roles of transhydrogenases remain poorly understood beyond a few organisms. In this study, we systematically explored how Pseudomonas putida, a model soil bacterium, integrates two distinct transhydrogenases (membrane-bound PntAB and soluble SthA) into a flexible and reversible redox-balancing system that supports metabolic robustness across diverse metabolic regimes. While single deletions of either enzyme had minimal impact on the overall fitness, the double {Delta}pntAB {Delta}sthA mutant exhibited growth […]
- by Berners-Lee, R., Smith, V. A.Bayesian networks provide a powerful framework for learning dependencies from data, and they are widely used to probe structure in biological systems. Biological systems are governed by complex networks of interactions, and uncovering these interactions and comparing them across conditions is central to understanding biological mechanisms. However, when comparing Bayesian networks, it can be difficult to determine whether observed differences are substantial enough to reflect genuine differences in the underlying systems generating the data. Here, we address this by developing […]
- by Lee, J., Kawasaki, T., Tabata, L., Chen, J., Uchiyama, T., Yamazaki, S., Umezawa, A., Akutsu, H.Human bone marrow generates blood cells but critically lacks the thymic environment required for T cell development. Developing an integrated in vitro platform that reconstitutes both functions simultaneously remains a major challenge in regenerative and immune medicine. We asked whether a synthetic marrow could be engineered to provide both capacities. Using human induced pluripotent stem cells, we created self-organizing bone marrow organoids (iBMOs) that faithfully reproduced native stromal and vascular structures and, remarkably, supported robust thymus-like T cell differentiation. iBMOs […]
- by Breau, K. A., Dunahey, E. G., Fosnocht, H. V., Magness, S. T., Elston, T. C.The Planar Cell Polarity (PCP) complex regulates many diverse phenotypes. While recent literature has elucidated key mechanisms underlying PCP, a mechanistic understanding of how these components function as a system to drive polarity is lacking. Here, we develop a comprehensive multicellular mathematical model centered around key PCP phosphorylation events, directly simulating the protein interactions that drive PCP. Our model confirms key PCP phenotypes, including robust single-junction asymmetry and multicellular polarity alignment in the absence of extrinsic signals. It predicts unique […]
- by Liu, Z., Dong, W., Gu, L., Ge, R., Zeng, X., Deng, J., Zhang, H., Ye, Z.Single-cell proteomics (SCP) enables direct measurement of protein heterogeneity but remains constrained by throughput and limited applicability to primary tissues. Here, we present an integrated workflow developed to address both challenges. We engineered SPRINT, an AI-powered bioprinting platform that prepares more than 10,000 single cells per day, over tenfold faster than existing systems, while maintaining stability and enabling identification of over 6,000 proteins from individual HeLa cells. To expand analytical capacity, we further designed a dual-spray tandem direct injection (TDI) […]
- by Mozdzanowski, P., Tarbier, M., S. Jeuken, G.Cell cycle progression is a dominant source of variation in single-cell RNA-sequencing (scRNA-seq) data, often obscuring informative signals of cell identity and state. Current computational methods to address this problem either discard biologically relevant information through regression or require unspliced transcript data. This limits their applicability to most existing datasets. Here, we present CycleVI, a deep generative model that disentangles cell cycle variation from all other transcriptional signals in static scRNA-seq data by learning a partitioned latent representation with a […]
- by Focil, C., Dalldorf, C., Martinez, D., Zepeda, A., Zuniga, C.Bacteria from the Pseudomonas genus are omnipresent in air, soil, and water. They have been widely studied for their broad metabolic versatility and presence in the epidemiological chain, bioproduction, bioremediation, and disease processes. Each year, more genomic sequences are reported in databases and repositories. However, the relationship between the genomic variability of Pseudomonas strains and the diversity in their metabolic capabilities under environmentally relevant phenotypes remains unknown. Additionally, predictive tools for the analysis of different strains in a systematic framework […]
- by Nguyen, P., Mousavi Karimi, Z., Layer, A., Wan, M., Su, H., Hasty, J., Hao, N.Yeast replicative lifespan is a crucial part of aging research, yet its quantification remains labor-intensive and time-consuming, particularly when using time-lapse imaging and microfluidics. Manual counting methods for cell division events are prone to bias and inefficiency, while existing automated approaches often require extensive annotated datasets. These limitations hinder the adaptability of such tools across different microfluidic setups. To address these challenges, we propose a versatile image analysis approach that accurately detects yeast cell division events. To reduce the burden […]
- by Hage, J., Koestler, D., Christensen, B.Biological measurements often result in proportional data, which derive from underlying biological counts. Proportion data are lacking a dimension of information as compared to counts, restricting available analysis methods and separating the data from the biology. We demonstrate a mathematical technique that estimates absolute counts corresponding to proportion data, which we refer to as Mahalanobis Count Inference (MCI). MCI uses information from a population-representative multivariate normal (MVN) distribution of component counts and ultimately outputs an estimated count and a confidence […]
- by Araujo, N. d. M. F., Santos, M. F., Pereira, R. F. A., Brum, R. C., Pinheiro, F. R., Silveira, M. C., Dure, F. M., Muller, B. d. L. A., de Souza, A. A. A., Souza, A. B. S. R., de Souza, A. F., Carvalho-Assef, A. P., Moreira, A. d. S., de Melo, A. C. M. A., dos Santos, M. T., Cortes, A. M. d. A., Penna, B., Chagas, T., Aguiar-Alves, F., Silva, F. A. B. d.Antimicrobial resistance represents an escalating global healthcare threat, complicating treatment and increasing both morbidity and mortality. Deep learning offers promising solutions, particularly for bacterial profiling using omics data. For instance, classifying bacterial strains as resistant or susceptible to antibiotics depends on identifying genomic signatures associated with resistance mechanisms. This study introduces DeepMDC, a deep learning architecture for bacterial profiling that utilizes whole-genome data as input. In genomics, obtaining precise labels for each gene or mutation is costly and often ambiguous; […]
- by Silfvergren, O., Rigal, S., Schimek, K., Simonsson, C., Kanebratt, K. P., Forschler, F., Yesildag, B., Marx, U., Vilen, L., Gennemark, P., Cedersund, G.Drug discovery utilises cell- and animal-systems to predict human responses. These different systems provide different drug discovery insights. However, there is currently no methodology to integrate all these insights into single quantitative framework. This study presents a new methodology — M4 drug discovery — which achieves such an integration. The method integrates: a) Multi-timescale data (short- to long-term responses); b) Multi-level data (intracellular to whole-organism responses); c) Mechanistic models (describing mechanistic underpinning); and d) Multi-species data (for example rodent and […]
- by George, A. V., Wingreen, N. S., Reddy, G.Single-cell experiments in yeast reveal two distinct heritable phenotypes–arresters and recoverers–when a clonal population experiences a negative shift in its growth environment. Recoverers exhibit a variable yet finite lag before resuming growth in the new environment, whereas arresters remain in a non-growing, arrested state until more favorable conditions return. Although the diversification of individual cells into arresters and recoverers is a robust phenomenon, it remains unclear whether this coexistence constitutes an evolutionarily stable strategy. Here, we demonstrate that a heterogeneous […]
- by Jiang, B., Wang, S., Xie, J., Kim, H., Tukker, A. M., Wang, J., Bowman, A. B., Yuan, C., Baloni, P.Understanding how distinct neuronal subtypes contribute to Alzheimers disease (AD) pathology remains a major challenge. Patient-derived induced pluripotent stem cell (iPSC) studies have shown neuronal subtype-specific molecular and pathological signatures, yet the underlying metabolic shifts driving this selective vulnerability are not completely understood. Here we present iNeuron-GEM, the first manually curated, genome-scale metabolic network of human neurons that integrates transcriptomic and metabolic knowledge to resolve subtype-specific metabolic states. By coupling iNeuron-GEM with single nucleus RNA sequencing data from post-mortem human […]
- by Liu, Y., Reisbitzer, A., Doresic, D., Hasenauer, J., Krauss, S., Tchumatchenko, T.RNA-binding proteins (RBP) are important regulators of RNA metabolism. In neurode-generative disorders such as Huntingtons Disease (HD), disrupted RBP-RNA interactions contribute to neuronal dysfunction. One such RBP, Midline 1 (MID1), has been shown to aberrantly associate with mutant huntingtin (Htt) RNA, enhancing its translation, yet the mechanism driving this effect remains unknown. Here, we develop a computational model to understand the role of MID1. Based on previously published data, our model predicts that MID1 increases the stability of the Htt […]
- by Emison, B., Lynn, C. W., Mugler, A., Ambrosio, F., Dixit, P. D.Aging is marked by the progressive loss of cellular function, yet the organizing principles underlying this decline remain unclear. Although molecular fingerprints of aging are diverse, many converge on disruption of the interrelated and overlapping communication networks that coordinate molecular activity. Here, we apply information theory to quantify age-related corruption in gene regulation by modeling regulatory interactions between transcription factors (TFs) and their target genes (TGs) as a multi-input multi-output communication channel. Using an analytically tractable probabilistic model and single-cell […]
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