- by Pinotti, F., Theze, J., Bailly, X., Fournie, G.Mathematical models are essential for understanding and forecasting infectious disease dynamics, yet parameter inference remains challenging when likelihoods are intractable or unknown. Simulation-based inference (SBI) offers a powerful alternative by leveraging model simulations in place of explicit likelihood evaluations. However, traditional SBI approaches such as Approximate Bayesian Computation often rely on ad-hoc summary statistics and suffer from reduced efficiency in high-dimensional settings. Recent advances in SBI address these limitations by employing flexible statistical or machine-learning surrogates to approximate likelihoods or […]
- by Duncan, A., Djakite, T., Echalard, A., Labat, B.We report on the elaboration of a biocompatible therapeutic model system (TMS) capable of detecting the state of chronicity of a wound and responding to the latter by releasing the appropriate healing agent (antibiotic but not only). Different formulations of PVA-borate hydrogel systems containing methylene blue (MB) and levofloxacin (L) drug antibiotic were prepared. We were able to demonstrate sensitivity to microenvironmental factors such as pH, and high levels of ROS – a major biomarker of a chronic inflammation state. […]
- by Henning, P., Schultz, J., Baltrusch, S., Uhrmacher, A. M.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 […]
- by Meena, R. K., Fan, Y., R, S., Pandey, A. J., Kannan, A., Subramanian, Y., Subramanian, Y., George, J. T., Jolly, M. K.Phenotypic plasticity plays a key role in cancer progression and metastasis, enabling cancer cells to adapt and evolve, but precisely how distinct axes governing phenotypic plasticity interact to shape tumour progression and patient outcomes remains unclear. We investigated five major interconnected axes of plasticity in ER-positive (ER+) breast cancer: Metabolic Reprogramming, Epithelial-to-Mesenchymal Plasticity (EMP), Luminal-Basal (Lineage) Switching, Stemness, and Drug-resistance using network dynamics simulations, integrative bulk and single-cell transcriptomic analyses and patient survival analyses. We show that these axes are […]
- by Morozova, O., Oravcova, I., Zabaikina, I., Bokes, P., Singh, A.Gene expression noise can be modulated by protein sequestration, a mechanism we investigate through a stochastic modeling framework. We examine how the distribution of free (non-sequestered) protein depends on sequestration cooperativity (monomers, dimers, multimers) and on the timescale separation between sequestration and protein turnover. For non-cooperative sequestration, faster kinetics drive the distribution from a high-noise to a lower-noise gamma form, while the right-tail remains governed by the high-noise limit — revealing a non-commutativity between tail asymptotics and fast sequestration. For […]
- by Zhang, T., Liu, L., Wang, Z., Zhao, Z., Guo, Y., Cao, H., Yang, Z.Climate change and recent heatwaves have elevated temperature to the level of nutrients in driving CHABs. In this new dimension of CHABs ecology, it is important to understand the thermal boundaries of each blooming species. One well-known example is the temporal and thermal partitioning between filamentous, nitrogen-fixing taxa such as Dolichospermum spp. and Pseudanabaena spp., which dominate in spring, and colonial/coccoid Microcystis aeruginosa, which predominates in summer and autumn. Here we show that Dolichospermum sp. and M. aeruginosa display converse […]
- by Kuznetsova, K. G., Vasicek, J., Skiadopoulou, D., Unger, L., Nethala, R. A., Wierer, M., Ghila, L., Johansson, S., Njoelstad, P. R., Chera, S., Johansson, B. B., Manning, A., Vaudel, M.We investigated the proteomic consequences of MODY-associated mutations in the transcription factors HNF1A and HNF1B using two cell line models. Quantitative label-free mass spectrometry, employing both data-dependent and data-independent acquisition methods, revealed consistent suppression of energy metabolism and interferon signaling pathways. Pathway and protein interaction analyses confirmed these findings. In cells with the HNF1A frameshift mutation, several predicted transcriptional targets, including A1CF, were significantly downregulated. These results reinforce the link between HNF1A/HNF1B function and mitochondrial activity as well as innate […]
- by Efimov, E., Fedotov, V., Malaev, L., Khrameeva, E. E., Kriukov, D.Somatic mutations accumulate with age and can cause cell death, but their quantitative contribution to limiting human lifespan remains unclear. We developed an incremental modeling framework that progressively incorporates factors contributing to aging into a model of population survival dynamics, which we used to estimate lifespan limits if all aging hallmarks were eliminated except somatic mutations. Our analysis reveals fundamental asymmetry across organs: post-mitotic cells such as neurons and cardiomyocytes act as critical longevity bottlenecks, with somatic mutations reducing median […]
- by Sharma, B. D., Thusoo, E., Stevenson, D. M., Amador-Noguez, D., Lynd, L., Olson, D. G.Microbial strains engineered for high-titer ethanol production achieve lower maximum titers compared to native producers such as Zymomonas mobilis. A central unresolved question is why fermentation ceases before substrate has been exhausted by these strains. Here, we integrate metabolite profiling with thermodynamic analysis to examine this phenomenon in engineered strains of Escherichia coli and Thermoanaerobacterium saccharolyticum and compare them to Z. mobilis, a native ethanol producer. In the engineered strains, fermentation cessation coincided with marked pyruvate accumulation, due to a […]
- by Fournie, C., Ventre, E., Herbach, U., Baradat, A., Gandrillon, O., Crauste, F.Cellular differentiation is the biological process that leads a cell to opt for a particular cellular identity. Recently, single-cell RNA-sequencing has enabled the simultaneous measurement of gene expression levels at specific times for a large number of individual cells and a large number of genes. Repeating such measurements at different time points gives then access to the temporal variation, or transport, of a distribution on a gene expression space. The whole temporal trajectory of distributions thus characterizes the differentiation process […]
- by Lopes-Ramos, C. M., Burkholz, R., Ben Guebila, M., Fanfani, V., Saha, E., Shutta, K. H., Glass, K., Quackenbush, J., DeMeo, D. L.Sex differences in the incidence rates of many cancer types are well-documented. While differences in lifestyle, environmental exposures, and hormone levels can influence disease risk and incidence, there is limited understanding of how cancer driver genes are differentially regulated between males and females in normal tissues, and how these differences may contribute to the observed sex differences in cancer epidemiology. We studied 8,279 gene regulatory networks across 29 non-cancerous tissues in the GTEx dataset, referred here as normal tissues. Using […]
- by Smith, E. N., Fargier, N., Pedro, J., Heinemann, M.Metabolic modelling, particularly through genome-scale stoichiometric models and flux balance analysis (FBA), has greatly advanced our understanding of metabolism. Yet, there is a continued quest to further improve the predictive capabilities of FBA. While thermodynamic constraints can allow for improved predictions, their addition to metabolic models has so far required cumbersome manual curation. To circumvent manual curation, we introduce Thermo-Flux, a semi-automated Python package, which converts stoichiometric metabolic network models into comprehensive thermodynamic-stoichiometric models for improved predictions. Thermo-Flux enables (i) […]
- by Majumder, M. M., Williams, E. C., Lindvall, M. O., Hamm, G., Jarnuczak, A., Setyo, L., Di Poto, C., Azim, A., Chen, J., Iannetta, A. A., Touza, J. L., Allman, E., Miele, E., Lindren, J., Sand, E., Anderberg, R. H., Oag, S., Franzen, L., Costyson, A., Keith, B. P., Tan, J., Jones, S., Fitzpatrick, P., Johansson, J., Prasse, A., Corkhill, D., Borde, A., Hess, S., Terrilon, S., Ostridge, K., Stahl, P., Aberg, P., Hornberg, J., Mohorianu, I., Ollerstam, A.Comprehensive understanding and early detection of drug-induced lung toxicity remain critical challenges in respiratory drug development. In this study, we propose a multi-omics framework that integrates spatial and temporal tissue-specific transcriptomic signatures with proteomics from minimally invasive biofluids to understand mechanisms and identify safety biomarkers associated with lung toxicity. Using this framework, we identified a panel of candidate biomarkers in bronchoalveolar lavage fluid and plasma, including LCN2/NGAL, RETNLA, SP-D, SPP1/osteopontin, and MMP7, that correlate with histopathological features (e.g., inflammation and […]
- by Haack, F., Burrage, K., Uhrmacher, A. M.Despite its central role in development, cell homeostasis, and cancer, the mechanisms that induce and transduce Wnt signaling, particularly the role and impact of receptor internalization, have been under discussion for almost two decades. To integrate seemingly contradictory experimental observations into a coherent explanatory framework, we developed a mechanistic computational model that dissects the spatiotemporal regulation of canonical Wnt signaling. For this, a newly optimized multi-level rule-based modeling and simulation approach is employed to describe and simulate the compartmental distribution […]
- by Mujchariyakul, W., Hachani, A., Stinear, T. P., Le Cao, K.-A., Howden, B. P., Walsh, C. J., Guerillot, R.The increasing availability of microbial multi-omics datasets has created new opportunities to explore complex biological systems. However, exploration remains limited by the lack of accessible, reproducible workflows that integrate multiple omics layers and deliver easily interpretable visualisations of functional and pathway-level insights. Here, we present an R-based workflow for integrated analysis and network-based pathway visualisation of microbial multi-omic data. The workflow enables microbiologists to analyse transcriptomic, proteomic, and metabolomic datasets either individually or in combination, apply univariate and multivariate approaches […]
- by Huckvale, E. D., Thompson, P. T., Flight, R. M., Moseley, H. N. B.Metabolism-level interpretation of metabolomics datasets requires aggregation analyses across metabolites. One highly-used aggregation analysis is pathway enrichment analysis (PEA), which involves detecting pathways enriched with metabolites that are differential between experimental groups. Annotating metabolites with pathway associations is a prerequisite for PEA. While several knowledgebases define pathways and include metabolite-pathway annotations, these definitions are often partially or even grossly incomplete due to limitations in current metabolic knowledge and its curation, which greatly limits the effectiveness of PEA. In this work, […]
- by Singh, A., Baek, O., Schaltz-Buchholzer, F., Campbell, J., West, N., Elgamoudi, B., Campbell, A., Ca, E., Tebbutt, S., Shannon, C., Aaby, P., Kollmann, T., Benn, C., Amenyogbe, N.Tuberculosis (TB) remains the leading cause of infectious death. The Bacille Calmette-Guerin (BCG) vaccine has been the only licensed vaccine available for TB prevention. Despite BCG being administered intradermally for over a century to >100 million individuals annually, the molecular events in the skin following BCG administration have not been investigated; as a result, measurable correlates of protection that could predict vaccine effectiveness already early after vaccination are lacking. Here we show that BCG immediately (within one day after vaccination) […]
- by Corbin-Agusti, P., Arevalo-Lalanne, A., Alvarez, P., Ramon, D., Pereto, J., Tortajada, M.Escherichia coli Nissle 1917 (EcN) is a well-characterized Gram-negative probiotic distinguished by its unique, strain-specific physiology. Genome-scale metabolic models (GEMs) are powerful tools for elucidating metabolic traits and predicting genotype-phenotype relationships. Although several EcN GEMs have been published, none have explicitly represented its probiotic physiology. Here, we present a manually curated GEM of EcN that, for the first time, incorporates the energetic costs associated with its cryptic plasmids. Inclusion of a plasmid-specific module improved biomass yield predictions and overall model […]
- by Corbin-Agusti, P., Arevalo-Lalanne, A., Alvarez, P., Ramon, D., Pereto, J., Tortajada, M.Escherichia coli Nissle 1917 (EcN) is a well-characterized Gram-negative probiotic distinguished by its unique, strain-specific physiology. Genome-scale metabolic models (GEMs) are powerful tools for elucidating metabolic traits and predicting genotype-phenotype relationships. Although several EcN GEMs have been published, none have explicitly represented its probiotic physiology. Here, we present a manually curated GEM of EcN that, for the first time, incorporates the energetic costs associated with its cryptic plasmids. Inclusion of a plasmid-specific module improved biomass yield predictions and overall model […]
- by Nikmaneshi, M., Padera, T. P., Munn, L. L.Antigen-based tumor vaccines rely on adjuvants to stimulate local inflammation, recruit antigen-presenting cells (APCs), and enhance immune activation. However, the complex interplay between antigen transport, lymphatic drainage, and immune cell dynamics across organs remains poorly understood, limiting the rational design of vaccination strategies. Here, we present a multiscale compartmental Physiologically Based Pharmacokinetic (PBPK) model of antigen vaccination that integrates systemic circulation, lymphatic connectivity, and immune cell activation at the whole-body level. The model incorporates arterial, venous, and lymphatic flows, organ-specific […]
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