- by Botticelli, M., Metzcar, J., Macklin, P., Keshavanarayana, P., Spill, F.The extracellular matrix (ECM) is a complex network of fibrous proteins and other macromolecules that provides crucial mechanical and biochemical cues that regulate cancer cell invasion and tumour progression. Its fibre organisation plays a critical role in guiding directional migration through contact guidance, in particular in cancer cell invasion. Mathematical modelling offers a powerful approach to explore how the ECM architecture regulates this process. Here, we present a hybrid computational model, implemented in PhysiCell, that integrates a discrete agent-based cell […]
- by Azevedo, M. M., Arsh, A. M., Jagadeesan, R., Ribeiro, A. S.Rifampicin, by hampering transcription, perturbs bacteria even at non-lethal concentrations. In response, Escherichia coli adapts its phenotype to minimize mortality, which is followed by beneficial mutations. Most genome-wide transcriptional regulatory mechanisms controlling the adaptations remain unidentified. We studied the genome-wide, time-resolved, transcriptional program of susceptible E. coli cells under non-lethal rifampicin stress. Dynamically, the transcriptome widely diverged from the control, but later partially realigned. The mechanisms were changes in RNAP and Gyrase levels, promoter sequences, transcription factor network, intergenic distance, […]
- by Herzog, C. M. S., Vavourakis, C. D., Theeuwes, B., Redl, E., Watschinger, C., Knoll, G., Hagen, M., Haider, A., Platzer, H.-P., Kumar, U., Zollner-Kiechl, S., Cavinato, M., Jansen-Duerr, P., Schmuth, M., Lammer, M., Knoflach, M., Lindner, V., Wimmer, A., Widschwendter, P., Greitemeyer, T., Sturm, S., Weinberger, B., Moschen, A., Hoeller, A., Schobersberger, W., Widschwendter, M.While intermittent fasting (IF) promotes longevity in animal models, its systemic effects in humans remain poorly understood. Here, we present a six-month longitudinal IF intervention in 114 women (BMI 25-35) with deep clinical, molecular, and microbiome profiling across >3,400 biospecimens from six tissues. Analyses spanning >2,200 multi-omic features and 11,000 microbial function predictions demonstrate coordinated clinical benefits, including improvements in body composition and cardiorespiratory fitness, and reveal coordinated molecular responses across tissues. Iron metabolism emerged as a central axis: transferrin […]
- by Nevo, N., Klein, Y., Alpert, A., Grau, A., Melamed, D., Milman, N., Few-Cooper, T. J., Shen-Orr, S. S.B-cell aplasia impairs the immune response to cancer, infections and vaccines. However, no B-cell accelerator is available in the clinic to date. Here, we utilized a system biology approach to discover drivers for B lymphopoiesis in the human Bone Marrow (BM). By integrating scRNA-seq data analyses with intercellular communication mapping, we created an initial list of putative drivers emanating from the BM microenvironment and interacting with nascent B lymphocytes. We further intersected our findings with clinical B-cell depletion studies and […]
- by Dragoi, C.-M.Progression through the eukaryotic cell cycle is governed by a complex biochemical network controlling the activation of cyclin-dependent kinases. Dynamically, the cell cycle control network can be viewed as a multi-stable system, in which nonlinear feedback loops generate multiple stable attractors, corresponding to distinct cell cycle phases (G1, S, G2, M). Transitions between these states are typically irreversible, ensuring ordered phase progression. However, recent studies of endocycles – variants in which subsets of phases are abrogated – have prompted the […]
- by Herzog, C. M. S., Vavourakis, C. D., Theeuwes, B., Redl, E., Watschinger, C., Knoll, G., Hagen, M., Haider, A., Platzer, H.-P., Kumar, U., Zollner-Kiechl, S., Knoflach, M., Gibitz-Eisath, N., Oehler, S., Lindner, V., Wimmer, A., Greitemeyer, T., Widschwendter, P., Sturm, S., Weinberger, B., Moschen, A., Hoeller, A., Schobersberger, W., Haring, C., Widschwendter, M.Smoking is one of the single most important preventable risk factors for cancer and other adverse health outcomes [1,2]. Smoking cessation represents a key public health intervention with the potential to reduce its negative health outcomes [2-4]. While epidemiological, cross-sectional, and individual longitudinal 'omic' or biomarker studies have evaluated the impact of smoking cessation, no study to date has systematically profiled molecular and clinical changes in several organ systems or tissues longitudinally over the course of smoking cessation that could […]
- by Oatman, H. R., Lad, B. C., Toettcher, J. E.In cell biology, optical techniques are increasingly used to measure cells' internal states (biosensors) and to stimulate cellular responses (optogenetics). Yet the design of all-optical experiments is often manual: a pre-determined stimulus pattern is applied to cells, biosensors are measured over time, and the resulting data is processed off-line. With the advent of machine learning for segmentation and tracking, it becomes possible to envision closed-loop experiments where real-time information about cells' positions and states are used to dynamically determine optogenetic […]
- by Jacobs, S., Vazquez, F., Frolov, N., Gelens, L.Temperature shapes all biological processes, particularly during the early development of ectothermic organisms. A widely used framework for describing temperature dependence is the Arrhenius equation, which predicts an exponential increase in rates with temperature. However, biological rates often deviate from this prediction when measured across broader temperature ranges. While negative apparent activation energies are often attributed to protein denaturation, this cannot explain similar behavior observed at temperatures where enzymes remain stable. These broader scaling patterns remain mechanistically unexplained. Here we […]
- by Gaidatzis, D., Graf-Landua, M., Methot, S., Woelk, M., Brancati, G., Hauser, Y. P., Meeuse, M., Nahar, S., Braun, K., van der Does, M., Aluri, S., Kohler, H., Smallwood, S., Grosshans, H.Genetic oscillators drive precisely timed gene expression, crucial for development and physiology. Using the C. elegans molting clock as a model, we investigate how oscillators can schedule the orderly expression of thousands of genes. Single cell RNA sequencing reveals a broad peak phase dispersion in individual issues, mirrored by rhythmic changes in chromatin accessibility at thousands of regulatory elements identified by time-resolved ATAC-seq. We develop a linear model to predict chromatin dynamics based on the binding of >200 transcription factors. […]
- by Komkova, D., Simon, M., Wolf, J., Steuer, R.Genome-scale metabolic models (GEMs) offer unprecedented possibilities to study human metabolism, including alterations in cancers. Yet, analyses of GEMs still entail several disadvantages. In particular, constraint-based methods, such as flux balance analysis, are typically restricted to analyse steady-state flux distributions. In contrast, kinetic models based on ordinary differential equations allow assessment of regulatory properties and dynamics. Building kinetic models, however, is still hampered by the lack of knowledge about kinetic parameters and is typically focused on individual pathways. Here, we […]
- Extracellular Matrix-Guided Tumor Stratification and Network Models Reveal Clinical Molecular Gradesby Dansik, A., Sarica, S., Ozturk, E., Tuncbag, N.The extracellular matrix (ECM) critically shapes tumor fate and treatment outcome, serving as a potent prognostic factor. Yet, its compositional heterogeneity across tumors makes it difficult to assess its impact on tumor dynamics. To address this, we introduce an ECM-guided patient stratification pipeline through integration of multi-omic data in lung cancer patients. We obtained four patient groups, representing ECM-grades that showed distinct clinical features, mutation profiles, and cellular heterogeneity. Investigation of patient-specific ECM-induced intracellular signaling via network modeling revealed strong […]
- by Mudibo, E. O., Sande, C., Ngari, M. M., Jenkins, B., Singa, B. O., Lancioni, C. L., Diallo, A. H., Mbale, E., Mupere, E., John, M., Bamouni, R. M., Prendergast, A. J., McGrath, C. J., Koulman, A., Bandsma, R. H. J., Tickell, K. D., Walson, J. L., Berkley, J. A., Gonzales, G. B., Njunge, J. M.Childhood illnesses including pneumonia, diarrhoea and malaria are leading causes of hospitalisation and mortality in resource-limited settings. However, we lack understanding of whether systemic responses to such diverse clinical syndromes are shared or specific, how they are impacted by malnutrition and how they differ from well children. We performed multi-omic profiling of plasma proteins, and serum metabolites and lipids in acutely ill hospitalised and well children in sub-Saharan Africa and South Asia. Using network-based clustering and mixed-effects modelling, we identified […]
- by Ji, J., Ye, M., Choi, C. S., Kim, C.-H., Son, A., Kim, H.Neurokine Sam2 deficiency is associated with behavioral abnormalities including heightened anxiety and fear responses across evolutionarily conserved model organisms. Here, we employed an integrated proteomics and metabolomics approach using liquid chromatography-mass spectrometry (LC-MS) to elucidate molecular signatures associated with autism spectrum disorder (ASD) in Sam2 knockout mice. Comparative analysis of blood plasma samples from Sam2 knockout and wild-type mice revealed substantial alterations in both proteomic and metabolomic profiles. Proteomic analysis identified 68 differentially expressed proteins (comprising 102 peptides), with notable […]
- by Allard, J.Efforts to develop quantitative models must face a trade-off between interpretability and quantitative accuracy, which often disfavores interpretability. Here we adopt an operational definition of interpretability, specifically that a model is described by an arrow diagram wherein each arrow corresponds to a positive effect or negative effect of one component upon a process, and fewer arrows is more interpretable than more arrows. We then develop a method to add flexibility — and thus accuracy in fitting data — to mathematical […]
- by van Ede, J. M., Paez-Watson, T., van Loosdrecht, M. C. M., Pabst, M.Microbial communities often face environmental fluctuations that occur on timescales much shorter than their growth rate or proteome turnover. In such cases, cellular responses are likely driven by rapid changes in metabolite pools, particularly energy nucleotides including ATP, ADP, and AMP. However, robust methods to quantify these metabolites in biofilm-forming microbial communities are lacking. Here, we developed and systematically evaluated a metabolomics workflow for a granular biofilm enrichment, which performs Enhanced Biological Phosphorous Removal (EBPR). We combined fast quenching in […]
- by Hishida, A., Himeoka, Y., Furusawa, C.Cells robustly maintain metabolic function despite environmental fluctuations affecting reaction kinetics, yet kinetic models often exhibit fragility. We investigated this discrepancy by examining the effects of temperature changes on a kinetic model of Escherichia coli central metabolism. A gradual temperature decrease caused an abrupt transition to a state with sharply reduced ATP production efficiency, triggered by an elevated ATP/ADP ratio creating a glycolysis bottleneck. Introducing a rapid ATP-ADP exchange reaction prevented this ATP/ADP ratio surge and sustained high ATP production […]
- by Herzog, C. M. S., Vavourakis, C. D., Redl, E., Hagen, M., Knoll, G., Watschinger, C., Kumar, U., Theeuwes, B., Gasser, J., Zollner-Kiechl, S., Reihs, R., Mueller, H., Cavinato, M., Sturm, S., Moschen, A., Weinberger, B., Greitemeyer, T., Schmuth, M., Moosbrugger-Martinz, V., Trafoier, T., Lindner, V., Wimmer, A., Widschwendter, P., Platzer, H.-P., Hoeller, A., Knoflach, M., Schobersberger, W., Widschwendter, M.Extending human healthspan requires understanding how lifestyle interventions impact molecular systems across tissues and time. Here, we present the TirolGESUND Lifestyle Atlas (ClinicalTrials.gov: NCT05678426), a longitudinal, multi-modal resource profiling 156 healthy women (aged 30-60 years) undergoing 6-month intermittent fasting (n=114) or smoking cessation (n=42) interventions. Participants were sampled up to four times across seven tissues and fluids, generating >3,450 biospecimens with harmonised DNA methylation, metabolomics, microbiome, and immune profiling, alongside skin histology, barrier measurements, and rich clinical metadata. We demonstrate […]
- by Hughes, S., Hamilton, T., Kolokotrones, T., Deeds, E. J.Manifold learning builds on the "manifold hypothesis," which posits that data in high-dimensional datasets are drawn from lower-dimensional manifolds. Current tools generate global embeddings of data, rather than the local maps used to define manifolds mathematically. These tools also cannot assess whether the manifold hypothesis holds true for a dataset. Here, we describe DeepAtlas, an algorithm that generates lower-dimensional representations of the datas local neighborhoods, then trains deep neural networks that map between these local embeddings and the original data. […]
- by Sedighi, S., Vafaee, K., Hardy, W. R., Kasmaeifar, V., Lin, Z.-Y., Kalloush, R., Kitaygorodsky, J., Seale, B., Hu, Q., Hasegan, M., Gingras, A.-C.Proximity-dependent biotinylation has become a powerful approach for mapping protein interactions and subcellular organization in living cells. Although a growing number of engineered biotin ligases have been introduced, their performance has not been systematically evaluated across diverse cellular contexts. Here, we benchmark ten proximity ligases spanning three bacterial lineages using standardized proteomic workflows across multiple labeling durations, subcellular compartments, and two human cell types. While all enzymes efficiently detect proximal associations, they differ in labeling kinetics, background activity, and spatial […]
- by Daher, A., Eftimie, R., Trucu, D.All physiological processes fundamentally rely on continuous cellular cross-talk to maintain organization and ensure proper function. Among the various modes of cellular communication, ligand-mediated chemical signaling, in which a ligand is secreted by one cell, diffuses through the extracellular environment, and binds to a receptor on another (or the same) cell to elicit a downstream response, is arguably the most ubiquitous and foundational. Given its importance, numerous mathematical models have been developed to describe this reaction-diffusion mechanism, capturing ligand secretion, […]
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