- by Qasim, R., BOUCHNITA, A.Alterations in epidermal growth factor receptor (EGFR) dynamics can influence tumor initiation by changing receptor abundance, ligand-dependent activation, and downstream proliferative signaling. Mathematically linking these receptor-scale processes to population-level tumor growth remains challenging because they couple molecular, cellular, and tissue-scale dynamics. Here, we develop multiscale models that explicitly captures receptor-ligand dynamics. We analyze the dynamics of a refined version of a 3D stochastic multicellular model with explicit EGFR-EGF interactions to derive a receptor-structured continuum model in which cells are organized […]
- by Charan, K., Kar, S.In mammalian cells, under normal circumstances, the p53 protein exhibits oscillatory dynamics in response to DNA damage and maintains the cells in a cell-cycle-arrested state. Intriguingly, some cells can escape this cell-cycle-arrested state even after prolonged DNA damage, and often undergo mitotic catastrophe. In this context, the precise role of p53 dynamics and its complex interplay with cell-cycle regulation remain poorly understood. Herein, by constructing a comprehensive network model, we have identified crucial crosstalk regulations between the p53 protein and […]
- by Shankar, T., Gao, Y., Erebholo, Z., Nakama, N., Kim, K., Williamson, I., Snyder, N., Kransdorf, E., DeBerardinis, R., Taegtmeyer, H., Faubert, B., Karlstaedt, A.BackgroundCardiovascular disease and cancer are the two leading causes of morbidity and mortality worldwide. Metabolic dysregulation of cancer cells extends beyond the tumor microenvironment and increases the risk for cardiovascular diseases. One common somatic mutation in cancer cells affects isocitrate dehydrogenase (IDH) 1 and 2, which catalyzes the oxidative decarboxylation of isocitrate to alpha-ketoglutarate in the cytosol and mitochondria, respectively. IDH1 and 2 mutations cause the production of the oncometabolite D-2-hydroxyglutarate (D2-HG), which allosterically inhibits -ketoglutarate dehydrogenase (-KGDH) and is […]
- by Weise, D. O., Gupta, K., Griffin, T. J., Jagtap, P. D., Mroz, M. M., Wagner, R., Macaluso, J. D., Mehta, S., Maier, L. A., Li, L., Vestal, B. E., Bhargava, M.We compared traditional data-dependent acquisition mass spectrometry (DDA-MS) with the increasingly adopted data-independent acquisition (DIA-MS) to evaluate their relative utility for large-scale quantitative biofluid proteomics of lung compartments, specifically paired bronchoalveolar lavage (BAL) cells and bronchoalveolar lavage fluid (BALF). Using beryllium-related granulomatous lung disease as a focused model, we analyzed BALF and BAL cells from beryllium-sensitized (BeS) individuals using both acquisition strategies to assess proteome depth, quantitative completeness, and analytical robustness. In BAL cells, 5,640 proteins were identified by DDA-MS […]
- by Galon, C. M., Charlebois, D. A.Fungi contribute substantially to the global antimicrobial resistance crisis. Tolerance is a novel form of antifungal resistance in which fungal pathogens emerge, grow slowly, and survive antifungal drug treatment. We quantitatively model the population and evolutionary dynamics of a multidrug resistant pathogen Candidozyma auris (formerly Candida auris) infecting an invertebrate host (Galleria mellonella) with an innate immune system. We find that the establishment, dominance, and co-existence of tolerant and resistant subpopulations depend on infection load, drug-treatment, and innate host immunity. […]
- by Varley, T. F., Pai, V., Levin, M., Bongard, J.The ability of self-organizing systems to display emergent, adaptive capabilities is a fundamental feature of biological life. Understanding the mechanisms by which cells co-ordinate at the micro-scale to produce macro-scale structures and behaviors is a fundamental problem in developmental biology. Moreover, it is an important goal of biomedicine to identify triggers that re-wire the physiological patterns of information flow and control signals. Here, we use a recently developed, synthetic biology platform known as basal Xenobots to explore how patterns of […]
- by Li, S., Wang, Y., Jiang, Q., Grima, R., Cao, Z.Single-cell multiomic technologies can now quantify complementary RNA species within the same cell, creating an opportunity to move beyond descriptive clustering toward mechanistically interpretable cell states. Yet most current methods depend on heuristic integration steps and become computationally burdensome at scale, limiting their ability to robustly detect subtle kinetic differences across heterogeneous populations. Here we introduce PRIME, a scalable framework for mechanistic cell-state discovery from multimodal single-cell count data. PRIME embeds multimodal measurements in a probability generating function (PGF) space, […]
- by Wang, H.-Y., Oshiro, B. T., Rahseparian, N., Crabtree, L., Robinson, J. F., Gaw, S., Gheorghe, C.Gastroschisis is a congenital abdominal wall defect in which fetal intestines herniate into the amniotic cavity. Despite 97% surgical repair success rate, 40% of affected infants require hospital readmission due to gastrointestinal complications, where underlying mechanisms remain poorly characterized. We hypopthesized that the cord blood metabolome of neonates with gastroschisis differs systematically from controls and may reveal pathway-level alterations relevant to neonatal physiology. Cord blood plasma collected at delivery (23 samples each group) was analyzed using ultra-performance liquid chromatography coupled […]
- by Kratzl, F. P., Scott, H., Jayasinghe, S., Huges, K., Osborne, M., Sher, D., Segre, D.Marine microbes metabolize a wide range of carbon and nitrogen sources, shaping global biogeochemical cycles. Despite being crucial at the global scale, the coupling between carbon and nitrogen remains poorly understood for individual metabolites and bacteria. By phenotyping a library of marine heterotrophic bacteria across increasingly complex carbon and nitrogen sources, we generated a snapshot of this coupling. Growth phenotypes were weakly explained by phylogeny, but could be organized around substrate properties, including C:N stoichiometry and degree of reduction, reflecting […]
- by Sriwilai, B., Nguantad, S., Jevapatarakul, D., Thungsatianpun, N., Chantaraamporn, J., Chaiwijit, P., Asian Immune Diversity Atlas Network,, Chatterjee, A., Majumder, P. P., Shin, J. W., Ando, Y., Park, J.-E., Park, W.-Y., Kock, K. H., Tan, L. M., Prabhakar, S., Pithukpakorn, M., Suktitipat, B., Matangkasombut, P., Charoensawan, V.Mainland Southeast Asia (MSEA) remains under-represented in global immunogenomic references despite its extensive genetic heterogeneity. We present the first single-cell immune atlas of an MSEA population, utilizing Thai individuals from the Asian Immune Diversity Atlas (AIDA) as a representative cohort. We demonstrate that the Thai population is highly genetically diverse, reflecting its history as a geographic nexus for Asian admixture. By integrating single-cell transcriptomics with high-resolution genotyping, we show that genetic ancestry significantly shapes innate immune profiles, specifically CD14+ monocytes, […]
- by Odendaal, C., Verheijen, M. A., Gonzalez-Cabaleiro, R.At neutral pH, Clostridial fermentative catabolism is typically acidogenic, with a product profile dominated by acetate and butyrate. H2 acts as a terminal electron acceptor via hydrogenases, which increases ATP-producing potential from glucose. Acetate production is characterised by both higher ATP and H2 yields, rendering it desirable but more thermodynamically limited. For this reason, is commonly understood that Clostridia can adjust the ratio of acetate to butyrate (Ace:But) produced to maximise ATP while maintaining sufficient pathway driving forces to sustain […]
- by Grauvogel, L., Zollbrecht, E., Heymann, T., Brennsteiner, V., Pensl, C., Michaelis, A. C., Mann, M.Although protein-protein interactions govern virtually all cellular processes, systematic interactome mapping by affinity enrichment mass spectrometry (AE-MS) is constrained by manual sample preparation and lengthy liquid chromatography (LC)-MS/MS acquisition. Here we present High-throughput Interactome Profiling by MS (HIP-MS), an automated, end-to-end pipeline that overcomes these limitations. It leverages the compact, high-affinity ALFA tag for on-plate nanobody capture in 384-well format, combined with on-plate tryptic digestion. It can process almost 10,000 samples per week from protein expression up to MS measurement […]
- by Choi, C. W., Ton, V., Gill, S. V., Song, S.Individuals with obesity exhibit gait adaptations including reduced early-stance knee flexion, altered muscle coordination, slower preferred walking speeds, and shorter step lengths. Although these features are well documented, the mechanisms by which obesity-related physiological changes produce these patterns and influence knee joint loading relevant to osteoarthritis (OA) remain unclear. This study used predictive neuromechanical simulation to examine how musculoskeletal changes and movement objectives interact to generate obesity-associated gait patterns and tibiofemoral loading. Predictive simulations were performed using a reflex-based neuromechanical […]
- by Yeoh, J. W., Patro, C. P. K., Wong, L., Poh, C. L.Genome-scale metabolic models (GSMs) underpin pathway and strain engineering by linking genes to metabolic reactions and enabling system-level simulation of cellular fluxes and intervention effects, yet end-to-end analysis workflows remain fragmented, expert-demanding, and slow to adapt. Large language models (LLMs) could transform this landscape, lowering the barrier by explaining concepts, interpreting GSM files, and turning natural-language instructions into valid analysis code, thereby substantially mitigating the time, effort, and expertise required. However, their reliability for domain-specific tasks remains unexplored. Here, we […]
- by Giuliano, E., Sidhu, J. S., Lopez-Valdivia, I., Feola Conz, R., DePew, C. L., Lynch, J. P., Six, J., Hartmann, M., Galindo-Castaneda, T.Drought threatens food security globally. Adaptive root phenotypes and microbiomes can improve maize (Zea mays L.) water uptake and tolerance to drought. However, synergisms between root phenotypes and microbiomes remain underexplored. We aimed to investigate the association between varying root phenotypes and rhizosphere microbiomes under field-scale drought. We grew 22 maize inbred lines in the field under optimal water availability and drought imposed by excluding rain with rainout shelters. We quantified grain yield and measured root architectural and anatomical phenotypes […]
- by Marti Baena, Q., Segura-Morales, C., Garcia Ojalvo, J., Serrano, L.IL-10 is a key anti-inflammatory cytokine whose activity is impaired in autoimmune diseases. However, IL-10 also promotes inflammation under certain conditions, limiting the efficacy of IL-10-based therapies. Because the principles underlying these opposing effects remain unclear, we developed a mathematical model of the IL-10 signaling pathway to understand how such pleiotropic responses arise. Considering that STAT3 signaling is buffered against changes in IL-10RB receptor affinity, we provide a minimal mechanistic explanation for IL-10 variants with anti-inflammatory or pro-inflammatory biased responses […]
- by Richmond, G. R., Cunha, E., Kelly, L., Dias, O., Chang, R.Lacticaseibacillus rhamnosus GG (LGG) is an important gut commensal bacterial strain that has been extensively studied in both industrial and health settings. Despite its long history of study, a high-quality genome-scale metabolic network model (GEM) for LGG has yet to be reconstructed. Only automatically-generated draft models have been published, which have notoriously limited functional accuracy. Furthermore, comprehensive nutrient requirements have not been established for well-controlled in vitro study. Here we present the first curated GEM for LGG using a new […]
- by Chen, Z., Erickson, A., Ito, N., Zhao, X.Oxidized phospholipids (OxPLs) play critical roles in inflammation, ferroptosis, and other oxidative stress-associated processes, yet their systematic characterization in biological systems remains a major analytical challenge owing to their low abundance and vast structural diversity. Here we report RISOP (Reference-Assisted Identification of Sample-specific Oxidized Phospholipids), an untargeted LC-MS/MS workflow that leverages chemically enriched OxPL reference pools to substantially improve OxPL annotation. Reference pools encompassing diverse oxidative modifications and a wide abundance range were experimentally generated using Fenton reaction and H2O2 […]
- by Jimenez-Dominguez, G., Audit, B., Borgnat, P., Ravel, P., Arbona, J.-M.Understanding how gene regulatory networks respond to global cell perturbations remains a central challenge in systems biology and network inference. Modular Response Analysis (MRA) provides a mathematical framework to infer gene-to-gene directed connectivity graphs from perturbation experiments; however, classical MRA captures direct gene-to-gene influences, and does not explicitly account for global stimuli that simultaneously change the graph. Here, we introduce MRA+, an extension of MRA, that incorporates the effect of global perturbations into gene-to-gene graph inference. MRA+ assumes a sequential […]
- by Wilken, S. E., Beyss, M., Kratochvil, M., Grebel, A., Methling, K., Stefanski, A., London, P., Lalk, M., Schaper, K., Axmann, I. M., Noeh, K. M., Westhoff, P., Ebenhoeh, O.Vibrio natriegens is a halophilic, Gram-negative marine bacterium that is increasingly used in metabolic engineering applications due to its fast growth rate. In sparse minimal medium the organism has a doubling time of 25 minutes, which is about twice as fast as Escherichia coli under similar conditions. Given that its protein density is similarly constrained to that of E. coli, this necessitates that its metabolic enzymes are able to catalyze flux at a higher rate to sustain its metabolism. In […]
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