- by Keshishian, H., Many, G. M., Smith, G., Clark, N. M., Iyer, G., Hart, P., Lindholm, M. E., Montalvo, S., Zhang, Z., Jin, C., Sanford, J. A., Carr, S. A., Adkins, J. N., Mani, D. R., Bodine, S. C., Trappe, S., Houmard, J. A., Musi, N., Huffman, K. M., Kraus, W. E., Sparks, L. M., Thalacker-Mercer, A. E., Sealfon, S. C., Xia, A. Y., Katz, D. H., Newgard, C. B., Burant, C. F., Coen, P. M., Goodpaster, B. H., MoTrPAC Study GroupThe Molecular Transducers of Physical Activity Consortium (MoTrPAC) was established to systematically characterize the molecular basis of the health benefits of exercise. Here, we present the integrative, multi-omics response of human skeletal muscle to acute endurance (EE) and resistance (RE) exercise. Distinct temporal responses were observed, with changes in ATAC-seq, phosphoproteome, and metabolome occurring before changes in the transcriptome and proteome. These distinct temporal multi-omic dynamics were used to identify transcriptional regulatory hubs converging around MEF2A and NFIC regulation of […]
- by Vlassakev, I., Savva, C., Zhou, L., Ritz, D., Schmidt, A., Jang, C., Saei, A. A., Petrus, P. P.Daily light-dark cycles impose predictable environmental fluctuations that require coordinated temporal regulation of cellular physiology. This coordination is mediated by the circadian clock, which operates as a network of tissue oscillators; however, the molecular signals that convey circadian information between organs remain incompletely defined. Here, we identify nicotinic acid riboside (NaR) as a circulating metabolite whose rhythmicity depends on the liver clock. In differentiating 3T3-L1 adipocytes, NaR engages unfolded protein response (UPR) gene programs and modulates adipogenic competence. Proteome-wide stability […]
- by Faulon, J.-L., Dursoniah, D., Ahavi, P., Raynal, A., Asin-Garcia, E.This study presents dAMN, a hybrid neural-mechanistic model that integrates neural networks with genome-scale dynamic flux balance analysis (dFBA) to predict bacterial growth curves across diverse nutrient environments. dAMN uses neural networks to infer dynamic behavior from initial metabolite concentrations, while mechanistic constraints ensure stoichiometric and thermodynamic consistency based on genome scale metabolic models. dAMN is trained on E. coli and P. putida experimental growth data from media containing various combinations of sugars, amino acids, and nucleobases, and evaluated on […]
- by MoTrPAC Study Group,, Brandt, A. R., Fleg, J., Goodpaster, B. H., Jaeger, B., Jin, C. A., Johannsen, N. M., Katz, D., Keshishian, H., Kohrt, W. M., Kraus, W. E., Lester, B., Melanson, E. L., Miller, M. E., Montalvo, S., Rejeski, W. J., Shimly, S. M., Smith, G. R., Stowe, C. L., Trappe, S., AbouAssi, H., Adams, N., Amar, D., Ashley, E., Aslamy, A., Bamman, M. M., Belangee, A., Bennett, W., Bergman, B. C., Bessesen, D. H., Bodine, S. C., Boyd, G., Buford, T. W., Burant, C. F., Carnero, E. A., Carr, S., Chambers, T. L., Chavez, C., Chen, H., Chen, S.-H., Christle, J. W., Claiborne, A., Clark, NThe goal of the Molecular Transducers of Physical Activity Consortium (MoTrPAC) is to examine the physiological and molecular basis for health benefits in response to acute and chronic exercise. Prior to COVID-19 suspension, healthy, sedentary participants (N=206, 18-74y) were randomized to endurance exercise (N=80), resistance exercise (N=81), or non-exercise control (N=45) interventions. The prescribed vigorous acute endurance and resistance exercise bouts induced physiological and metabolic perturbations relative to resting homeostasis. The supervised chronic (3d/wk, 12wk) endurance or resistance training programs […]
- by Feng, Y., Robers, Z., Rasheed, L., Miao, Y., Wen, S., Lee, K., Sohigian, J., Brbic, M., Hickey, J. W.Spatially resolved omics technologies reveal tissue organization at single-cell resolution but remain limited by the cost of the assays, incomplete spatial coverage, 2D-only imaging, and experimental artifacts. These factors motivate the need for textit{in silico} methods that can reconstruct or extend tissue context beyond what current spatial measurements provide. We present MORPHE (MOdeling of stRuctured sPatial High-dimensional Embeddings), an AI framework that learns to synthesize biologically faithful tissue architecture directly from spatial-omics data. MORPHE introduces a graph-informed probabilistic embedding that […]
- by Sturrock, M., Sturrock, A.Phenotypic selection can cause the transient, selective upregulation of fitness-conferring genes in isogenic cell populations under stress, producing selective enrichment of the fitness gene relative to a neutral reference gene. While computational models have shown that such enrichment requires noisy gene expression and a cellular memory linking growth rate to gene expression (Ciechonska et al., 2022), the precise mechanistic requirements and the analytical principles governing enrichment have remained unclear. Here, we present an exact analytical framework that unifies enrichment mechanisms […]
- by Pak, H. H., Rassmussen, E. S., Palluth, L., Takahashi, J. S.The molecular basis of caloric restriction (CR) has been defined primarily at a metabolic steady state, leaving the initiating events that drive the transition from ad libitum feeding to an adapted CR state largely unresolved. Here, we combine continuous indirect calorimetry with longitudinal bulk RNA-seq of liver and inguinal white adipose tissue (iWAT) sampled at six circadian timepoints across four stages of adaptation to 30% CR in male C57BL/6J mice. We show that whole-body metabolic adaptation proceeds through two discrete […]
- by Preston, R., Hoyle, A., Stevenson Harris, A., Williams, E., Birtles, T., Chang, J., Swift, J., Eckersley, A., Lennon, R.At least 10% of the global population is impacted by chronic kidney disease (CKD) and ageing is a key risk factor. CKD is characterised by the build-up of extracellular matrix and a loss of functional nephrons. However, the mechanisms that maintain matrix homeostasis across the physiological lifespan remain elusive. Using {superscript 1}3C-lysine metabolic labelling, we quantified kidney matrix protein turnover in healthy mice at four timepoints (8, 22, 52, and 78 weeks). We found that basement membrane components, including collagen […]
- by Robbins, J. M., Katz, D. H., Many, G., Rao, P., Smith, G. R., Tiwari, G., Spielmann, G., Montalvo, S., Iyer, G., Amar, D., Leach, D. T., Coyne, B. J., Lindholm, M. E., Goodpaster, B. H., Walsh, M. J., Clish, C. B., Burant, C. F., Gerszten, R. E., MoTrPAC Study GroupExercise benefits numerous organ systems and tissues, however limited knowledge exists about its underlying molecular pathways. Identifying the exercise-induced biochemical changes that occur in the circulation may provide further insights into how exercise confers systemic health changes. Here, we perform large-scale plasma proteomic, metabolomic, and whole blood transcriptional profiling in sedentary human participants undergoing acute endurance exercise (EE), resistance exercise (RE), or a non-exercise control (CON) in up to 7 timepoints over a 24 hour period. We observe 7066 transcript, […]
- by Zhang, Z., Nudelman, G., Pincas, H., Iyer, G., Smith, G. R., Keshishian, H., Jin, C. A., Trappe, S., Katz, D. H., Burant, C. F., Nair, V. D., Zaslavsky, E., Sealfon, S. C., MoTrPAC Study GroupThe diverse health benefits of exercise are associated with multi-organ molecular responses. Alternative RNA splicing (AS) is an important determinant of transcriptome and proteome diversity. We profiled the temporal effects of acute endurance and resistance exercise on the AS landscape of human skeletal muscle, adipose tissue, and blood, and studied regulatory mechanisms through integrated multi-omic analyses. We identified 5102 distinct differential AS (DAS) events, with the majority modifying protein-coding sequence (89%) and being independent of altered RNA expression (67%). Endurance […]
- by De Temmerman, M., Vandemoortele, B., Vermeirssen, V.Metabolic reprogramming is a hallmark of glioblastoma, yet how distinct malignant and tumor microenvironment cell populations contribute to this metabolic heterogeneity remains poorly defined. Since direct single-cell metabolomics remains technically limited, transcriptomics-based computational inference offers a powerful alternative. Here we apply and systematically compare three complementary computational methods: (1) metabolic pathway activity scoring, (2) gene regulatory network inference focused on metabolic enzyme gene regulation, and (3) single-cell metabolic flux prediction. These methods were applied to snRNA-seq data from a set […]
- by MoTrPAC Study Group,, Katz, D. H., Jin, C. A., Many, G. M., Smith, G. R., Keshishian, H., Clark, N. M., Iyer, G., Ahn, C., Lindholm, M. E., Sagendorf, T. J., Amar, D., Barber, J. L., Brandt, A. R., Coen, P. M., Ge, Y., Hart, P., Hsu, F.-C., Jaeger, B. C., Jimenez-Morales, D., Leach, D. T., Mani, D. R., Montalvo, S., Pincas, H., Rao, P., Sanford, J. A., Smith, K. S., Vetr, N. G., Adkins, J. N., Ashley, E. A., Carr, S. A., Miller, M. E., Montgomery, S. B., Nair, V. D., Robbins, J. M., Snyder, M. P., Sparks, L. M., Tracy, R., Walsh, M. J., Wheeler, M. T., Xia, A. Y., Sealfon, S. C., Gerszten, RRegular physical activity represents one of the greatest mechanisms for maintaining human health, yet the underlying molecular transducers of these benefits remain incompletely understood. Multi-omic assays now provide new opportunities to study the coordinated molecular responses of body tissues to different exercise modalities. The Molecular Transducers of Physical Activity Consortium (MoTrPAC) was established to address this need by creating a molecular map of the response to physical activity. Described here is the first human cohort of MoTrPAC: sedentary adults enrolled […]
- by Abbott, K., Hardo, G., Li, R., Bradley, J., Zarkan, A., Bakshi, S.Antibiotic treatment failure, often driven by non-genetic mechanisms such as tolerance and persistence, remains a major global health challenge. {beta}-lactams, the most widely prescribed antibiotic class, are particularly compromised by tolerance in dormant, non-growing cells; yet, how these drugs act on cells resuscitating from dormancy remains poorly understood. Here, we investigate the resuscitation phase at an unprecedented scale using Hi-DFA (High-throughput Dynamic Fate Analyser), a single-cell microfluidic platform integrating time-lapse imaging with machine-learning-based image analysis for dynamic cell-fate tracking. We […]
- by Fares, W. A., Janes, K. A.Transforming growth factor-{beta} (TGF{beta}) ligands and receptors interact with overlapping selectivity to form different signaling complexes. This many-to-many wiring provides versatility in how ligands are perceived and cell types become activated, but the systems-level impact of coreceptors, which bind TGF{beta} ligands yet do not signal, remains unresolved. We examined the role of canonical surface-bound coreceptors by numerically simulating TGF{beta} ligand-receptor systems of increasing complexity and pairing results with single-cell measurements in acutely stimulated cells. Using sampled combinations of biologically plausible […]
- by Biane, C., Moon, K., Lee, K., Pauleve, L.Boolean networks are discrete dynamical models that use Boolean states and logical functions to represent the dynamics of biological systems. A primary application of Boolean networks is to identify controls (e.g., genetic mutations or knockouts) that drive the system toward a desired phenotype. However, existing computational tools often produce inconsistent results because they rely on differing modeling assumptions. To better understand these differences, we survey existing tools and propose a taxonomy of control problems. Our taxonomy unveils hidden coverage relationships […]
- by Kuijjer, M. L., De Marzio, M., Glass, K.1Analysis of biological networks can provide unprecedented insights into the mechanisms underlying disease. Although many methods have been developed to estimate biological networks, these approaches typically use multiple experimental samples to estimate a single aggregate network, which fails to capture population-level heterogeneity. Recently, several methods have been developed that overcome this limitation by inferring networks for individual samples, i.e. single-sample networks. However, each approach for inferring single-sample networks has been formulated differently, making it challenging to compare them. To address […]
- by Abdelwahab, A. A., Hardy, B.The Adverse Outcome Pathway (AOP) framework is a cornerstone of modern mechanistic toxicology, providing a structured representation of causal biological events linking molecular initiating events to adverse health outcomes. However, the practical exploration and interpretation of AOPs remain challenging due to the fragmentation of mechanistic knowledge across heterogeneous biological databases and the limited availability of integrated, interactive tools. Here, we present AOPGraphExplorer 2.0, an interactive graph-based platform for the visualization, annotation, and analysis of AOP networks derived from AOP-Wiki. This […]
- by Yoo, S., Vannur, L., Li, L., Young, C., Liu, Q., Wen, Z., Zhang, Y., Florens, L., Si, K., Zhuang, J., Zheng, F., Zhou, C.Aging is marked by a decline in cellular functions accompanied by widespread changes in mRNA and protein abundance, yet whether aging broadly remodels subcellular protein localization and concentration–and why some proteins change while others remain stable–remains unclear. This gap matters because cellular function depends not only on expression levels but also on correct spatial organization. Using yeast replicative aging as a model, we built a robotic pipeline to enrich old cells from 5,661 strains, acquired 90 million single-cell 3D images, […]
- by Yoo, S., Young, C., Li, L., Vannur, L., Zhuang, J., Zheng, F., Wu, M., Andersen, J., Zhou, C.Aging is accompanied by conserved hallmarks including genomic instability, epigenetic alterations, loss of proteostasis, and mitochondrial dysfunction, but how these processes emerge and become mechanistically linked remains unclear. Here we leverage a proteome-wide, single-cell, subcellular atlas of protein expression, localization, and aggregation across yeast replicative aging to map hallmark-linked remodeling in its spatial context. We identify hundreds of previously unappreciated molecular changes that underlie major hallmarks of aging and show that hallmark phenotypes frequently manifest as compartment-specific erosion of spatial […]
- by Sontake, V., Kartha, V., Sahu, N., Fuentes, D., Chio, L., Miyazaki, H., Chen, J., Gupta, A., Nonora, J., Vaidyanathan, A., Shambhu, S., Donepudi, G., Le, C., Fung, L., Lim, A., Bowman, C., Garcia, D., Popov, D., Fagan, K., Longtine, C., Cruz Sampedro, J., Hayward, S., Biedrzycki, A., Powell, B., Doroschack, K., Watson Levings, R., Carrico, C., Driver, I., Towne, C., LePort, F., Borch Jensen, M.Validating therapeutic targets for complex diseases requires investigating gene functions within native tissue architectures rather than reductionist in vitro models. Here we present a modality-agnostic AAV-based in vivo high-throughput screening platform capable of delivering knockouts, gain-of-function, and synthetic miRNA knockdowns directly to cells within the diseased environment. This system scales to hundreds of perturbations and is adaptable to diverse species and organ systems. To translate high-dimensional screen data into therapeutic assessment, we established a curated analysis framework that scores single-cell […]
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