- by Monte, R. E. C., Magnusson, R., Söderberg, C., Green, H., Elmsjö, A., Nyman, E.Subtyping of ketoacidosis, a metabolic state characterized by blood acidification due to various causes, remains challenging in forensic casework. Postmortem omics samples paired with machine learning offers an independent tool to address this challenge. However, such data, especially related to real forensic cases, are rare. In Sweden, high-resolution mass spectrometry data routinely collected in forensic toxicology, can be leveraged for metabolomic analysis. Here, we integrate postmortem metabo-lomics and machine learning models to detect and subtype ketoacidosis-related deaths using real forensic […]
- by Malhotra, N., Samanta, S., Deshpande, A.Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by coordinated dysregulation of multiple genes, requiring system-level approaches to elucidate underlying molecular mechanisms. While existing computational studies largely focus on differential expression analysis or machine–learning–based feature selection, they often overlook inter-gene relationships and network topology, limiting biological interpretability. In this study, we present a network-based framework for prioritizing candidate genes in Alzheimer's disease by integrating gene co-expression network analysis with multiple centrality measures. Transcriptomic data comprising approximately 39,000 genes across […]
- by Lopez-Malo, M., Maerkl, S. J.Transcription factors (TFs) regulate gene expression by binding cis-regulatory DNA elements, yet how trans-regulatory characteristics such as TF affinity, concentration, and localization interact with cis-regulatory elements remains largely unclear. We systematically analyzed TF affinity mutants across abundance, and localization states and found that promoter binding-site strength most readily modulated expression levels, followed by TF localization and concentration, while affinity variations were mainly buffered. We further uncover performance trade-offs between TF abundance, localization, and affinity. Together, these results reveal how trans […]
- by Mangrum, D. S., Finley, S. D.Anticancer drug resistance is challenging to overcome because it can arise through both intrinsic and acquired mechanisms, each driven by distinct cellular machinery. In particular, there is a sharp need for therapies that target hormone-insensitive prostate tumors due to the growing incidence of castration-resistant prostate cancer. Optimizing the pathways that regulate apoptosis in prostate cancer offers a promising strategy to induce apoptosis and inhibit tumor progression, since these mechanisms do not depend on hormonal signaling. Here, we identified strategies to […]
- by Duarte de Araujo Caldas, M., de Assis Bento Lima, A., Lopes, F. J. P.AO_SCPLOWBSTRACTC_SCPLOWTransitions between stable states are a defining feature of nonlinear dynamical systems, yet the factors controlling their probabilities and timescales remain poorly understood in non-conservative settings. In many theoretical frameworks, such control is commonly interpreted in terms of potential depth, a concept that becomes ambiguous outside equilibrium. By analyzing a gene regulatory network associated with breast cancer subtypes, we uncover a geometric framework in which the phase-space distance between stationary states, together with the bifurcation structure organizing multistability, provides a […]
- by Yuan, L., Zheng, Y., Zhang, S., Beroukhim, R., Deshpande, A.In imaging-based spatial transcriptomics, transcript-to-cell assignment shapes downstream biological interpretation including cell typing, ligand-receptor inference, and niche characterization. However, two-dimensional segmentation of volumetric tissue often yields mixed cellular profiles, while cells without detected nuclei are missed entirely, distorting the aforementioned downstream analyses. We present TRACER, which refines cellular representations in imaging-based transcriptomics by leveraging gene-gene coherence and spatial co-localization of transcripts observed directly in the data, without requiring external annotations or reference atlases. TRACER resolves mixed cellular profiles and reconstructs […]
- by Ahn, C., Jin, C. A., Whytock, K. L., Many, G. M., Sagendorf, T. J., Sanford, J. A., Hou, Z., Viggars, M. R., Nie, J., Espinoza, S., Musi, N., Sun, Y., Pino, M. F., Hart, P., Katz, D. H., Keshishian, H., Smith, G. R., Trappe, S., Clark, N. M., Bodine, S. C., Goodyear, L. J., Esser, K. A., Newgard, C. B., Bergman, B. C., Adkins, J. N., Walsh, M. J., Sparks, L. M., The MoTrPAC GroupExercise induces widespread health benefits across multiple tissues, yet the acute molecular responses in human adipose tissue remain poorly defined. The Molecular Transducers of Physical Activity Consortium (MoTrPAC) profiled temporal molecular changes in abdominal subcutaneous adipose tissue (ASAT) following a single bout of exercise. Healthy sedentary adults were randomized to endurance (EE), resistance (RE), or control (CON) groups. ASAT biopsies were collected pre-exercise and at 45min, 4hr, and 24hr post-exercise, followed by transcriptomic, proteomic, phosphoproteomic, and metabolomic analyses. EE and […]
- by Vargas-Villamil, L. M., Garcia Medina, A. D. C., Zaldivar Cruz, J. M., Bautista Ortega, J., Tedeschi, L. O., Izquierdo Reyes, F., Medina Peralta, S.This study evaluated the effects of short-term, low-dose supplementation with high-fructose corn syrup (HFS) and Momordica charantia (Mo) on pulmonary arterial hypertension (PAH) and system dynamics in hypertensive broiler chickens. Thirty male Cobb broilers were divided into three groups (n=10): HFS, Mo, and control. PAH was surgically induced at day 17, and supplementation was provided from days 20 to 37. Measurements included body weight, feed intake, heart indices, and tissue composition. A dynamic model (Yaantal fe Bro A1) using differential […]
- by Simensen, V., Almaas, E.Metal-binding proteins account for nearly half of the characterized proteome, and they rely on metal-binding sites (MBSs) as critical determinants of their structural stability and biological function. However, methods for comparing their local binding environments lag behind those for whole-structure alignment. Here, we represent MBSs as atomic point clouds surrounding bound metal ligands and align them with a fine-tuned iterative closest point algorithm. Applying this framework to a redundancy-reduced collection of MBSs derived from all metalloproteins in the Protein Data […]
- by Eliason, J., Popel, A. S.Quantitative systems pharmacology (QSP) models require calibration data from published literature, yet manual curation produces inconsistent documentation while large language model (LLM) extraction exhibits hallucination and fabrication errors unacceptable for quantitative modeling. We present MAPLE (Model-Aware Parameterization from Literature Evidence), a framework that uses structured validation schemas as a collaboration interface between LLMs and modelers. Two complementary schemas capture calibration data at different scales: one for isolated experiments that constrain individual parameters through simplified forward models, and one for clinical […]
- by Jones, A., Loeffler, T., Wu, E., Varma, V. R., Im, H. K., Thambisetty, M.Despite a growing body of evidence implicating genetic variants and proteins encoded by them with risk and pathogenesis of Alzheimers disease (AD), this knowledge has not been successfully translated into effective AD treatments. We integrated current genomic, transcriptomic and proteomic profiles of AD into a network pharmacology framework that leverages comprehensive gene-gene and drug-target interactions. This approach allowed us to screen 2,413 drugs for repurposing opportunities in AD. Computational validation and drug prioritization was followed by experimental validation in 33 […]
- by Camacho-Mateu, J., Burgio, G., Quiros-Rodriguez, I., D Fernandez-de-Bobadilla, M., Sanchez, A.The function of microbial communities is often dominated by additive and pairwise interactions, raising the question of whether this reflects intrinsic biological simplicity or fundamental limits of detection. Here, we leverage the theory of fitness landscapes to bridge microbial ecology and genetics, and show that this apparent simplicity is a generic consequence of structural and statistical constraints rather than evidence for intrinsically weak higher-order interactions (HOIs). We separate the detectability of individual epistatic interactions from their contribution to functional variance, […]
- by Oh, C., Wilkie, K. P.We present the Toroidal Search Algorithm (TSA), a novel population-based metaheuristic optimization method inspired by the topology of a torus. Conventional metaheuristics frequently suffer from boundary stagnation, a phenomenon that severely degrades performance in bounded and high-dimensional search spaces. TSA addresses this limitation by embedding the search domain into a toroidal geometry, thereby eliminating artificial boundaries and enabling continuous cyclic exploration. Beyond boundary handling, TSA uses winding numbers to capture the history of agent movement across periodic dimensions, which are […]
- 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 Faulon, J.-L., Dursoniah, D., Ahavi, P., Raynal, A., Asin-Garcia, E.SummaryThis 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 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 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 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 […]
Mass spectrometry websites, social media, journal feeds, and other links and items of interest to the mass spectrometry community.
