- by Lu, Z., Ying, B.-W.Fitness increase, impacted by genetic and environmental traits, requires evolutionary changes in genomes or ecological changes in habitats. Whether and how habitat reconstruction can compensate for the genetic changes remains unclear. The present study offers an experimental comparison of bacterial fitness increase via evolutionary and ecological strategies to verify that habitat reconstruction has the potential to avert genetic restriction, challenging the genetic-only view of adaptation. Six finely tuned media with different combinations and five evolved lineages with different mutations, both […]
- by Li, Y., Neuffer, S. J., Wider, J., Ma, S., Zhao, N., McCracken, L., Sanderson, T., Dong, J.-f., Deng, Y., Xiao, Y.Traumatic brain injury (TBI) is a major cause of mortality and long-term disability worldwide, giving rise to complex neurological complications that impact millions of individuals each year. Cellular stress and neuronal injury vary dramatically across cortical layers, vascular niches, and between the ipsilateral (injured) or contralateral (uninjured) hemispheres. There is a critical need for quantitative measures that capture the spatial distribution of injury-induced cellular changes, as well as the gene regulatory elements that drive them. Here, we developed OmicGlaze, an […]
- by Schmollinger, S., Strenkert, D., Purvine, S. O., Nicora, C. D., Soubeyrand, E., Basset, G. J., Merchant, S.An unbiased, quantitative view of biomolecules in a living cell is a prerequisite for accurate modeling approaches and informs our understanding of cellular metabolism at scale. In this work, we used the total protein approach (TPA), in which the total protein mass of a given proteomics sample is used as a calibrator for absolute protein quantification, to determine protein abundances during the Chlamydomonas reinhardtii diurnal cycle. We use external, independently measured quantitative markers (metals, pigments) to assess the absolute protein […]
- by Toldo, S., Luger, D., Vozenilek, A., Abbate, A., Kelly, J., Mezzaroma, E., Shibao, C. A., Abd-ElDayem, M. A., Klenerman, P., Waksman, R., Virmani, R., Maynard, J. A., Harrison, D., Flugelman, M. Y., Epstein, S. E.Abstract: Severe forms of inflammation-induced acute and chronic myocarditis have a poor prognosis. Promising therapeutic efforts focused on monoclonal antibodies (mAbs) inhibiting inflammation-inducing molecules. However, most mAbs target only one or a limited number of such molecules. Since inflammation involves multiple redundant pathways, we postulated that an mAb inhibiting multiple inflammatory pathways would be a potent therapeutic agent. We initially tested the commercially available anti-natural killer (NK) cell mAb (anti-NK1.1), which binds a receptor expressed on NK cells and depletes […]
- by Nanda, P., Murray, A. W.Fast glycolytic growth in the budding yeast, Saccharomyces cerevisiae, produces two epigenetic states: arrestors, which primarily ferment, and recoverers, which respire. Positive feedback in mitochondrial translation produces the two states: mitochondrial membrane potential drives the import of positively charged nuclear-encoded proteins of the mitochondrial ribosome and mitochondrial ribosomes produce key electron transport chain subunits, sustaining the membrane potential and completing the positive feedback loop. The co-operative incorporation of three mitochondrially encoded and translated subunits of respiratory complex IV converts the […]
- by Dönmez, E. M., Siebels, B., Drotleff, B., Nissen, P., Derous, D., Fabrizius, A., Siebert, U.Harbour porpoises (Phocoena phocoena) in the North and Baltic Seas are increasingly impacted by anthropogenic pressures, including underwater noise, fisheries and pollution. These pressures correlate with declining population health, particularly affecting the respiratory system. Growing pathological lesions, partly resulting from high prevalence of parasitic infestations and subsequent diseases, can impair tissue function and oxygen supply to distant end-organs. In this study, we applied an integrative MultiOmics approach (proteomics, metabolomics, lipidomics) to analyse the lungs and muscles of 12 wild harbour […]
- by Perez, L., Iradukunda, M., Krizanc, D., Thayer, K., Weir, M. P.Developing approaches to link structure and function is an ongoing challenge in computational and structural biology. Using a systems-level framework, we present here an analysis pipeline in a Python package, mdsa-tools, that constructs network representations of structures in a time series of trajectory frames from molecular dynamics (MD) simulations. Here, we demonstrate its use on a ribosomal subsystem. The subsystem is centered on the CAR interaction surface, a "brake pad" adjacent to the aminoacyl (A-site) decoding center that tunes protein […]
- by Shen, S., Tan, C., Cao, Y., Chow, C. S. Y., Mizikovsky, D., Reid, J., Dingwall, S., Prowse, A., Sun, Y., Wu, Z., Negi, S., Bao, S. C., Sinniah, E., Shim, W. J., Zhao, Q., Thorpe, J., Zahabi, A., Hanna, A., Cheng, T., Hill, A., Hudson, J. E., Chong, J. J. H., Palpant, N. J.Human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) are widely used to model cardiovascular disease, yet numerous differentiation protocols generate cardiomyocytes with heterogeneous molecular and functional properties, complicating experimental design. Here we systematically compare sixteen commonly used cardiomyocyte differentiation protocols and characterize their resulting cell states using single-nucleus RNA sequencing, functional phenotyping and computational integration with human genetic data. Despite similar cardiomyocyte yields, protocols produced distinct transcriptional programs, subtype compositions and physiological properties. By integrating protocol-specific gene expression signatures with genome-wide […]
- by Johnson, R., Blanco, R., Hernandez Vargas, E. A.Influenza infection results from tightly coupled interactions between viral replication, host immune responses, and the emergence of clinical symptoms. While mathematical models have extensively characterized viral and immune dynamics, the mechanistic link between immune activity and disease severity remains poorly understood. Here, we develop an integrative within-host modeling framework that explicitly connects infection dynamics, immune responses, and symptom manifestation through a unified dynamical system. Using murine influenza data, we incorporate key immune components alongside a mechanistic representation of symptom progression, […]
- by Akman, T., Pietras, K., Köhn-Luque, A., Acar, A.Cancer-associated fibroblasts (CAFs) are a central component of the tumor microenvironment that facilitate a supportive niche for cancer progression and metastasis. Experimental evidence suggests that CAFs can facilitate estrogen-independent tumor growth, thereby reducing the efficacy of anti-hormonal therapies. Understanding and quantifying the complex interactions between tumor cells, hormonal signalling, and the microenvironment are crucial for designing more effective and individualized treatment strategies. We propose a mathematical framework to explore the influence of CAFs on ER+ breast cancer progression and to […]
- by Nguyen, A. T., Nguyen, B. A.Stachys affinis (Chinese artichoke) tubers contain 50-80% stachyose by dry weight, the most concentrated dietary source of raffinose-family oligosaccharides (RFOs) known. Because humans lack sufficient -galactosidase activity, stachyose transits intact to the colon where microbial fermentation yields short-chain fatty acids (SCFAs). However, the quantitative impact of stachyose-derived SCFAs on host hepatic energy metabolism has not been systematically explored using genome-scale metabolic models. Three stachyose dose scenarios (Low/Mid/High: [~]25, 50, 100 g fresh tubers) were translated to SCFA availability vectors. Hepatic […]
- by Chauhan, V., Chen, M., Sridharan, A. T., Pan, L.Cellular therapies, toxicity screening, and regenerative medicine depend on selecting mammalian cell types with optimal lifespan, persistence post-transplant, immunogenicity, and chemical resilience. This review synthesizes data from over 50 immune, parenchymal, stem, and emerging engineered cell populations–including gamma-delta T cells, iNKT cells, CAR-macrophages, and hypoimmune iPSC derivatives–drawing from in vivo lifespan studies (including 1{blacksquare}C birth-dating and deuterium labeling), engraftment dynamics, immune rejection risk, and stress sensitivity profiles. We introduce a Programmability & Persistence Score (PPS; 0-20) that integrates these features […]
- by taye, m.Across adult warm-blooded vertebrates, the product of resting heart rate fH and maximum lifespan L is approximately constant: N[*] = fH L {approx} 109 cardiac cycles. This empirical regularity, noted since Rubner (1908), has lacked a widely accepted thermodynamic interpretation. We derive N[*] {approx} 109 from the non-equilibrium second law by treating the adult organism as a metabolic non-equilibrium steady state (NESS) and introducing the empirical closure[e] p ={sigma} 0f, which links entropy production rate to heart rate via a […]
- by Rahmani, S., Pouliopoulos, J., W. C. Lee, A., Barrows, R. K., Solis-Lemus, J. A., Strocchi, M., Rodero, C., Qayyum, A., Lashkarinia, S., Roney, C., Augustin, C. M., Plank, G., Fatkin, D., Jabbour, A., Niederer, S. A.Patient-specific four-chamber electromechanical models provide a physics-constrained framework for investigating whole-heart cardiac physiology and disease mechanisms. Identifying which model parameters impact whole-heart function is important for understanding cellular-, tissue-, and organ-scale determinants of cardiac performance and for calibrating patient-specific models. However, previous global sensitivity analyses of cardiac electromechanical models have typically been performed on a single heart, and systematic evaluation of how parameter influence compares across anatomically different subjects remains limited. We created four-chamber electromechanical models using cardiac MRI from […]
- Environmental statistics and sensory experience shape patch foraging strategies in Drosophila larvaeby Mudunuri, A., Tuckova, K., El Hady, A., Vogt, K.Animals foraging in patchy environments must balance exploiting current resources with exploring for better alternatives to maximize resource intake and to survive. However, the neural and computational mechanisms underlying such adaptive decisions have just recently begun to be understood. Using Drosophila larvae as an experimentally tractable model, we combine long-timescale behavioral tracking in controlled patchy environments with varying statistics, along with quantitative analysis and computational modeling, to dissect foraging decision strategies. We show that larvae flexibly adjust their behavior according […]
- by Chap, B. S., Santoro, T., Kosti, P., Barras, D., Fahr, N., Desbuisson, M., Benedetti, F., Minasyan, A., Andreoli, A., Ghisoni, E., De Carlo, F., Benkortbi, K., Salivaris, A., Achtari, C., Hastir, D., Berezowska, S., Abdelhamid, K., Sempoux, C., Perentes, J. Y., Mathevet, P., Garcia, J. C., Coukos, G., Dunn, S. M., Lanitis, E., Dangaj Laniti, D.Adoptive cell therapy (ACT) in solid tumors is limited by tumor microenvironment (TME)-imposed resistance mechanisms that are inadequately addressed by conventional systems. We developed tissue-preserving patient-derived explants (PDEs) from lung and ovarian cancer to interrogate redirected T cell immunity in intact human tissue. Using mesothelin-targeting bispecific T cell engager (BiTE(R), Amgen trademark)-secreting T cells, we observed antigen-dependent but heterogeneous responses across lesions. An integrated ex vivo response score stratified responder and non-responder TMEs, revealing that resistance associates with reduced antigen […]
- by Zhang, J., Han, J., Xie, L.-L.Biological rhythms are governed by intricate interactions among oscillatory subsystems, yet how they balance functional demands and energy efficiency remains unclear. We present a bimodal coupling optimization strategy where physiological systems dynamically alternate between synchronized (energy-saving) and desynchronized (function-priority) coupling modes. By employing the water-filling principle developed in communications engineering, we prove synchronized heart rate(HR)-respiration oscillations maximize energy efficiency (oxygen uptake per cardiac work). Then, system modeling confirms task/stress-induced oxygen demands enhance oxygen uptake at the cost of desynchronization and […]
- by Mostov, R., Lewis, G. R., Das, M., Marshall, W. F.Mitochondria often form branching membrane networks distributed throughout the cell interior. In many, though not all, cell types, these networks are observed to consist of one large connected component together with many smaller fragments. Why does this pattern arise? Does it reflect a specific biological function, an external biophysical constraint, or something simpler? Using results from extremal graph theory, we prove a new theorem which suggests that, under a sufficiently broad sampling of the space of mitochondria-like graphs, the predominance […]
- by Dai, Z., Yang, K., Sun, K., Zhu, H., Liu, Y.Amino acid composition of proteome reflects principles of metabolic resource allocation. While amino acids with higher biosynthetic costs are used less frequently in unicellular organisms, whether this rule extends to complex multicellular life remains elusive. Here we show that amino acid composition of human metabolic enzymes does not follow a simple cost-minimizing mode but instead segregate into four distinct amino-acid composition modules each associated with specific metabolic functions, a phenomenon we term emergence of amino acid archetypes (AArchetypes). By comparing […]
- by Silfvergren, O., Rigal, S., Schimek, K., Simonsson, C., Kanebratt, K. P., Forschler, F., Yesildag, B., Marx, U., Vilen, L., Gennemark, P., Cedersund, G.Experimental cell systems support the development of pharmacological therapies such as glucagon-like peptide-1 receptor agonists (GLP-1RAs). However, their utility in drug discovery is limited due to study variability, which complicates formation of unified conclusions based on all available data. To address this, we conducted a comprehensive analysis of the GLP-1RA exenatide, incorporating 16 new and five pre-existing mono- or co-culture studies of human liver and pancreatic models. We employed a new pragmatic model-based approach designed to handle the common situation […]
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