- by Chakraborty, D., Rengaswamy, R., Raman, K.A unique balance of seemingly contradictory properties like robustness and plasticity, or evolvability and functional canalisation, characterises biological systems. To understand the basis of these properties, we look into gene regulation, which is at the core of biological function. We simulate dynamical models of over 190 million genetic circuits covering all possible three-gene circuit structures. We develop a computational pipeline to classify these circuits into functional clusters by matching the shape of their temporal responses. Thus, we generate a dataset […]
- by Pare, L., Bordron, P., David, L., Mahe, M., Bihouee, A., Eveillard, D.Transcriptomic analysis is a key tool for exploring gene expression, but the complexity of biological systems often limits its insights. In particular, the lack of intermodal or multi-layered analysis hinders the ability to fully capture key cellular functions such as metabolism from transcriptomic data alone. Here, we introduce a novel approach that integrates transcriptomic data with metabolic network modeling to address this. Unlike traditional methods, HUMESS prioritizes genes based on their metabolic significance, offering a deeper understanding of condition-specific gene […]
- by Durot, S., Doubleday, P. F., Schulla, L., Sabine, A., Petrova, T. V., Zamboni, N.Endothelial cells (ECs) line the vascular system and are key players in vascular homeostasis, yet their metabolic diversity across tissues, vascular beds, and growth states remains poorly understood. This study examines metabolic differences between proliferating and quiescent ECs and compares blood and lymphatic endothelium using proteomics and metabolomics. Our findings indicate that metabolism in quiescent ECs is not dormant but reorganized in a cell-specific manner, with decreased heme intermediates in human umbilical vein ECs and increased branched-chain amino acid catabolism […]
- by Greco, B. M., Zapata, G., Dandage, R., Papkov, M., Pereira, V., Lefebvre, F., Bourque, G., Parts, L., Kuzmin, E.Whole-genome duplication (WGD) events are common across various organisms however the retention and evolution of WGD paralogs is not fully understood. Quantitative measure of protein redistribution in response to the deletion of their WGD paralog provides insight into sources of gene retention. Here, we describe PARPAL (PARalog Protein Retribution using Abundance and Localization in Yeast), a web database that houses results of high-content screening and deep learning neural network analysis of the redistribution of 164 proteins reflecting how their subcellular […]
- by Lebel, Y., Chevee, V., Gupta, A., Alon, U., Schneider, D. S.If the immune system is an interconnected network, then the evolution of an archetype that is ideal for fighting one pathogen should result in tradeoffs decreasing its ability to fight others. How many archetypes are there in an immune system? We infected diverse mice with Plasmodium chabaudi, and identified five distinct archetypes of responses based on the host's position in microbial load, immune activity, and host damage space. To better understand the nature of these archetypes, we developed a mathematical […]
- by Lee, Y., Fang, Y., Kuila, S., Imoukhuede, P. I.Angiogenesis, the formation of new vessels from existing vessels, is mediated by vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF). Despite discoveries supporting the cross-family interactions between VEGF and PDGF families, sharing the binding partners between them makes it challenging to identify growth factors that predominantly affect angiogenesis. Systems biology offers promises to untangle this complexity. Thus, in this study, we developed a mass-action kinetics-based computational model for cross-family interactions between VEGFs (VEGF-A, VEGF-B, and PlGF) and PDGFs […]
- by Lopez-Maroto, A., Meijer, W. J. J., Buceta, J., Ares, S.Horizontal gene transfer (HGT) is a major evolutionary process in bacteria, driving the dissemination of genetic traits including antibiotic resistance (AR). In this study, we employ a hybrid modeling approach, combining agent-based simulations and Ordinary Differential Equation (ODE) models, to investigate bacterial conjugation-a key HGT mechanism whose dynamics remain poorly understood. Our agent-based simulations of the transfer dynamics of the conjugative plasmid pLS20 from Bacillus subtilis reveal that spatial organization, colony growth dynamics, and quorum-sensing regulation significantly influence plasmid dissemination. […]
- by Moses, A. M., Stajich, J. E., Gasch, A. P., Knowles, D. A.Gene expression patterns are determined to a large extent by transcription factor binding to non-coding regulatory regions in the genome. However, gene expression cannot yet be systematically predicted from genome sequences, in part because non-functional matches to the sequence patterns (motifs) recognized by transcription factors (TFs) occur frequently throughout the genome. Large-scale functional genomics data for many TFs has enabled characterization of regulatory networks in experimentally accessible cells such as budding yeast. Beyond yeast, fungi are important industrial organisms and […]
- by Lastad, S. B., Mitarai, N.Bacteria can enter dormancy triggered by stress, such as starvation. When stress is removed, a large part of the population will exhibit some lag time before regrowth. It has been observed that even under stress-free conditions that allow for exponential growth, a small subpopulation can spontaneously enter dormancy temporarily. The dormant population often survives antibiotic application because many types of antibiotics target the cell growth and division process. If bacteria are in an environment where antibiotics are sometimes applied, the […]
- by Otani, Y., Koga, D., Wakizaka, Y., Shimizu, H.The escalating threat of infections caused by drug-resistant bacteria poses a significant global health challenge, with projections estimating 10 million annual deaths by 2050. While the development of conventional antibiotics has stagnated since the late 1990s, antimicrobial peptides (AMPs), short amino acid sequences exhibiting potent antimicrobial activity, have emerged as a promising alternative, demonstrating efficacy even against drug-resistant bacteria. However, despite the identification of numerous AMPs, their translation into clinically approved therapeutics remains limited, highlighting the critical need for accelerated […]
- by Li, L., Mdluli, T., Buzzard, G., Umulis, D. M.Spatially distributed, nonuniform morphogen gradients play a crucial role in tissue organization during development across the animal kingdom. The Bone Morphogenetic Protein (BMP) pathway, a well-studied morphogen involved in dorsal-ventral (D-V) axis patterning, has been extensively studied in zebrafish, Drosophila, and other organisms. Given that this pathway is highly conserved in both form and function, we sought to determine whether a core mathematical model that constrained topology and biophysical parameters could fully reproduce the observed dynamics of gradient formation in […]
- by Borkowski, K., Liang, N., Zhao, N., Arnold, M., Huynh, K., Karu, N., Mahmoudiandehkordi, S., Kueider-Paisley, A., Kanekiyo, T., Bu, G., Kaddurah-Daouk, R., Alzheimer's Disease Metabolomics ConsortiumAlzheimers disease (AD) risk and progression are significantly influenced by APOE genotype with APOE4 increasing and APOE2 decreasing susceptibility compared to APOE3. While the effect of those genotypes was extensively studied on blood metabolome, less is known about their impact in the brain. Here we investigated the impacts of APOE genotypes and aging on brain metabolic profiles across the lifespan, using human APOE-targeted replacement mice. Biocrates P180 targeted metabolomics platform was used to measure a broad range of metabolites probing […]
- by Sabino, A. U., Guerreiro, D. d. M., Kim, A.-R., Ramos, A. F., Reinitz, J.Understanding how the genome encodes the regulatory logics of transcription is a main challenge of the post-genomic era to be overcome with the aid of customized computational tools. We report an automatic framework for analyzing an ensemble of fittings to data of a thermodynamics-based sequence-level model for transcriptional regulation. The fittings are clustered accordingly with their intrinsic regulatory logics. A multiscale analysis enables visualization of quantitative features resulting from the deconvolution of the regulatory profile provided by multiple transcription factors […]
- by Lakshmikanthan, A., Kay, M., Oomen, P.Biological sex plays a crucial role in the outcomes of cardiac health and therapies. Sex hormones are known to strongly influence cardiac remodeling through intracellular signaling pathways, yet their underlying mechanisms remain unclear. To address this need, we developed and validated a logic-based systems biology model of cardiomyocyte hypertrophy that, for the first time, incorporates the effects of both estradiol (E2) and testosterone (T) alongside well-established hypertrophic stimuli (Strain, angiotensin II (AngII), and endothelin-1 (ET-1)). We qualitatively validated the model […]
- by Maasayi, M. S., Swai, J. K., Muganga, J. B., Moore, J., Stevenson, J. C., Coleman, M., Lobo, N. F., Tambwe, M. M.Controlling mosquito-borne diseases is increasingly challenging due to factors such as outdoor and early biting mosquitoes and logistical or behavioral barriers, particularly in displaced populations where the use and efficacy of core interventions are inadequate. This study evaluated the impact of BiteBarrier, a transfluthrin-based spatial emanator, over eight weeks of aging against multiple mosquito species in semi-field system simulating both indoor and outdoor settings. We assessed the protective efficacy using both landing rate and feeding success methods across five mosquito […]
- by Frost, M. R., Ball, B. K., Pendyala, M., Douglas, S. R., Brubaker, D. K., Chan, D. D.ObjectiveTranslation of biological insights from preclinical studies to human disease is a pressing challenge in biomedical research, including in osteoarthritis. Translatable Components Regression (TransComp-R) is a computational framework that has previously been used to synthesize preclinical and human OA data to identify biological pathways predictive of human disease conditions. We aimed to evaluate the translatability of two common murine models of post-traumatic osteoarthritis – surgical destabilization of the medial meniscus (DMM) and noninvasive anterior cruciate ligament rupture (ACLR) – to […]
- by Hu, S., Lu, Y., Yu, G., Zheng, Z., Wang, W., Ni, K., Giri, A., Zhang, J., Zhang, Y., Watanabe, K., Yao, G., Xing, J.Numerous computational approaches have been developed to infer cell state transition trajectories from snapshot single-cell data. Most approaches first require projecting high-dimensional data onto a low-dimensional representation, raising the question of whether the dynamics of the system become distorted. Using epithelial-to-mesenchymal transition (EMT) as a test system, we show that both biology-guided low-dimensional representations and stochastic trajectory simulations in high-dimensional state space, not representations obtained with brute force dimension-reduction methods, reveal multiple distinct paths of TGF-{beta}-induced EMT. The paths arise […]
- by Elsässer, F., Florea, R., Räsch, F., Weis, K., de Souza, N., Picotti, P.The function of a protein is determined by its structure, which may change dynamically in response to post-translational modifications, interaction with other molecules, or environmental factors like temperature. Limited proteolysis-coupled mass spectrometry (LiP-MS) captures such structural alterations on a proteome-wide scale via the detection of altered protease susceptibility patterns of proteins. However, this technique has so far required cell lysis, which exposes proteins to non-native conditions and can disrupt labile interactions such as those occurring within biomolecular condensates. To study […]
- by Lazari, L. C., Silva, J. M., Donado, P. R. S., Shinjo, S. M. O., Fernandes, L. R., Ieva, A. D., Palmisano, G., Marie, S. K. N.Gliomas account for most brain malignancies, with astrocytomas being the most common subtype. Among these, glioblastoma (GBM) stands out as the most aggressive form, exhibiting a median survival time of just 15 months despite intensive therapy. Current diagnostic practices rely on magnetic resonance imaging (MRI) and histopathological analysis, which often necessitate invasive surgical sampling. This underscores the need for minimally invasive diagnostic tools capable of characterizing glioma progression and guiding treatment strategies. Advances in glioma classification have integrated histological and […]
- by Yeganegi, A., Robels, K., Richardson, W. J.Matrix metalloproteinases (MMPs) are a family of proteases that drive degradation of extracellular matrix (ECM) across many tissues. MMP activity is antagonized by tissue inhibitors of metalloproteinases (TIMPs), resulting in a complex multivariate system with many MMP isoforms and TIMP isoforms interacting across a network of biochemical reactions – each with their own distinct kinetic rates. This system complexity makes it very difficult to identify which specific molecules are most responsible for driving ECM turnover in vivo and therefore the […]
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