- by Cadavid, J. L., Meimetis, N., Griffith, L. G., Lauffenburger, D. A.Preclinical models are used extensively to study diseases and potential therapeutic treatments. Complex in vitro platforms incorporating human cellular components, known as microphysiological systems (MPS), can model cellular and microenvironmental features of diseased tissues. However, determining experimental conditions — particularly biomolecular cues such as growth factors, cytokines, and matrix proteins — providing most effective translatability of MPS-generated information to in vivo human subject contexts is a major challenge. Here, using metabolic dysfunction-associated fatty liver disease (MAFLD) studied using the CNBio […]
- by Sahu, A., Abdullah, M., Gupta, S., Singh, S. v., Dhillon, A., Yadav, P., Azam, S.Johne's disease (JD), caused by Mycobacterium avium subsp. paratuberculosis (MAP), is a chronic enteric disease with significant economic impacts on the dairy industry. To elucidate molecular mechanisms underlying MAP infection in desi cattle (Bos indicus), we conducted a comprehensive transcriptomic study. This revealed 1,905 protein-coding and 3,123 lncRNA genes as differentially expressed in MAP-infected samples, alongside the first comprehensive annotation of 45,947 lncRNAs in desi cattle. Weighted Gene Co-expression Network Analysis identified 11 co-expressed gene modules, with the turquoise module […]
- by de Pins, B., Malbranke, C., Jablonska, J., Shmuel, A., Sharon, I., Bitbol, A.-F., Mueller-Cajar, O., Noor, E., Milo, R.Rubisco is the main gateway through which inorganic carbon enters the biosphere, catalyzing the vast majority of carbon fixation on Earth. This pivotal enzyme has long been observed to be kinetically constrained. Yet, this impression is based on kinetic measurements heavily focused on eukaryotic rubiscos, a rather conserved group of low genetic diversity. Moreover, the fastest rubiscos that we know of so far were found among the sparsely sampled prokaryotes. Could there be yet faster rubiscos among the uncharted regions […]
- by Subramaniam, S., Napoleon, M. A., Lotfollahzadeh, S., Kamal, M. H., Kurniawan, H., Elsadawi, M., Kenney, D., Dhouam, F., Bosmann, M., Whelan, S., Cabral, H., Burks, E. J., Zhao, G., Kolachalama, V., Ravid, K., Chitalia, V.SARS-CoV-2 infection disturbs the coagulation balance in the blood, triggering thrombosis and contributing to organ failure. The role of prothrombotic metabolites in COVID-19-associated coagulopathy remains elusive. Leveraging K18-hACE2 mice infected with SARS-CoV-2, we observed higher levels of the tryptophan metabolite, kynurenine, compared to controls. SARS-CoV-2 infected mice showed a significant upregulation of enzymes controlling Kynurenine biogenesis, such as indoleamine 2,3-dioxygenase (IDO-1) and tryptophan 2,3-dioxygenase levels in kidneys and liver, respectively, as well as changes in the enzymes involved in kynurenine […]
- by Smith, L. P., Malik-Sherif, R. S., Nguyen, T. V. N., Hermjakob, H., Karr, J., Shaikh, B., Drescher, L., Moraru, I. I., Schaff, J., Agmon, E., Patrie, A., Blinov, M. L., Hellerstein, J., May, E., Nickerson, D., Gennari, J., Sauro, H.The BioModels Repository contains over 1000 manually curated mechanistic models drawn from published literature, most of which are encoded in the Systems Biology Markup Language (SBML). This community-based standard formally specifies each model, but does not describe the computational experimental conditions to run a simulation. Therefore, it can be challenging to reproduce any given figure or result from a publication with an SBML model alone. The Simulation Experiment Description Markup Language (SED-ML) provides a solution: a standard way to specify […]
- by Ruys de Perez, A., Dimitrova, E. S., Kemp, M. L., Anderson, P. E.Understanding how stem cells organize to form early tissue layers remains an important open question in developmental biology. Helpful in understanding this process are biomarkers or features that signal when a significant transition or decision occurs. We show such features from the spatial layout of the cells in a colony are sufficient to train neural networks to classify stem cell colonies according to differentiation protocol treatments each colony has received. We use topological data analysis to derive input information about […]
- by Escos, A., Ambikan, A., Schuster, S., Svensson-Akusjärvi, S., Gelpi, M., Mansouri, S., Naval, P., Junior, R. L., Sood, V., Knudsen, A. D., Pathade, P. P., Mikaeloff, F., Hogh, J., Lourda, M., Vesterbacka, J., Nowak, P., Benfield, T., Pawar, V., Siegfried, W., Muvva, J. R., Vegvari, A., Gupta, S., Savai, R., Poulsen, S. D., Neogi, U.Cells of the myeloid lineage, particularly monocytes and macrophages, play a key role in HIV infection by contributing to viral replication, immune response, and maintaining immune balance during suppressive therapy. We hypothesized that metabolic reprogramming and altered chemokine signaling in people living with HIV (PWH) on long-term antiretroviral therapy (ART) affect monocyte transport and polarization due to ongoing inflammation. Therefore, the present study aimed to identify the mechanism of impaired monocyte/macrophage function in PWH on well-treated ART that can lead […]
- by Kamzolas, I., Koutsandreas, T., Barker, C. G., Vathrakokoili Pournara, A., Weston, H. N., Vacca, M., Papatheodorou, I., Vidal-Puig, A., Petsalaki, E.Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) has emerged as a silent pandemic, affecting nearly one-third of the global population. This condition encompasses a spectrum of liver disorders, ranging from simple steatosis to Metabolic Dysfunction-Associated Steatohepatitis (MASH), which is characterised by liver steatosis, lipotoxicity, hepatocellular damage, inflammation, and fibrosis. Left unchecked, MASLD/MASH can progress to cirrhosis and hepatocellular carcinoma. Despite the progressive nature of MASLD/MASH, current research primarily relies on static, histopathologically defined stages, which fail to capture the dynamic disease […]
- by Agasso, L., Molineris, I., Caselle, M.Two rounds of whole-genome duplication (WGD) occurred about 500 million years ago and played a major role in the evolution of the vertebrate genomes. Human genes derived from WGD are called "ohnologs". Ohnologs are involved in fundamental biological processes and significantly contributed to the complexity of the human gene regulatory network. Given the central role of miRNAs in gene regulation, we investigated the contribution of ohnolog miRNAs (Ohno-miRNAs) to the human gene regulatory network. We worked on the identification of […]
- by Idumah, G., Li, L., Yehia, L., Mahdi, H., Ni, Y.Modifiers of immune checkpoint inhibitor (ICI) responses in cancer patients are complex and remain poorly characterized, especially in gynecologic cancers. In this study, we explored fluxomic biomarkers that differentiate responders from non-responders to ICIs in a series of 49 patients with gynecologic cancers, including ovarian, cervical, and endometrial cancers. By applying metabolic enzyme expression as constraints, we utilized an objective-customizable flux balance analysis within a genome-scale metabolic model to predict the metabolic flux differences between responders versus non-responders of ICI […]
- by Ounsinegad, A., Mitchell, C., Komar, N.The Eastern equine encephalitis virus (EEEV) is a neurological mosquito-borne disease that spans the northeastern coast of the United States and Canada. Prior studies have focused on how mosquitoes prefer to take blood meals from hatch-year avian hosts rather than adult avian hosts to determine the rate at which the virus is spread between the Black-Tailed Mosquito (Culiseta melanura) and select avian species. In these studies, it was found that mosquito blood meal preference correlated well with avian brooding seasons […]
- by de Rooij, M., van Riel, N. A. W., O'Donovan, S. D.Universal differential equations (UDEs) are an emerging approach in biomedical systems biology, integrating physiology-driven mathematical models with machine learning for data-driven model discovery in areas where knowledge of the underlying physiology is limited. However, current approaches to training UDEs do not directly accommodate heterogeneity in the underlying data. As a data-driven approach, UDEs are also vulnerable to overfitting and consequently cannot sufficiently generalise to heterogeneous populations. We propose a conditional UDE (cUDE) where we assume that the structure and weights […]
- by Zambelli, F., Pancaldi, V., De Domenico, M.Climate change, increasing urbanization and global human mobility have increased the risk of emergent infectious diseases and the risk for their pandemic potential. Consequently, there is a pressing need for methods that can provide rapid insights about the potential enduring effects on the human hosts. In-silico methods can be more suitable than in-vitro and in-vivo methods to identify effects potentially manifesting after a long time, under the hypothesis that the underlying causes can be ascribed to perturbed biomolecular processes. Here […]
- by Tannenbaum, E., Markiewitz, D., Kalisky, T., Kugler, H.The inference of gene regulatory networks (GRNs) from single-cell RNAseq data allows for mechanistic characterization of the different cell states and their dynamics in complex biological processes. While numerous algorithms have been proposed to infer GRNs from single-cell transcriptomic data, multiple network solutions may explain the same dataset, posing a challenge for biologically meaningful interpretation. Here, we use the Reasoning Engine for Interaction Networks (RE:IN), a computational tool based on formal reasoning, to characterize GRN ensembles in the context of […]
- by Supo-Escalante, R., Plata, G., Usmanova, D. R., Vitkup, D.Microbial species exhibit a remarkable diversity in their metabolic properties, genome composition, and ecological distribution. A central challenge of systems biology is to understand the relationships between genomic, metabolic, and phenotypic properties of bacteria. However, it is currently not well understood how the structure of metabolic network defines and reflects the lifestyle of diverse bacterial species across the tree of life. By analyzing thousands of genome-scale metabolic models of bacteria, we found a percolation-like transition in their ability to grow […]
- by Gupta, A., Morella, N., Sutormin, D., Li, N., Gaisser, K., Robertson, A., Ispolatov, Y., Seelig, G., Dey, N., Kuchina, A.AbstractSuccess of phage therapies is limited by bacterial defenses against phages. While a large variety of anti- phage defense mechanisms has been characterized, how expression of these systems is distributed across individual cells and how their combined activities translate into protection from phages has not been studied. Using bacterial single-cell RNA sequencing, we profiled the transcriptomes of [~]50,000 cells from cultures of a human pathobiont, Bacteroides fragilis, infected with a lytic bacteriophage. We quantified the asynchronous progression of phage infection […]
- by Loman, T. E., Schwall, C. P., Saez, T., Liu, Y., Locke, J.Genetic circuits with only a few components can generate complex gene regulatory dynamics. Here, we combine stochastic modelling and single-cell time-lapse microscopy to reveal the possible dynamics generated by a key gene circuit motif: the mixed positive/negative feedback loop. Our minimal stochastic model of this motif reveals ten distinct classes of dynamic output, including stochastic pulsing, oscillations, and bistability. These dynamics are influenced by only a few important biological parameters, such as the strength of the positive and negative feedbacks. […]
- by Szilagyi, G. S., Gulyas, A., Vassy, Z., Csermely, P., Fenyves, B.Nervous systems are complex biological networks with largely unknown structural and functional characteristics. Motif analysis is a robust tool that can reveal unique aspects of connectivity of a complex network. An ideal candidate for motif analysis is the connectome of the nematode Caenorhabditis elegans which is the only fully reconstructed nervous system. Utilizing recent data on the connection signs of this network and a novel structure-preserving randomization method, we performed signed motif analysis on the C. elegans connectome for the […]
- by Hospelhorn, B. G., Kesler, B. K., Jashnsaz, H., Neuert, G.Characterizing the movement of biomolecules in single cells quantitatively is essential to understanding fundamental biological mechanisms. RNA fluorescent in situ hybridization (RNA-FISH) is a technique for visualizing RNA in fixed cells using fluorescent probes. Automated processing of the resulting images is essential for large datasets. Here we demonstrate that our RNA-FISH image processing tool, TrueSpot, is useful for automatically detecting the locations of RNA at single molecule resolution. TrueSpot also performs well on images with immunofluorescent (IF) and GFP tagged […]
- by Willis, N. B., Papoutsakis, E. T.Syntrophic cocultures (hitherto assumed to be commensalistic) of Clostridium acetobutylicum and Clostridium ljungdahlii, whereby CO2 and H2 produced by the former feeds the latter, result in interspecies cell fusion involving large scale exchange of protein, RNA and DNA between the two organisms. Although mammalian cell fusion is mechanistically dissected, the mechanism for such microbial-cell fusions is unknown. To start exploring this mechanism, we used RNA sequencing to identify genes differentially expressed in this coculture using two types of comparisons. One […]
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