- by Gosselin-Monplaisir, T., Jallet, D., Harscoet, E., Uttenweiler-Joseph, S., Heux, S., Millard, P.Escherichia coli, a key workhorse in industrial biotechnology, is commonly grown on glucose, which supports rapid growth but leads to acetate overflow, which instead inhibits growth, diverts carbon from the production pathway, and reduces productivity. Recent studies suggest that acetate may also have beneficial effects in glucose-grown E. coli, but its potential in bioprocesses remains unexplored. In this study, we systematically investigated acetate's impact on bioproduction using a kinetic model of glucose and acetate metabolism in E. coli. The model […]
- by Glass, E. M., Kolling, G. L., Papin, J. A.Probiotic supplements are marketed for diverse health benefits, yet species inclusion often lacks functional rationale. We surveyed 352 U.S. probiotic products and found 36 unique microbial species, with most supplements containing only one species and no clear link between species and intended health benefit. To evaluate probiotic function, we developed CoPaPro, a collection of 1,012 genome-scale metabolic models spanning commensal, pathogenic, and probiotic bacteria. Flux balance analysis revealed that current probiotic species fail to capture the metabolic diversity of native […]
- by Merzbacher, C., Mac Aodha, O., Oyarzun, D. A.Predicting the impact of gene deletions is crucial for biological discovery, biomedicine, and biotechnology. For example, identifying lethal deletions is key for new cancer therapies or antimicrobial treatments that bypass drug resistance. In biotechnology, non-lethal deletions are a powerful strategy to redirect chemical flux toward production of high-value compounds for the food, energy, and pharmaceutical sectors, using genetically engineered cells as an alternative to petrochemicals. Owing to the cost and complexity of large-scale deletion screens, there is a growing interest […]
- by van Lingen, H. J., Ke, C., Saccenti, E., Lada, Z. G., Baccaro, M., van den Brink, N. W., Suarez-Diez, M.Zinc oxide containing nanomaterials may elicit toxic responses in environmental organisms such as earthworms. Although toxic responses in earthworms have been reported, few studies have attempted to understand the molecular mode of action dynamics explaining the observed toxicity at a transcriptional level. This study investigates the time-dependent gene expression response in earthworms exposed to ZnO nanomaterials and ZnO:Mn multicomponent nanomaterials. Earthworms were exposed to ZnO or ZnO:Mn for 7 days and to ZnO:Mn or MnCl2 for 14 days. Strong differential […]
- by Zhan, J., Jarrell, Z. R., Kemp, M. L., Weinberg, J., Go, Y.-M. G., Martin, G. S., Jones, D. P.Gene centric pathway mapping tools, widely used to interpret untargeted LCMS metabolomics data, may underperform because a single metabolite can generate multiple spectral features, inflating false positive rates. Classic enzymology, which established metabolite flow long before gene sequencing, offers experimentally validated precursor product relationships that could overcome these ambiguities. We evaluated whether enzymology defined precursor product correlations are consistently detectable in human plasma LCMS data and explored their potential to enhance pathway analysis and metabolite identification. Using a high resolution […]
- by Vaisbourd, E., Glass, D. S., Yang, Y., Mayo, A., Bren, A., Alon, U.Subinhibitory antibiotic exposures are common in clinical and environmental contexts, yet their effects on bacterial growth dynamics remain incompletely understood. We studied the temporal response of Escherichia coli to a panel of bactericidal ("cidal") and bacteriostatic ("static") antibiotics at sub-minimum inhibitory concentrations (sub-MIC). We uncover a sharp dynamical distinction between the two classes. Bacteriostatic antibiotics reduce the initial growth rate in a dose-dependent manner, similar to a nutrient starvation response. In contrast, bactericidal antibiotics do not alter initial growth rates […]
- by Zhou, Z., Chen, X., Simsek, E., Hamrick, G. S., Baig, Y., Holmes, Z. A., Du, Z., Karig, D. K., You, L.Microbial communities often exhibit apparently complex dynamics driven by myriad interactions among community members and with their environments. Yet, practical modeling and control are often based on limited number of observables, raising a fundamental question: to what extent are these observed dynamics predictable given unobserved background complexity? Here, we report an emergent simplicity that the temporal dynamics of observable microbial populations can be captured by low- dimensional representations. Using variational autoencoders (VAEs), we define a critical latent dimension (Ec) that […]
- by Levien, E., Kang, J. H., Biswas, K., Manalis, S. R., Amir, A., Miettinen, T. P.Cell growth rates exhibit cell-intrinsic cell-to-cell variability, which influences cell fitness and size home-ostasis from bacteria to cancer. Whether this variability arises from noise in cell growth or cell division processes, or originates from cell-size-dependent growth rates, remains unclear. To separate these potential sources of growth variability, single-cell growth rates need to be examined across different timescales. Here, we study cell-intrinsic size and growth regulation by tracking lymphocytic leukemia cell mass accumulation with high precision and minute-scale temporal resolution along […]
- by Choi, Y., Nam, U., Kim, J., Yoon, S.-Y., Lee, N., Cho, H., Kim, S., Yu, S., Kim, J., Moon, H.-N., Lew, B.-L., Lee, Y., Kim, M. S., Kwon, S.-H.IntroductionCellular senescence is associated with altered lipid metabolism, including increased cellular lipid uptake, upregulated lipid biosynthesis, and deregulated lipid breakdown. Previous studies have reported that carnitine palmitoyltransferase (CPT), the rate-limiting enzyme in fatty acid oxidation that catalyzes the conversion of acyl-CoA to acylcarnitine, is involved in various senescence-related diseases. Although solar lentigo (SL) is an age-related pigmentary disorder characterized by the accumulation of senescent cells, its role in metabolic dysregulation has rarely been investigated. Methods and ResultsIntegrated transcriptomic profiling of […]
- by Kenaston, M. W., Cherkashchenko, L., Skawinski, C. L. S., Fishburn, A. T., Peddamallu, V., Florio, C. J., Robertson, A. E., Bhattacharya, T., Young, J. M., Malik, H. S., Shah, P. S.Pathogenic mosquito-borne flaviviruses infect mosquito and human hosts, relying on host protein interactions to replicate, evade immunity, and mediate pathogenesis. Prior proteomic studies mapped such interactions for some flaviviruses, but yellow fever virus (YFV)–a pathogen of resurgent concern–remains understudied. Here, we map YFV interactomes in human and mosquito cells to identify interactions common among divergent flaviviruses or unique to YFV. Functional assays reveal a previously unrecognized YFV restriction factor: RBBP6 inhibits YFV genome replication by interacting with the viral polymerase […]
- by Lee, S. H., Myers, P. J., Brown, K. S., Loew, L. M., Sorkin, A., Lazzara, M. J.The RAF kinases are central links between RAS, once activated by receptor tyrosine kinases (RTKs), and the extracellular signal-regulated kinases (ERK). In many cancer cells, RAFs are the least abundantly expressed RTK-ERK pathway proteins and can be present at just hundreds of copies per cell at the plasma membrane, but the consequences of limited RAF expression are unclear. By developing continuum and stochastic computational models of the epidermal growth factor receptor (EGFR)-ERK pathway, we showed that low RAF abundance creates […]
- by Umirbaeva, A., Kurenkov, A., Seisenov, B., Zhumanov, K., Tajiyev, K., Mustafin, M., Vorobjev, I. A., Barteneva, N. S.Data analysis of sperm morphology is critical for evaluating bull fertility, yet it is often performed using light microscopy and staining techniques in a highly subjective and manual manner. In this study, we introduce a scalable, high-resolution approach combining label-free Imaging Flow Cytometry (IFC) with deep learning for automated classification of bovine sperm morphology. We analyzed 436,374 single-cell images obtained from three prominent bull breeds in Kazakhstan – Kazakh Whitehead, Auliekol, and Simmental from fresh and cryopreserved sperm – providing […]
- by Cho, Y., Lee, J. W., Shin, S. M., Hernandez, A. G., Yuan, X., Schneider, J., Hooper, J. E., Wood, L. D., Jaffee, E. M., Deshpande, A., Ho, W. J.Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer, with liver metastases significantly worsening outcomes. However, distinct features of the tumor microenvironment (TME) between primary and metastatic sites remain poorly defined. Cellular neighborhoods within the TME are recognized as functional units that influence tumor behavior. Conventional spatial methods, which assign equal weights to all cells in a region, fail to capture the nuances of cellular interactions. To address this, we developed Functional Cellular Neighborhood (FunCN) quantification, which integrates both the […]
- by Wu, M. Y. M., Rocamora, F., Samoudi, M., Robinson, C., Kuo, C.-C., Pristovsek, N., Grav, L. M., Kildegaard, H. F., Lee, G. M., Campos, A. R., Lewis, N. E.Recombinant proteins, in particular monoclonal antibodies and related molecules, have become dominant therapeutics. As they are produced in mammalian cells, they require the concerted function of hundreds of host cell proteins in the protein secretion pathway. However, the comprehensive set of host cell machinery involved remains unclear. Thus, it is often unknown why some recombinant proteins fail to express well. Here we present and deploy an approach called Fc-targeting Biotinylation by Antibody Recognition (FcBAR), which allows for the in situ […]
- by Simons, B. D., Karin, O.Tissue homeostasis requires a precise balance between cellular self-renewal and differentiation. While fate decisions are known to be closely linked to cell cycle progression, the functional significance of this relationship is unclear. Here, we develop a mechanistic framework to analyse cellular dynamics when cell fate is coupled to cell cycle length. We focus on a distinct feature of cell cycle regulation where mitogens act as control parameters for a bifurcation governing the G1-S transition. Under competitive feedback from cell-cell interactions, […]
- by Park, J., De Gregorio, R., Hissong, E., Ozcelik, E., Bartelo, N., Dezem, F. S., Zhang, L., Marcao, M., DuBose, H., Zheng, Y., Abila, E., Kim, J., Proszynski, J., Agyemang, A. A., Arikatla, M. R., Metzger, E., Rogers, S., Divakar, P., Dulai, P. S., Reeves, J. W., Liang, Y., Pan, L., Bhattacharjee, S., Young, K., Heck, A., Korukonda, M., McGuire, D., Wu, L., Wardhani, A., Beechem, J., Church, G., Lipkin, S. M., Patel, S., Socciarelli, F., Monette, S., Robinson, B., Loda, M., Elemento, O., Martelotto, L., Plummer, J. T., Rendeiro, A. F., Alonso, A., Schwartz, R. E., Houlihan, S. L., Mason, C. E.The Spatial Atlas of Human Anatomy (SAHA) represents the first multimodal, subcellular-resolution reference of healthy adult human tissues across multiple organ systems. Integrating spatial transcriptomics, proteomics, and histological features across over 15 million cells from more than 100 donors, SAHA maps conserved and organ-specific cellular niches in gastrointestinal and immune tissues. High-resolution profiling using CosMx SMI, 10x Xenium, RNAscope, GeoMx DSP, and single-nucleus RNA-seq reveals spatially organized cell states, rare adaptive immune populations, and tissue-specific cell-cell interactions. Comparative analyses with […]
- by Jeong, E. M., Chung, C. Y., Kim, J. K.Ultrasensitive transcriptional switches are essential for converting gradual molecular inputs into decisive gene expression responses, enabling critical behaviors such as bistability and oscillations. While cooperative binding, relying on direct repressor-DNA binding, has been classically regarded as a key ultrasensitivity mechanism, recent theoretical works have demonstrated that combinations of indirect repression mechanisms–sequestration, blocking, and displacement–can also achieve ultrasensitive switches with greater robustness to transcriptional noise. However, these previous works have neglected key biological constraints such as DNA binding kinetics and the […]
- by Higginbotham, L., Shantaraman, A., Guo, Q., Fox, E. J., Bagchi, P., Wu, F., Lah, J. J., Levey, A. I., Seyfried, N. T.Lewy body dementia (LBD), which encompasses Parkinsons disease dementia (PDD) and Dementia with Lewy bodies (DLB), currently lacks established biofluid markers reflective of its complex molecular pathophysiology. Multiplex proteomic tools, such as the recently released NUcleic acid Linked ImmunoSandwich Assay (NULISATM), can simultaneously assess a diverse array of neurodegenerative targets and address this critical biomarker gap. We used the NULISA CNS disease panel to analyze 852 baseline and longitudinal cerebrospinal fluid (CSF) samples from control, PD without cognitive impairment (PD-NCI), […]
- by Shinde, S., Raju, A.Turing patterns are a well-studied model of reaction-diffusion equations for developmental patterning. Their applicability has often been limited by the difficulty in identifying candidate molecules that satisfy the requisite criteria for patterning. Here, we build on recent work on geometric models to describe Turing patterning as a potential flow. We use the mathematics of normal form theory to capture the universal dynamics of Turing patterning, largely independent of the underlying reaction-diffusion equations. We apply our framework to three-component systems and […]
- by Maiti, S., Chedere, A., Jolly, M. K., Chandra, N., Rangarajan, A.Although several cancer cells are shed into the circulation, most die due to the stresses they encounter. Detachment from the underlying extracellular matrix is one major stress; cell death due to matrix detachment is known as anoikis. Few cancer cells overcome this stress, become anoikis-resistant, and survive to seed metastasis. Autophagy, a cell survival mechanism during stressful conditions that promotes cellular homeostasis by recycling cellular components, is activated upon matrix detachment. On the other hand, apoptosis is a cellular mechanism […]
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