- Heterogeneous therapy-resistant cancer cells have distinct and exploitable drug sensitivity profilesby Busch, G. T., Boe, R. H., Li, J., Gruener, R. F., Arnett, M. J., Ravindran, P. T., Herlyn, M., Huang, R. S., Raj, A.Resistance to targeted therapies is a significant clinical problem, but eliminating resistant cancer cells has proven difficult. One potential reason for this difficulty is heterogeneity in the resistant population: even genetically homogeneous cancer cell populations can give rise to a variety of resistant subtypes, each potentially with their own specific second-line drug vulnerabilities. Using high-throughput drug screening of genetically-identical resistant clones with varying transcriptomes and morphologies, we show that each clone had a distinct drug sensitivity profile. These results admitted […]
- by Davis, C. N., Hill, E. M., Jewell, C. P., Rysava, K., Thompson, R. N., Tildesley, M. J.Since 2020, large-scale outbreaks of highly pathogenic avian influenza (HPAI) H5N1 in Great Britain have resulted in substantial poultry mortality and economic losses. Alongside the costs, the risk of circulation leading to a viral reassortment that causes zoonotic spillover raises additional concerns. However, the precise mechanisms driving transmission between poultry premises and the impact of potential control measures in Great Britain, such as vaccination, are not fully understood. We have developed a spatial transmission model for the spread of HPAI […]
- by Ambaw, Y. A., Ljubenkov, P. A., Singh, S., Hamed, A., Boland, S., Boxer, A. L., Walther, T. C., Farese, R.Developing new treatment strategies for frontotemporal dementia (FTD) and other forms of neurodegeneration requires biomarkers to monitor disease progression. Dysregulated brain lipid metabolism, particularly sphingolipids enriched in the nervous system, is a key feature of neurodegeneration. However, plasma lipids have been investigated less for their potential as biomarkers than brain imaging and serum proteins. Here we examined the plasma lipidomes of a cohort of heterozygous carriers of gene variants associated with autosomal dominant familial FTD (including GRN, C9orf72, and MAPT […]
- by Okubo, R., Morikura, T., Hiki, Y., Tokuoka, Y., Kobayashi, T. J., Yamada, T. G., Funahashi, A.Identifying regulatory relationships between transcription factors (TFs) and genes is essential to understand diverse biological phenomena related to gene expression. Recently, deep learning-based models to predict TFs that bind to genes from nucleotide sequences of the target genes have been developed, yet these models are trained to predict known TFs only. In this study we developed a deep learning model, GReNIMJA (Gene Regulatory Network Inference by Mixing and Jointing features of Amino acid and nucleotide sequences), to predict gene regulation […]
- by Liu, Y., Pathirana, D., Hasenauer, J.Oncolytic virus therapy (OVT) is emerging as a potent alternative to conventional cancer treatments by employing engineered viruses that selectively infect and lyse tumor cells while sparing normal tissues. Although mathematical models have been developed to elucidate the dynamics of OVT and inform personalized therapies, they are often specific to certain organisms. Mathematical models tailored to more recently developed animal models of OVT, such as zebrafish, are not yet available. Here, we introduce the first mathematical model of OVT trained […]
- by Marku, M., Chenel, H., Bordenave, J., Hurtado, M., Domagala, M., Raynal, F., Poupot, M., Ysebaert, L., Zinovyev, A., Pancaldi, V.How do cancer cells respond to their environment, and what are the key regulators behind their behaviour? While immune cell reprogramming in the tumour microenvironment (TME) has been extensively studied, the dynamic regulatory changes within cancer cells in response to interactions with immune cells remain poorly understood. In Chronic Lymphocytic Leukaemia (CLL), this knowledge gap limits our ability to fully grasp the disease progression and to design effective, personalised interventions. To tackle this, we combine time-series transcriptomics with data-driven gene […]
- by van der Jagt, P. L., Oud, S., Vroomans, R. M. A.Developmental systems drift (DSD) is a process where a phenotypic trait is conserved over evolutionary time, while the genetic basis for the trait changes. DSD has been identified in models with simpler genotype-phenotype maps (GPMs), however the extent of DSD in more complex GPMs, such as developmental systems, is debated. To investigate the occurrence of DSD in complex developmental GPMs, we constructed a multi-scale computational model of the evolution of gene regulatory networks (GRNs) governing plant meristem (stem cell niche) […]
- by Wu, Y., Li, J., Bartley-Dier, E. L., Pitts, C., Cohen, B. A.Long-range activation is an essential property of enhancers, yet the features determining long-range enhancer activities have not been systematically investigated due to a lack of high-throughput methods to measure long-range enhancer activities efficiently. To address this gap, we present a long-range massively parallel reporter assay (long-range MPRA), an assay allowing the measurement of hundreds of enhancers at multiple distances from a genome-integrated promoter. The long-range MPRA assay features two independent landing pads, allowing modular control over the genome-integrated promoter and […]
- by Kulathungage, H., Aretakis, J. R., Vaidya, K., Al-Husini, N., Muthunayake, N. S., Kim, S., Schrader, J. M.While transcription and translation have been shown to be coordinated with mRNA decay across various single-gene studies, their global coordination remains poorly defined. Therefore, we performed Rif-seq experiments in C. crescentus to measure genome-wide mRNA lifetimes and analyzed the impact of transcription and translation. Based upon the RNAP elongation speed, we identified that approximately 20% of mRNAs were cotranscriptionally degraded. We generated absolute quantitative estimates of mRNA copy numbers in C. crescentus, a useful systems biology resource, revealing that some […]
- by Zhang, M., Abbey, J. A., Bost, P., Usui, G., Haefliger, S., Muenst, S., Lim, M. J., Yagnik, G. B., De Souza, N., Rothschild, K. J., Bodenmiller, B.Highly multiplexed, antibody-based protein imaging of tissue has yielded many insights but does not yet allow the routine analysis of more than 50 markers simultaneously. By leveraging the ability of Matrix-Assisted Laser Desorption/Ionization (MALDI) imaging to resolve hundreds of m/z peaks without spectral overlap, MALDI-IHC with photocleavable mass-tag (PCMT)-labelled antibodies offers the possibility to dramatically increase the number of markers that can be imaged. Here, we demonstrate 100+ plex MALDI-IHC imaging and describe our development of gutenTAG, an open-source analysis […]
- by Scott, W. T., Nataya, E. D., Belzer, C., Schaap, P. J.Flavonifractor plautii, a prevalent gut commensal, uniquely combines flavonoid degradation with the capacity to produce health-promoting short-chain fatty acids (SCFAs), notably butyrate and propionate. However, its metabolic pathways, ecological roles, and health impacts remain poorly characterized. To explore its probiotic potential and ecological functions, we developed a genome-scale metabolic model (GEM), iFP655, using automated reconstruction, deep-learning-based gap-filling, thermodynamic constraints, and transcriptomics. The iFP655 model substantially improved the predictions of growth rates and SCFA profiles compared to previous models. Simulations identified […]
- by Maehara, K., Ohkawa, Y.The differentiation potency of cells is governed by dynamic changes in gene expression, which can be inferred from single-cell RNA sequencing (scRNA-seq) data. While velocity-based approaches have been used to analyze cell state changes as vector fields, extracting acceleration (change of change) information remains challenging because of the sparsity and high dimensionality of the data. Here, we developed ddHodge, a framework based on Hodge decomposition for precise vector field reconstruction. ddHodge accurately recovers all basic components of the vector field, […]
- by Karlstaedt, A., Cullen, F., Drinkwater, R., Kim, K., Young, M., Rossiter, S., Aksentijevic, D.AimThe present study aimed to elucidate which pathways contribute to cardiometabolic adaptation in Egyptian fruit bats. MethodsUtilising cardiac tissues from Egyptian fruit bats (Rousettus aegyptiacus) and C57BL/6J mice, we combined liquid chromatography-mass spectrometry metabolic profiling, non-targeted 1H NMR spectroscopy, and in silico computational modelling using the genome-scale mammalian network CardioNet. Main FindingsOur analyses revealed that bat hearts exhibit a distinct metabolic profile characterised by depleted glycogen reserves and increased reliance on lipid oxidation to meet energy demands. Notably, bat hearts […]
- by Ertl, J., Prodjinotho, U. F., Rao, Z., Anisuzzaman, A., Schluckebier, J., Hamway, Y., Baar, P., Haslbeck, M., Grevelding, C. G., Haeberlein, S., Falcone, F. H., Schulz, S., Koeberle, A., Prazeres da Costa, C.BackgroundSchistosomiasis, a major neglected tropical disease, is currently treated with only one drug, praziquantel (PZQ), effective only against adult worms. However, high reinfection rates and potential development of drug resistance following widespread use of PZQ emphasize the need for a deeper molecular understanding of the host-parasite crosstalk as a basis for urgently needed novel drugs. Here, we identify and characterize a soluble host-derived schistosomicidal phospholipase that influences the diacylglycerophospholipid metabolism and, thereby, the survival and development of Schistosoma mansoni. MethodsLarge-scale […]
- by Kim, A. H., Krummenacher, B., Yeung, J., Koes, D. R., Lee, R. E. C.Cells use a limited number of receptors to sense and process molecular information from their environment. In the classical view of signaling, receptor-ligand affinities determine binding kinetics, in timescales of diffusion, where their time-averaged contact duration regulates rapid cytoplasmic signaling events to coordinate cellular responses. For some cytokines, single receptor-ligand binding events can initiate large multiprotein complexes in the cytoplasm that assemble over tens of minutes, bringing to question how cytokine affinity influences the sensitivity and strength of signaling. Here, […]
- by Cruz, E. R., Johnson, A. N., Pujari, V., Nguyen, T., Stadlmeier, M., Wang, J., Jacob, C., McAlister, G. C., Remes, P. M., Wühr, M.Proteomics workflows have traditionally been divided into discovery-based and targeted approaches, with instrumentation optimized specifically for each. Discovery experiments typically utilize high-resolution analyzers while targeted workflows rely on the sensitivity and specificity of triple quadrupole systems. Recently, a quadrupole-ion trap instrument (Stellar MS) demonstrated superior performance for targeted applications compared to conventional triple quadrupoles. In this study, we expand the capabilities of this platform to multiplexed shotgun proteomics using complement reporter ion quantification in an ion trap (iTMTproC). Benchmarking experiments […]
- by Ripamonti, A., Lacassin, M., Droghetti, R., Bokinsky, G., Cosentino Lagomarsino, M.Cells regulate gene expression by balancing transcriptional resources across different functional groups of genes. In bacteria, second messengers such as ppGpp and cAMP control ribosome biogenesis and metabolic gene expression, respectively. While these regulators are typically studied in isolation, we provide a theory showing that their effects are intertwined due to global transcriptional competition. Using experimental data from RelA overexpression and a mechanistic modeling framework, we show that ppGpp-mediated repression of ribosomal genes competes for transcriptional resources with cAMP-driven activation […]
- by Totska, K., Barata, J. C. V. V., Sandt, W., Meyer, D. H., Schumacher, B.The aging process is characterized by a general decrease in physical functionality and poses the biggest risk factor for a variety of diseases such as cancer, cardiovascular diseases, and neurodegenerative disorders among others. Understanding the naturally evolved mechanisms that slow aging and rejuvenate an animal could reveal important concepts how to prevent age-associated diseases and even revert aging. The C. elegans dauer state is a robust and long-lived alternative developmental state that after dauer exit has a normal adult lifespan […]
- by Banker, R. M. W., Stachowicz, J. J., Gold, D.The study explores the effects of elevated pCO2 on shell calcification, microbiome composition, and gene expression in a strain of Pacific oyster (Magallana gigas) selectively bred for low-pH resistance. Juvenile oysters reared under low-pH conditions exhibited increased shell mass compared to the control population by 51 days post-fertilization, despite high variance in shell size at earlier stages. Microbiome analyses revealed significant shifts in community composition under low-pH conditions, particularly in bacterial taxa involved in CO2 production and biogeochemical cycling, which […]
- Transcriptomic analysis of mitohormesis associated with lifespan extension in Caenorhabditis elegansby Kim, J., Garcia, G., Dutta, N., Higuchi-Sanabria, R.Non-lethal exposure to mitochondrial stress has been shown to have beneficial effects due to activation of signalling pathways, including the mitochondrial unfolded protein response (UPRmt). Activation of UPRmt restores function of the mitochondria and improves general health and longevity in multiple model systems, termed mitohormesis. In C. elegans, mitohormesis can be accomplished by electron transport chain inhibition, decline in mitochondrial translation, decreased mitochondrial import, and numerous other methods that activate UPRmt. However, not all methods that activate UPRmt can promote […]
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