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Cancer pathway connectivity resolved by drug perturbation and RNA sequencing

Pathway inhibitors are a backbone of cancer treatment. The configuration of pathway dependencies varies from tumour to tumour. Better treatment for individual patients could be designed if the pathway wiring were readily measurable. Here, we characterise the transcriptional responses of 116 lymphoma patient samples exposed to ten drug perturbations. We used factor analysis to decompose individual and shared drug effects, thereby generating a pathway connectivity map of chronic lymphocytic leu...

— Do, T. H. L., Lohoff, C., Jung, F., Kummer, S., Pohly, M. F., Scheinost, S., Huellein, J., Benes, V., Huber, W., Lu, J., Zenz, T. 2025-12-14 00:00:00

The cytosolic PRMT5-CDK4 complex impairs cell cycle kinase signaling

Both, protein arginine methyltransferases (PRMTs) and protein kinases are critical regulators of cellular processes and frequently dysregulated in malignancy. To systematically study the crosstalk of the two regulatory enzyme classes, we used parallel yeast two-hybrid matrix screening and defined 45 interactions connecting 4 PRMTs and 20 human kinases. The PRMT-kinase network revealed a strong association between PRMTs and cell cycle/mitogen-activated kinases. Notably, the PRMT5-CDK4 emerged ...

— Masser, S., Lotteritsch, T., Ludwig, A. E., Halwachs, B., Annerer, E., Mussbacher, M., Stelzl, U. 2025-12-14 00:00:00

Multi-omics analysis reveals vitamin D metabolism, hyper-IgE genes, and epithelial barrier dysfunction in hazelnut allergy

Background: Hazelnut allergy is a major cause of food-induced anaphylaxis yet remains poorly defined at the molecular level. Objective: We aimed to identify molecular differences between individuals with primary hazelnut allergy and nonallergic controls by investigating a comprehensive spectrum of omics profiles in immune cells. Methods: We analysed DNA methylation, transcriptomic and proteomic profiles in hazelnut-stimulated and unstimulated immune cells. Results: Across analyses, we identif...

— Jeanrenaud, A. C. S. N., Arnau Soler, A., Ghauri, A., Marenholz, I., Mertins, P., Beyer, K., Worm, M., Lee, Y.-A. 2025-12-13 00:00:00

DISCO-seq: 3D single-cell transcriptomics of intact biological systems

Single-cell transcriptomics has transformed tissue analysis, yet current methods struggle to integrate whole-tissue 3D architecture. Conventional techniques restrict molecular profiling to pre-selected 2D sections, losing systemic context and introducing anatomical bias by sampling less than 0.001% of a whole organism. To overcome these challenges, we developed DISCO-seq, a tissue-clearing chemistry that enables superior RNA accessibility compared to fresh or fixed tissues. DISCO-seq integrat...

— Bhatia, H. S., Simons, L. H. A., Kuemmerle, L. B., McCabe, C., Jansen, S., He, Z., Ali, M., Jeridi, D., Todorov, M. I., Hoeher, L., Padmarasu, S., Park, H. E., Thevis, J. F., Bartos, L. M., Singh, I., Ussar, S., Gorgulu, K., Alguel, H., Roberts, K., Bayraktar, O. A., Brendel, M., Theis, F. J., Treutlein, B., Regev, A., Erturk, A. 2025-12-13 00:00:00

RhizoGrid: Illuminating Spatial Rhizosphere Dynamics

The rhizosphere microbiome directly influences plant health and acclimation to extreme environments, yet plant-microbe interactions in the rhizosphere have proven complex and difficult to study. We present RhizoGrid, a new methodological framework that integrates a 3D-printed pot structure with spatial measurements of root structure, metabollite and taxonomy to detect links between metabolites and microbes along a soil-grown root system. The RhizoGrid identifies microhabitats hidden belowgrou...

— Handakumbura, P. P., Rivas Ubach, A., Battu, A., Anthony, W. E., Schultz, K., McClure, R., Varga, T., Jansson, C., Egbert, R. 2025-12-13 00:00:00

Evaluating the performance of photon- and electron-based fragmentation methods in Omnitrap-LCMS analysis of N-glycopeptides

To date, collision-induced dissociation and methods based on electron transfer dissociation are considered the standard approaches for the mass spectrometry analysis of N- and O-glycopeptides, respectively, allowing for identification of both peptide and glycan compositions. In recent years, alternative fragmentation methods such as ultraviolet photodissociation (UVPD) and more energetic versions of electron-based techniques (such as electron ionisation dissociation, EID) have been shown to b...

— Levin, N., Mohammed, S. 2025-12-12 00:00:00

Bifunctional transcriptional effector domains control gene expression pulses in an occupancy-dependent manner

Dynamic gene expression pulses enable adaptive response to stimuli and can be generated in natural and synthetic systems. Controlling these dynamics typically involves circuits consisting of multiple genes and transcription factors (TFs). Here, we discover a new class of bifunctional transcriptional effector domains that can first activate and subsequently repress the same gene, producing dynamic gene expression pulses from a single input. These pulse dynamics arise from distinct, temporally ...

— Andrews, C. J., Costa, E. J., Janer Carattini, G. L., DelRosso, N. V., Fujimori, T., Shimasawa, M., Bintu, L. 2025-12-12 00:00:00

Climate risk for Italian habitats

Climate change is a major driver of global biodiversity loss, and Europe is no exception with several areas exposed to high climate velocity and/or magnitude. Within the rapidly warming Europe, Italy is facing particularly high risk as part of the Mediterranean region with potentially dramatic consequences for its diverse habitat types. While species-level effects of climate risk are widely investigated, habitat-level exposure to climate change has rarely been assessed. This reduces the compr...

— Mezzanotte, V., Cimatti, M., Burrascano, S., Di Marco, M. 2025-12-12 00:00:00

Single-cell heterogeneity in interferon induction potential is heritable and governed by variation in cell state

Type I and III interferons (IFNs) are among the first lines of defense against viral infections, yet they are generally only produced by a tiny fraction of infected cells. Here, we show that variability in tonic cell signaling significantly influences cells ability to produce IFN upon stimulation with the synthetic double-stranded RNA, polyinosinic:polycytidylic acid (pIC). Using single-cell approaches, we found that members of the activator protein (AP)-1 transcription factor were implicated...

— Thayer, E. A., Shipman, G., Rivera-Cardona, J., Mahajan, T., Teo, Q. W., Paez, J. S., Lederer, J., Chen, J., Wu, N. C., Maslov, S., Brooke, C. B. 2025-12-12 00:00:00

StereoMapper: Clarifying Metabolite Identity Through Stereochemically Aware Relationship Assignment

Inaccuracies in metabolite cross-mapping frequently introduce errors into genome-scale metabolic models (GEMs). A key challenge lies in distinguishing truly identical metabolites from closely related structural variants, such as stereoisomers, across biochemical databases. StereoMapper addresses this issue by establishing stereochemically aware relationships that clarify metabolite identity. It operates entirely on structural information, using molecular structures to infer equivalence and de...

— McGoldrick, J., Pagni, M., Alwer, S., Cooney, J., Makosa, N., Niknejad, A., Moretti, S., Murphy, J., Martinelli, F., Bridge, A. J., Thiele, I., Fleming, R. M. 2025-12-11 00:00:00

Time-dependent bistability leads to critical slowing down during floral transition in Arabidopsis

Developmental transitions occur in the life cycles of all multicellular organisms. Despite their fundamental relevance, the underlying dynamics remain poorly understood. In plants, floral transition is a key developmental process whereby the shoot apical meristem changes from producing leaves to flowers. Using quantitative imaging, developmental genetics and dynamical systems theory, we show that a time-dependent bistable switch between APETALA2, a key floral inhibitor, and the floral activat...

— Rodriguez-Maroto, G., Wang, K., Casanova-Ferrer, P., Cerise, M., Coupland, G., Formosa-Jordan, P. 2025-12-11 00:00:00

Image-based morphological profiling of autophagy phenotypes in Zika virus infected cells

Autophagy is a dynamic intracellular process that is essential in maintaining cellular homeostasis. Its potential as a therapeutic target is exemplified by its dysregulation in many disease states such as Zika virus (ZIKV) infection. ZIKV poses a significant burden to human health and hijacks autophagy to disrupt development. Here, we develop an experimental and computational pipeline to dissect ZIKV hijacking of autophagy in live cells. We build on our previously developed high-throughput sc...

— Adia, N. A. B., Shah, P. 2025-12-11 00:00:00

Building dynamical models of multi-step state transitions from single cell gene expression trajectories

Multi-step cell state transitions often occur in biological processes, such as cell differentiation and disease progression, yet the regulatory mechanisms governing these transitions remain unclear. Here, we introduce NetDes, a computational method that integrates top-down and bottom-up systems biology to infer core transcription factor regulatory networks and build ODE-based dynamical models from single-cell gene expression trajectories. We demonstrate that NetDes predicts regulatory interac...

— You, Y., Caranica, C., Lu, M. 2025-12-11 00:00:00

Model-driven exploration of underground metabolism reveals drivers of metabolic innovation in Pseudomonas putida

Beyond the heterologous expression of genes to generate microbes with novel properties, evolutionary engineering offers a complementary approach by exploiting adaptive processes to refine and expand cellular functionalities in biotechnology. A promising source for the generation of novel metabolic functions is the so-called underground metabolism, i.e., the subnetwork conformed by catalytically inefficient promiscuous enzymatic activities without an apparent physiological role. In this work, ...

— Canalejo, F. J., Nogales, J. 2025-12-11 00:00:00

Discovering cell types underlying rare disease phenotypes using scRNA-seq data from non-diseased tissues

Despite their low individual prevalence, rare diseases collectively pose a significant health burden, affecting millions of people worldwide. These conditions often result from single-gene mutations, yet the cellular contexts in which these alterations act remain largely unknown--information crucial for improving diagnosis and treatment. As patient-derived samples are scarce, we use single-cell RNA sequencing (scRNA-seq) data from non-diseased tissues to identify relevant cell populations. We...

— Novoa, J., Pazos, F., Chagoyen, M. 2025-12-11 00:00:00

When Task-Specific Learning Outperforms Transfer Learning: A Benchmark of Gene and Expression Encoding Strategies

AO_SCPLOWBSTRACTC_SCPLOWSingle-cell foundational models have emerged as a powerful tool for learning generalizable cellular representations from large-scale data. Most models in this domain use transformer backbones, which require careful engineering of gene and expression encoding strategies, yet there is no consensus on which encoding techniques are effective. While benchmarking efforts up to date have focused on evaluating downstream applications using already pretrained models, we take a ...

— Sadalski, I. 2025-12-09 00:00:00

Prediction variability in physiologically based pharmacokinetic modeling of tissue disposition under deep uncertainty

Physiologically based pharmacokinetic (PBPK) models are increasingly invoked in virtual screening workflows for therapeutics. These mechanistic models project pharmacokinetic outcomes from molecular properties, with data-driven models acting as intermediaries to map molecular structure to PBPK input parameters. Errors in predicted parameters and unvalidated assumptions within PBPK models expose PK predictions to deep uncertainty. Herein, we examine how these uncertainties affect the predictio...

— Farahat, M., Flaherty, D., Fox, Z. R., Akpa, B. S. 2025-12-09 00:00:00

An integrative framework identifies cooperative targeting of host pathways by tick salivary miRNAs

Ticks are ectoparasites that modulate host responses to sustain prolonged blood feeding, and in Ixodes ricinus, salivary microRNAs (miRNAs) represent promising candidates for manipulating host gene expression. Using phylogenetic footprinting combined with cooperative targeting analysis, we identified deeply conserved miRNA-mRNA interactions that appear essential for the tick lifecycle and its ability to parasitize diverse vertebrate hosts. Our findings show that conserved tick miRNAs can mimi...

— Medina, J. M., Kotsyfakis, M., Hackenberg, M. 2025-12-09 00:00:00

NeighborFinder: an R package inferring local microbial network around a species of interest

1MotivationUnderstanding interactions from microbiome data is a central aspect in microbial ecology, as it provides insights into ecosystem stability, disease mechanisms, and can be used to design synthetic communities. Current network inference tools reconstruct global networks from co-abundance data, which means they capture the overall correlation structure for the entire set of taxa considered. These approaches are computationally intensive and suboptimal when the focus is on the local ne...

— Sola, M., Paravel, A., Auger, S., Chatel, J.-M., Plaza Onate, F., Le Chatelier, E., Leclerc, M., Veiga, P., Frioux, C., Mariadassou, M., Berland, M. 2025-12-09 00:00:00

RamanOmics Decodes Spatial Vibrational-Molecular Architecture and Rewiring in Aging and Repair

Aging and tissue repair involve multilayered and spatially heterogeneous remodeling across transcriptional, biochemical, and cellular dimensions, yet prevailing definitions rely on isolated molecular markers that obscure how biochemical and transcriptional states co-evolve in tissues. Here we present RamanOmics, a multimodal framework that integrates single-nucleus RNA sequencing (snRNA-seq), spatial transcriptomics, and label-free Raman imaging to map the spatial vibrational-biochemical and ...

— Zhang, K., Chen, X., Monticolo, F., Sorrentino, S., Huang, H., Callahan, C., Qiao, Y., Zhou, J., Brodowska, S., Sapantzi, S., Qi, J., Wu, Y., Dang, T. N. S., Viggiani, F., Ho, C.-K., Xu, Y., J. Kobayashi-Kirschvink, K., Mung, T., Phatnani, H., Dou, Z., Kang, J. W., So, P. T. C., Shu, J. 2025-12-08 00:00:00

The Gibbs free energy landscape based on liver metabolome revealed thermodynamic robustness against fasting and obesity

Mammalian liver metabolism undergoes a substantial shift during fasting. Thermodynamic principles impose fundamental constraints on metabolism, and the Gibbs free energy change of reaction ({Delta}rG') indicates the reactions direction and distance from equilibrium. However, {Delta}rG' landscapes in intact mammalian organs remain largely uncharacterized. Here, we mapped {Delta}rG' profile of glucose metabolism in mouse liver during fasting, using experimentally measured absolute metabolite co...

— Abekawa, T., Ohno, S., Hirayama, A., Soga, T., Kuroda, S. 2025-12-08 00:00:00

Spatially distinct chromatin compaction states predict neoadjuvant chemotherapy resistance in Triple Negative Breast Cancer

Organisation and dynamics of chromatin play a key role in regulation of cell state and function. In cancer, chromatin plasticity is known to be important in control of drug resistance, but the relationship between chromatin compaction and chemotherapy response within complex tissue settings remains unclear. Here, we measured single nuclei chromatin compaction using fluorescence lifetime imaging microscopy (FLIM) in situ in whole biopsies from 53 pre treatment and 14 post surgery tissue sample...

— Mealem, R., Phillips, T. A., Rose, L. A., Marcotti, S., Parsons, M., Zaritsky, A. 2025-12-08 00:00:00

Longitudinal Metabolomic Profiling of Biogenic Amines in Plasma and CSF, and Their Correlation, Reveals Sex-Specific and Age Changes in TgF344 Alzheimer's Disease Transgenic and Wildtype Rats

BackgroundAlterations in amine metabolism have been implicated Alzheimers disease (AD). Cerebrospinal fluid (CSF) and plasma are key biofluids in AD research. CSF is considered to better reflect brain metabolic alterations than plasma, while plasma can be obtained more easily. However, plasma-CSF relationships are unclear. AimTo investigate longitudinal changes of amines in plasma and CSF, and their correlation across the two, in male and female TgF344 AD transgenic versus wildtype (WT) rats...

— Yin, C., Nelen, I., Harms, A., Hartman, R., Bos, S., Nijgh-van Kooij, C., Hankemeier, T., Kindt, A., de Lange, E. 2025-12-08 00:00:00

CRISPR-based neuromorphic computing for solving regression and classification

The CRISPR-dCas9 system has emerged as a versatile platform for programmable gene regulation, offering unique advantages in modularity and orthogonality for constructing synthetic genetic circuits. Here, we present a novel architecture for biomolecular neural networks based on dCas9, guide RNAs, and antisense RNA sequestration. Through mathematical modeling and steady-state analysis, we demonstrate that this system functions as a molecular perceptron with a threshold activation function analo...

— Montufar, C., Wang, Y., Britto Bisso, F., Mehta, A., Cuba Samaniego, C. 2025-12-07 00:00:00

Meta-PepView: a metaproteomics performance evaluation and visualization platform

Microbial community proteomics is rapidly gaining traction as it allows exploration of functional processes in microbial ecosystems. Consequently, there is a growing need for user-friendly tools that enable performance evaluation and interactive visualization of the increasingly complex community proteomics data. We introduce meta-PepView, a web-based platform that enables performance evaluation and interactive visualization of metaproteomics data, ensuring transparent and reproducible metapr...

— van der Zwaan, R., van Olst, B., van Loosdrecht, M. C., Pabst, M. 2025-12-07 00:00:00

Bioactive Cationic Lipidated Oligomers (CLOs) as Antimicrobial Materials: Metabolomic Insights into MRSA Membrane Disruption

The escalating incidence of antimicrobial resistance in Staphylococcus aureus, particularly the methicillin-resistant strain (MRSA), necessitates the development of novel therapeutic strategies. Cationic lipidated oligomers (CLOs) have emerged as promising membrane-active antimicrobial agents; however, their mechanisms of action remain insufficiently understood. In this study, untargeted metabolomics was employed to systematically profile the temporal metabolic perturbations induced by two st...

— Mahboob, M. B. H., Tait, J. R., Anderson, D., Hussein, M., Quinn, J. F., Velkov, T., Creek, D. J., Whittaker, M. R., Landersdorfer, C. B. 2025-12-07 00:00:00

Discovering Glycosylation-Dependent Protein Function by Thermal Proteome Profiling

Protein glycosylation regulates essential cellular processes including protein folding, stability, and cell-cell interactions; however, how aberrant glycosylation impacts protein function and interaction networks remains poorly understood. Here we combine mass spectrometry-based proteomics, chemical glycobiology, and molecular dynamics simulations to systematically investigate glycosylation dependent protein stability and function. By perturbing the secretory pathway at defined steps, we gene...

— Hevler, J. F., Sojitra, M., Caval, T., Schoof, M. L., Mateus, A., Bertozzi, C. 2025-12-07 00:00:00

The analysis of a large dataset of PCR-test results in the community reveals the impact of age, variants and vaccination status on SARS-CoV-2 viral dynamics

The COVID-19 pandemic has shown the value of large-scale community PCR tests for epidemic surveillance, but the viral load measurements they provide have seldom been exploited to reconstruct within-host trajectories. Because these data are collected for diagnostic rather than research purposes, they are characterized by sparse longitudinal follow-up, heterogeneous sampling, and missing metadata, raising uncertainty about their usefulness to reconstruct with-host viral dynamics. We first cond...

— Beaulieu, M., Hoze, N., Vieillefond, V., Goetschy, T., Cosentino, G., Blanquart, F., Debarre, F., Guedj, J. 2025-12-07 00:00:00

Core elements play distinct roles in promoter birth and transcriptional regulation

Gene expression shapes phenotypes and evolution. However, studies of gene regulation focus on transcription factors, overlooking core promoters. To investigate how promoters emerge and regulate transcription, we determined the sequence-function landscapes of core elements, -35 and -10, in constitutive and transcription factor-regulated promoters in Escherichia coli. Characterization of in vivo transcriptional landscapes and in vitro RNA polymerase-promoter interactions showed the -10 element ...

— Kuo, S.-T., Shen, W.-Y., Lai, S.-W., Ni, C.-W., Chang, C.-C., Palmai, Z., Yang, L.-W., Chan, N.-L., Lee, I.-R., Chou, H.-H. D. 2025-12-04 00:00:00

Sequestration-based Protein Neural Networks Tolerate the Effects of Shared Translational Resources

Biomolecular neural networks (BNNs) offer a promising framework for implementing advanced computation in living cells, but their performance in vivo is fundamentally constrained by competition for cellular resources. In this work, we develop a mathematical and computational framework to analyze how shared translational resources (i.e., competition for ribosomes) affect protein neural networks implemented via molecular sequestration. Focusing on classification tasks, we show that ribosome comp...

— He, E., Britto Bisso, F., Cuba Samaniego, C. 2025-12-04 00:00:00