- BioRxiv Biochemistry
- BioRxiv Bioinformatics
- BioRxiv Biophysics
- BioRxiv Cancer Biology
- BioRxiv Pharmacology and Toxicology
- BioRxiv Systems Biology
- BioRxiv Zoology
- by Mercuri, R. L. V., Mombach, D. M., dos Santos, F. R. C., Perez-Schindler, J., Huang, Y., Spealman, P., Pintacuda, G., Al'Khafaji, A., Donnard, E. R., Claussnitzer, M., Galante, P. A. F.Transposable elements (TEs) not only account for half of the human genome sequence but also generate transcripts that contribute to transcriptomic diversity. Yet, their repetitive nature has hindered accurate quantification of the full TE-derived transcriptome, a challenge that long-read sequencing can overcome. Here, we combined multiplexed arrays isoform sequencing (MAS-ISO-seq) with a dedicated computational framework (TEscape) to perform an in-depth annotation of the human TE transcriptome. To capture the breadth of human transcriptome diversity, we profiled six representative cell types […]
- by Steenwyk, J. L.Protein language models learn general-purpose representations from large collections of protein sequences and structures, and have advanced the prediction of protein structure and function. ESM3 is a multimodal protein language model that ingests a protein through several channels at once, including amino-acid sequence, three-dimensional structure, secondary structure (SS8), solvent accessibility (SASA), and discrete functional annotations, summing their embeddings into a single residual stream. Little is known about whether these modalities occupy separate subspaces and the depth at which they fuse. […]
- by Bowen, A. E., Hadjivasiliou, Z.Developmental patterns can scale with size during growth, a phenomenon commonly attributed to morphogen scaling. Although patterning is orchestrated by gene regulatory networks (GRNs) activated by morphogens, how GRN dynamics interact with growth is not understood. We present a theoretical framework that integrates morphogen signalling, GRN dynamics, and tissue growth. We show that pattern scaling emerges from the interplay of GRN dynamics and growth, even in the absence of morphogen scaling. This relies on memory effects encoded in the GRNs, […]
- by Amoah, E. I., Bunch, Z., Thomas, H. M., Patch, H. M., Grozinger, C.1. Morphological traits such as floral area and body size are fundamental to ecological research, serving as inputs for studies of pollinator-plant interactions, habitat quality, and biodiversity monitoring. However, accurately measuring these traits from images remains challenging, particularly in complex field conditions where existing tools exhibit reduced accuracy and limited generalizability across taxa. 2. We present EcoMorph, a modular morphological measurement system that leverages the Segment Anything Model 3 (SAM3) to quantify traits across diverse ecological contexts. Unlike task-specific segmentation […]
- by Gur, C., Ravkaie, L., Sharet-Eshed, R., Shalita, R., Avellino, R., Rauchbach, E., Xie, K., David, E., Yagel, G., Zada, M., Yehuda, M. B., Mazuz, K., Von Locquenghien, M. N., Peleg, H., Naparstek, Y., Atlan, K., Kfir-Erenfeld, S., Kuznetsov, Y., Tzemach, R., Lidar, M., Balbir-Gurman, A., Phan, T. S., Freitag, K., Amit, I.Despite major therapeutic advances, a substantial fraction of patients with autoimmune disease remains refractory to treatment. While B cell-targeted CAR-T therapies have shown considerable efficacy, the central contribution of pathogenic T cells to rheumatoid arthritis (RA) suggests that complementary T cell-directed strategies may enable deeper disease control. Using single-cell multi-omics of human RA and experimental models, PDCD1 was identified as a selective marker of synovial disease-associated T cells. We developed PD-1-directed CAR-T cells that potently eliminate these cells in vitro […]
- by Rathod, D., Parrott, K., Levitus, M.Protein oligomerization equilibria are central to many biological processes and are often highly sensitive to environmental conditions such as ionic strength, pH, and ligand binding. Quantitative characterization of these equilibria remains experimentally challenging because stable protein complexes frequently dissociate only at concentrations that are difficult to access with conventional biophysical methods. Fluorescence correlation spectroscopy (FCS) is uniquely suited to this problem, as it provides direct access to diffusion coefficients of fluorescently labeled proteins at nanomolar concentrations. However, the quantitative interpretation […]
- by Lin, C.-Y., Gaweda, B., Manthatis, N., Sreedhar, S., Dubey, V. K., Goodyke, A., Timek, T. A., Rausch, M. K.Tricuspid valve regurgitation is a frequent valve lesion and, if severe, an independent predictor of mortality. In most patients, the valve itself has historically been considered intact. Yet, we have previously shown that the valve may not be an innocent bystander. In multiple sheep models, we have shown that the tricuspid valve thickens and stiffens. This remodeling may contribute to valve disease. Our goal is to extend our investigation of tricuspid valve remodeling to a rodent model, potentially opening scientific […]
- by Chen, Z., Luo, Q.Protein function prediction traditionally relies on structured gene ontology (GO) labels or multi-label classifiers. However, these labels or classifiers cannot flexibly describe molecular function, biological process, cellular component, and free-text functional narratives in a single output. In comparison, generation-based approaches offer an intuitive paradigm for flexible free-text protein annotation, with large language models (LLMs) as a representative method for protein-text modeling. Recent efforts on utilizing LLMs for protein semantic understanding and annotation generation have adopted sequence-only encoding or sequence-text contrastive […]
- by Garcia-Puga, M., Huergo, C., Vidal-Gil, A., Rodriguez-Hidalgo, M., Pikataza-Menoio, O., Levchuk, M., Elicegui, A., Azcue, I., Romero-Grana, L., Moreno-Martinez, L., Osta, R., Lopez de Munain, A., Fernandez, J. A., Alonso-Martin, S.Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease whose diagnosis often remains delayed. Skeletal muscle is increasingly recognized as an early contributor to ALS pathology. Using lipid imaging mass spectrometry (LIMS) in Tibialis anterior muscle from hSOD1G93A mice across disease stages, we identified fiber-type-specific and sex-dependent lipid remodeling. Lipid alterations were detected at the presymptomatic stage, preceding motor neuron loss and clinical symptoms. LIMS distinguished fast-twitch oxidative-glycolytic (type IIA) and glycolytic (type IIB/IIX) fibers and revealed their differential vulnerability […]
- by Evans, W. R., Wells, H. G., Jacob, C., Vellore, A., Huda, R.Brain neuromodulatory systems exert powerful effects on local neuronal circuit function and behavior. In addition to classical actions directly on neurons, growing evidence indicates that neuromodulators also recruit Ca2+-dependent astrocyte mechanisms to regulate synaptic plasticity and network function. The dorsal striatum integrates cortical and thalamic inputs under strong dopamine (DA) and acetylcholine (ACh) neuromodulatory control. To what extent the circuit and behavioral effects of striatal ACh and DA depend on astrocyte Ca2+ activity remains unclear. We show that locomotion elicits […]
- by Arneson, R., Wittstock, W., Marceau, A., Yuan, Y.The continuous transfer of organellar DNA into the nuclear genome during eukaryotic evolution has resulted in the widespread occurrence of nuclear plastid DNA insertions (NUPTs) and nuclear mitochondrial DNA insertions (NUMTs). However, their functional significance in nuclear gene expression and genome evolution remains largely unresolved. In this study, we employed Oxford Nanopore Direct RNA Sequencing (DRS) to investigate the transcription of NUPTs and NUMTs in the Populus nuclear genome and compared their transcriptional characteristics with their genome-wide insertion patterns. Our […]
- by Beard, E. K., Gamer, J. P., Raz, A., Inaba, M.Transposable elements (TEs) are powerful drivers of genome evolution, yet how they persist under selection and become incorporated into host regulatory networks remains poorly understood. In the Drosophila male germline, TEs are highly expressed during the spermatocyte stage, coinciding with activation of giant fertility genes on the Y chromosome. These genes contain megabase-scale introns enriched for repetitive DNA, and three of these genes form prominent nuclear structures known as Y-loops, providing a unique system to investigate gene regulation. Here, we […]
- by Gromak, D., Shaytan, A. K., Herbert, A., Poptsova, M.The p150 isoform of the double-stranded RNA editing enzyme ADAR1 binds Z-DNA and Z-RNA through the conserved winged helix-turn-helix Z domain. Here, we describe an inverse computational design strategy to map protein interactors of Z. We used RFdiffusion and ProteinMPNN to generate around 10,000 synthetic binders optimized for the Z recognition surface, then used their sequences as structural templates for BLASTp searches against the human proteome. Multi-stage screening of around 1,200 candidate regions from 298 proteins via ColabFold pDockQ identified […]
- by Marechal, J. D., Fernandez Diaz, R., Pena Losada, R., Sanchez Aparicio, J. E., Gao, W., Alemany, M.Predicting the location of metal-binding sites in proteins is crucial for fundamental biological questions and biotechnological applications. Over the past decade, the rise in metal-bound protein structures in the Protein Data Bank, combined with advanced statistical models such as deep learning, has accelerated the development of metal-binding site prediction tools. Several approaches are now available, offering high-quality benchmarks and predictive performance. Our initial development in this area is BioMetAll, whose first version was based on backbone pre-organization. Here, we introduce […]
- by Mantuano, P., Mele, A., Boccanegra, B., Tanganyika-de Winter, C., Van De Vijver, D., Schneider, A.-F., Mele, M., Cappellari, O., Tulimiero, L., Engelbeen, S., Suidgeest, E., van der Weerd, L., Aartsma-Rus, A., De Luca, A., Gordish-Dressman, H., van Putten, M.Introduction. The quality of preclinical studies for rare diseases, such as Duchenne muscular dystrophy (DMD), relies on the availability of comprehensive natural disease history data. In addition to the classic BL10-mdx mouse, in recent years, the D2-mdx model has increasingly been used as an alternative model due to its reportedly more severely impaired phenotype. To improve our understanding of disease progression in these two DMD models, we conducted a comprehensive natural history study. Materials and Methods. This involved a cross-sectional […]
- by Zhang, C., Sun, J., Xu, Z., Liao, R., Yin, A., Gao, H., Liu, E., Bao, Y., Zhao, L., Wang, G.Computational modeling of cellular behavior – the virtual cell – has emerged as a stated grand challenge at the intersection of artificial intelligence and biology, yet existing foundation models remain specialized: single-cell models process dissociated transcriptomes only, spatial models require dedicated spatial-aware architectures, and perturbation predictors depend on manually curated knowledge bases that cap generalization. Here we introduce OCellus, a single nine-billion-parameter language model (Qwen3.5-9B) fine-tuned on twenty-two biological tasks that simultaneously addresses all three limitations through three coordinated technical […]
- by Tian, X., Fung, A. A., Shang, X., Zhang, D., Chen, B., Zhang, L., Li, K., Zhong, M., Deng, Y., Yang, M., Lu, Y., Tao, B., Gao, F., Baysoy, A., Lin, X. L., Ivovic, A., Chen, S., Li, F., Xu, M. L., Zhang, X., Gerstein, M., Yang, X., Liu, C., Fan, R.Glycosylation is a fundamental process regulating cellular function, tissue organization, and disease progression. However, comprehensive glycan profiling at single cell spatial resolution remains largely inaccessible, particularly in clinical archival tissues. Here we develop spatial GPT, a multimodal platform for simultaneous profiling of glycans, proteins, and/or transcripts in archival formalin-fixed paraffin-embedded (FFPE) tissues. Using a panel of 30 DNA encoded lectins recognizing major mammalian glycan motifs and structural classes, sequencing-based spatial-GPT (DBiT GPT) mapped the spatial glycome, proteome, and transcriptome across […]
- by Han, J., Opoku, E., Smith, J. D.Background: We previously performed a strain intercross between atherosclerosis resistant AKR Apoe-/- mice and atherosclerosis sensitive DBA/2 Apoe-/- mice and identified the Ath28 quantitative trait locus (QTL) on the distal end of chromosome 2. Congenic strain fine mapping identified the Ath28.1 QTL atherosclerosis modifying subregion, encompassing 217 Kb, containing for only three protein-coding genes, Zbp1, Pck1, and Pmepa1, encoding respectively, Z-DNA binding protein 1, phosphoenolpyruvate carboxykinase 1, and prostate transmembrane protein androgen induced 1. Methods: The effect of macrophage-specific knockout […]
- by Cokol, M., Chorbadjiev, L., Lee, Y.-h., Jamsandekar, M., Gergova, I., Todorov, I., Iossifov, I.Interpretation of genomic variants, positions, and regions depends on reliable annotation – adding evidence such as predicted effect, conservation, population frequency, and gene-level context – yet the underlying resources are numerous, versioned, and assembly-specific. We present the Genomic Annotation Infrastructure (GAIn), a platform that generates transparent, reproducible annotations via declarative pipelines that define annotation tasks as ordered lists of components, called annotators, that produce annotation attributes using genomic resources from Genomic Resource Repositories (GRRs). We provide two public GRRs: a […]
- by Sauer, D. B., Song, J., Marden, J. J., Wang, B., Sowerby, K., Sudar, J. C., Rice, W. J., Wang, D.-N.The human sodium-citrate cotransporter NaCT imports various tri- and dicarboxylates into the cell as TCA cycle intermediates. This substrate uptake process is driven by an inward sodium gradient. The protein is a member of the Divalent Anion-Sodium Symporter (DASS) family. Whereas extensive biochemical and structural studies have been carried out for NaCT, how the substrate binding and translocation is coupled to the sodium gradient remains unclear. Here using single particle cryo-electron microscopy, we determined the structures of the human NaCT […]