bioRxiv Preprints

{
  "doi": "10.64898/2026.07.27.740939",
  "url": "https://www.biorxiv.org/content/10.64898/2026.07.27.740939v1",
  "title": "Live single-molecule imaging reveals global shifts in mRNA mobility during human stem cell differentiation",
  "source": "biorxiv",
  "authors": "Bamford, A.-D.; Gut, G.; Bucholz, T.-O.; Okamoto, R.; Seimiya, M.; Santel, M.; Treutlein, B.; Voigt, F.",
  "version": "1",
  "abstract": "Spatiotemporal regulation of mRNA localisation is fundamental to cell identity specification and function, yet tracking transcript dynamics in living differentiating cells remains technically challenging. Here, we establish a robust pipeline for MS2 tagging of endogenous transcripts in human induced pluripotent stem cells (iPSCs), coupled with single-particle tracking and Hidden Markov Modelling to map mRNA mobility landscapes during differentiation and cell state transitions. Applying this approach to different cytoskeleton-encoding transcripts in diverse contexts -- neural organoids, directly programmed neurons, and vascular organoids -- we reveal a conserved principle: Both, {beta}-actin and {beta}2b-tubulin particle dynamics progressively shift towards constrained, compartmentalised patterns as cells acquire cell type identity. Perturbation experiments demonstrate that microtubule-dependent tethering is a common, conserved mechanism controlling {beta}-actin mRNA localisation in all cell types studied, whereas translation-dependent anchoring and actin filaments contribute in a context-dependent manner. Analysis of particle dynamics in migrating blood vessel progenitors further s",
  "category": "cell biology",
  "published_at": "2026-07-28T00:00:00.000Z",
  "corresponding_author": "Franka Voigt",
  "journal_published_doi": null,
  "corresponding_institution": "University of Zurich"
}

{
  "doi": "10.64898/2026.06.11.731717",
  "url": "https://www.biorxiv.org/content/10.64898/2026.06.11.731717v2",
  "title": "RAI1 safeguards fidelity and tempo of human neurodevelopmental gene expression",
  "source": "biorxiv",
  "authors": "Zhou, B.; Mohanty, S.; Riggle, P.; Tsukahara, T.; Lin, G.; Dang, L. T.; Sutton, M. A.; Iwase, S.",
  "version": "2",
  "abstract": "Human brain development proceeds on an unusually long timeline relative to other species, a feature that is thought to foster advanced cognitive abilities. The Retinoic Acid Induced 1 (RAI1) gene encodes a nucleosome-binding protein, and its haploinsufficiency is responsible for Smith-Magenis Syndrome (SMS), a neurodevelopmental disorder characterized by cognitive impairment with autistic features. However, the role of RAI1 in human neurodevelopment remains unexplored experimentally. Here, we generated isogenic heterozygous and homozygous RAI1 loss-of-function human embryonic stem cell lines and interrogated the roles of RAI1 in neurodevelopmental gene regulation. A longitudinal transcriptome analysis during in vitro cortical development revealed that RAI1 deficiency accelerates the progression of developmental gene expression. Single-cell RNA-seq analysis revealed that RAI1-deficient neuroprogenitors acquire a transient mesoderm-like gene expression signature, followed by a pro-neuronal maturation signature in postmitotic neurons. Unexpectedly, the developmental acceleration signature was exacerbated during NGN2-induced excitatory neuron differentiation, isolating the roles of RAI",
  "category": "neuroscience",
  "published_at": "2026-07-28T00:00:00.000Z",
  "corresponding_author": "Shigeki Iwase",
  "journal_published_doi": null,
  "corresponding_institution": "Department of Human Genetics and Division of Pediatric Neurology, Department of Pediatrics, University of Michigan Medical School, Ann Arbor, MI 48109, USA"
}

{
  "doi": "10.1101/2024.11.21.624653",
  "url": "https://www.biorxiv.org/content/10.1101/2024.11.21.624653v3",
  "title": "Identifying spatially variable genes by projecting to morphologically relevant curves",
  "source": "biorxiv",
  "authors": "Nicol, P. B.; Ma, R.; Xu, R. J.; Moffitt, J. R.; Irizarry, R. A.",
  "version": "3",
  "abstract": "Spatial transcriptomics enables high-resolution gene expression measurements while preserving the two-dimensional spatial organization of the biological sample. A common objective in spatial transcriptomics data analysis is to identify spatially variable genes within predefined cell types or regions within the tissue. However, these regions are often implicitly one-dimensional, making standard two-dimensional coordinate-based methods less effective as they overlook the underlying tissue organization. Here we introduce a methodology grounded in spectral graph theory to elucidate a one-dimensional curve that effectively approximates the spatial coordinates of the examined sample. This curve is then used to establish a new coordinate system that reflects tissue morphology. We then develop a generalized additive model (GAM) to estimate spatial patterns which permits the detection of genes with variable expression in the new morphologically relevant coordinate system. Our approach directly models gene counts, thereby eliminating the need for normalization or transformations to satisfy normality assumptions. A second important advantage over existing hypothesis-testing approaches is that",
  "category": "bioinformatics",
  "published_at": "2026-07-28T00:00:00.000Z",
  "corresponding_author": "Rafael A Irizarry",
  "journal_published_doi": null,
  "corresponding_institution": "Harvard University"
}

{
  "doi": "10.64898/2026.07.24.740580",
  "url": "https://www.biorxiv.org/content/10.64898/2026.07.24.740580v1",
  "title": "Functional Deorphanization and Subtype-Selective Pharmacology of Three Tyramine Receptors in the Disease Vector, Aedes aegypti",
  "source": "biorxiv",
  "authors": "Afifi, S.; Paluzzi, J.-P. V.",
  "version": "1",
  "abstract": "Biogenic amines such as tyramine (TA) and octopamine (OA) are central regulators of insect physiology and behaviour, acting through G protein-coupled receptors (GPCRs) to control reproduction, locomotion, metabolism, olfaction and hydromineral homeostasis. Although TA was once considered solely a biosynthetic precursor to OA, it is now recognized as an independent signaling molecule acting through distinct tyramine receptors (TARs). Owing to their invertebrate-specific roles and absence in vertebrates, TARs represent promising molecular targets for selective insecticide development. In the mosquito Aedes aegypti, a major arboviral vector of dengue and Zika viruses, the functional and pharmacological properties of TARs have not been characterized. Here, we functionally deorphanized and comparatively characterized three putative A. aegypti tyramine receptors (AaTAR1-AaTAR3) using a heterologous assay, revealing subtype-specific pharmacological profiles and antagonist sensitivities. All three receptors were robustly activated by TA in a concentration-dependent manner, whereas OA exhibited significantly lower potency on each receptor subtype, consistent with a strong preference for TA.",
  "category": "zoology",
  "published_at": "2026-07-27T00:00:00.000Z",
  "corresponding_author": "Jean-Paul V. Paluzzi",
  "journal_published_doi": null,
  "corresponding_institution": "York University"
}

{
  "doi": "10.64898/2026.07.24.740627",
  "url": "https://www.biorxiv.org/content/10.64898/2026.07.24.740627v1",
  "title": "PWO1 and TRB proteins coordinate chromatin regulation to prevent premature differentiation and ectopic lignin deposition in Arabidopsis",
  "source": "biorxiv",
  "authors": "Khan, A.; Kusova, A.; Skalak, J.; Ghosh, B.; Yang, T.; Kelling, A. L. V.; Hagemann, L.; Panigrahi, K. C. S.; Hejatko, J.; Prochazkova Schrumpfova, P.; Zhou, Y.; Farrona, S.; Mozgova, I.; Schubert, D.",
  "version": "1",
  "abstract": "The Arabidopsis PWWP-DOMAIN INTERACTOR OF POLYCOMBS1 (PWO1) and Telomere Repeat-Binding Proteins 1-3 (TRB1-3, TRBs) associate with distinct and shared protein complexes involved in epigenetic regulation, yet their cooperative roles in chromatin control and plant development remain largely unexplored. Here, we show that the interaction between PWO1 and TRBs is evolutionarily conserved. Both PWO1 and TRBs associate with plant telomeres, interact at these regions, and are co-enriched at subsets of interspersed telo-box motifs across regulatory regions genome-wide. TRBs facilitate PWO1 binding at shared genomic regions, including telo-box motifs. PWO1 and TRBs share a substantial number of genomic targets and preferentially bind chromatin regions associated with transcriptionally active states, whereas TRBs alone associate with repressive marks at thousands of loci. Genetic analyses show that the pwo1 trb1 trb3 triple mutant displays severe developmental defects, including main stem arrest and early maturation associated with aberrant lignin deposition in interfascicular tissues. In the triple mutant, key enzymes in the lignin biosynthesis pathway are upregulated, indicating that PWO1,",
  "category": "plant biology",
  "published_at": "2026-07-27T00:00:00.000Z",
  "corresponding_author": "Daniel Schubert",
  "journal_published_doi": null,
  "corresponding_institution": "Institute of Biology, Freie Universitat Berlin, 14195 Berlin, Germany."
}

{
  "doi": "10.64898/2026.07.24.740541",
  "url": "https://www.biorxiv.org/content/10.64898/2026.07.24.740541v1",
  "title": "Functional diversification of UBP6 in plant immunity through N-degron pathway regulation",
  "source": "biorxiv",
  "authors": "Dambire, C.; Sanchez, G.; Izquierdo, Y.; Valverde, J. R.; Manrique, I.; Fernandez, A. D.; Gevaert, K.; van Breusegem, F.; Oldham, N. J.; Holdsworth, M. J.; Vicente, J.",
  "version": "1",
  "abstract": "Deubiquitylases are key proteolytic regulators of ubiquitin-dependent cellular processes, catalyzing the removal or remodelling of ubiquitin modifications on substrate proteins, including those targeted for proteasomal degradation. UBIQUITIN PROTEASE (UBP)6 is a deubiquitylase that promotes the abundance of NONEXPRESSOR OF PATHOGENESIS-RELATED GENES (NPR)1, a conserved master regulator of plant immunity. Here, we show that the Arabidopsis thaliana protease METACASPASE (MC)9 site-specifically processes UBP6, generating the E157-UBP6 proteoform, whose stability is controlled by the Arginyl-transferase (ATE) N-degron pathway. We observed that pathogen recognition both triggers UBP6 cleavage and leads to conditional stabilisation of E157-UBP6, which is enhanced as the defence response intensifies. Our data suggest that E157-UBP6, which lacks deubiquitylating activity, may induce inhibition of the proteasome, elevating NPR1 levels and enhancing salicylic acid (SA)-induced gene activation, all of which collectively contribute to restricting pathogen growth. Thus, UBP6 cleavage and N-degron pathway regulation provide distinct proteoforms of UBP6 with specific effects on the immune process",
  "category": "plant biology",
  "published_at": "2026-07-27T00:00:00.000Z",
  "corresponding_author": "Jorge Vicente",
  "journal_published_doi": null,
  "corresponding_institution": "National Centre for Biotechnology (CNB)"
}

{
  "doi": "10.64898/2026.07.24.739825",
  "url": "https://www.biorxiv.org/content/10.64898/2026.07.24.739825v1",
  "title": "Lysyl oxidase drives ccRCC progression by coordinating HIF-2α transcription program with tumor microenvironment",
  "source": "biorxiv",
  "authors": "Ulukan, B.; Saatci, O.; Madrigal, A.; Kim, M.; Tian, W.; Soytas, M.; Mehrjoo, Z.; Sahin, O. S.; Sreenivas, K.; Rao, C. N.; Nishimura, T.; Pillon, V.; Anoma, J.-S.; Hill, E.; Rak, J.; McInnes, C.; Park, M.; Brimo, F.; Tanguay, S.; Russell, R. C.; Najafabadi, H. S.; Riazalhosseini, Y.; Sahin, O.",
  "version": "1",
  "abstract": "Clear cell renal cell carcinoma (ccRCC) is driven by persistent HIF-2 transcription program initiated by VHL loss, yet molecular mediators sustaining this program are poorly defined. Using single-cell transcriptomics, we identified lysyl oxidase (LOX) as a driver of ccRCC progression, selectively enriched in a hypoxia/epithelial-mesenchymal transition (EMT) gene program associated with poor outcome. While LOX oxidizes and stabilizes HIF-2 by antagonizing HUWE1-mediated ubiquitination and degradation, thereby sustaining HIF-2-driven transcription in cancer cells, it also remodels extracellular matrix (ECM) and promotes angiogenesis in the tumor microenvironment (TME). Genetic or pharmacological inhibition of LOX destabilizes HIF-2, disrupts ECM, inhibits angiogenesis, and suppresses tumor initiation, growth, and metastasis in vivo. LOX inhibition enhances anti-angiogenic therapy response and remains effective in belzutifan-resistant HIF-2 G323E-mutant tumors. Nuclear LOX protein correlates with nuclear HIF-2 in high-grade patient tumors. Together, LOX coordinates HIF-2 transcription program with TME and is a therapeutic target in ccRCC.",
  "category": "cancer biology",
  "published_at": "2026-07-27T00:00:00.000Z",
  "corresponding_author": "Ozgur Sahin",
  "journal_published_doi": null,
  "corresponding_institution": "Medical University of South Carolina"
}

{
  "doi": "10.64898/2026.07.24.740568",
  "url": "https://www.biorxiv.org/content/10.64898/2026.07.24.740568v1",
  "title": "Integrated Patient-Derived Xenograft and Patient-Derived Cell Models Reveal Therapeutic Vulnerabilities Beyond Standard-of-Care Therapy in Endometrial Cancer",
  "source": "biorxiv",
  "authors": "Li, T.; Huang, F.; Huang, X.; Pate, E. I.; Rosenmeyer, R.; Messenger, M.; McSweeney, K.; Robinson, S.; Deters, A.; Buchanan, L.; Meehan, M.; Patel, N.; Diekema, A.; Xiong, Y.; Zhang, X.; Meng, X.; Yang, S.",
  "version": "1",
  "abstract": "Endometrial cancer (EC), the most common gynecologic malignancy in the USA, has seen limited improvement in patient outcomes over recent decades, underscoring the need for relevant preclinical models. To address EC heterogeneity, we established an integrated platform of patient derived xenografts (PDXs) and matched patient derived primary cancer cells (PDCs) for disease modeling and systematic drug sensitivity testing. Fresh tumor specimens (n=103) were collected from EC patients to generate PDXs in immunodeficient mice and corresponding PDCs. Fifty-three PDX models were successfully established (52% engraftment rate), with higher success observed in high grade, recurrent, metastatic tumors (70%), compared with their low-grade counterparts (56%). Histopathologic and immunohistochemical analyses confirmed that PDX tumors faithfully preserved morphology, hormone receptor status, and intertumoral heterogeneity across multiple passages. Using 13 PDC models, we performed an unbiased screening of 179 FDA-approved oncology drugs, revealing marked intertumoral variability in drug response. Almost all PDC models exhibited limited sensitivity to NCCN-recommended therapies, highlighting the n",
  "category": "cancer biology",
  "published_at": "2026-07-27T00:00:00.000Z",
  "corresponding_author": "Shujie Yang",
  "journal_published_doi": null,
  "corresponding_institution": "Department of Pathology, University of Iowa, Iowa City, IA, 52242 Department of Pathology, University of Iowa, Iowa City, IA, 52242 Holden Comprehensive Cancer "
}

{
  "doi": "10.1101/2025.05.29.656931",
  "url": "https://www.biorxiv.org/content/10.1101/2025.05.29.656931v3",
  "title": "WITHDRAWN: Deviation Error: assessing machine learning predictions for replicate measurements in genomics and beyond",
  "source": "biorxiv",
  "authors": "Abdulnabi, H.; Westwood, J. T.",
  "version": "3",
  "abstract": "A quantitative measurement can have variation, referred to here as measurement variation, which is a probability distribution. Machine Learning models typically produce a prediction corresponding to the mode of the measurement variation. The Deviation Error is a novel metric, described here, to assess predictions that accounts for measurement variation. Measurement variations in genomics data were explored. Towards a general prescription for modelling genomics measurements, different loss functions were used to fit models on synthetically generated data that mimics genomics measurements. Synthetically generated data offers the ability to know the true underlying value and to control the forms and amounts of noise injected at different stages of data processing. Different datasets were generated with varying levels of noise. Of the loss functions tried, only models fit with the Deviation Error performed as well if not better on any of the combinations of the metrics and datasets.",
  "category": "bioinformatics",
  "published_at": "2026-07-27T00:00:00.000Z",
  "corresponding_author": "Husam Abdulnabi",
  "journal_published_doi": null,
  "corresponding_institution": "University of Toronto Mississauga"
}

{
  "doi": "10.64898/2026.07.24.740621",
  "url": "https://www.biorxiv.org/content/10.64898/2026.07.24.740621v1",
  "title": "Predictive Feature Engineering for Stress Detection using Physiological Signals, A Comparative Study",
  "source": "biorxiv",
  "authors": "Gonzalez Nunez, J. G.; Sabri, S.; Kebria, P.; Crook, J.; Brattain, L.",
  "version": "1",
  "abstract": "This paper presents a two-stage pipeline for implicit feature engineering in time series-based physiological stress detection using electrodermal activity (EDA) signals. In the first stage, we forecast three descriptive statistics of future EDA signals over short horizons (3, 5, and 10 seconds) based on a 60-second context window. In the second stage, a lightweight linear classifier detects stress from these predicted statistics. We evaluate three forecasting architectures spanning the domain expertise spectrum: a domain-specific bidirectional long short-term memory (BiLSTM) recurrent neural network, zero-shot and fine-tuned variants of Amazon Chronos T5 time series foundation model, and the Tabular Prior-data Fitted Network (TabPFN) applied to engineered physiological features. Experiments on the publicly available Wearable Stress and Affect Detection (WESAD) dataset, comprising chest-worn multimodal physiological signals from 15 subjects under baseline and stress conditions, demonstrate that the domain-specific BiLSTM achieves the highest classification performance, with area under the receiver operating characteristic curve (AUC) values ranging from 0.913 to 0.962. TabPFN follow",
  "category": "bioengineering",
  "published_at": "2026-07-27T00:00:00.000Z",
  "corresponding_author": "Jose Gabriel Gonzalez Nunez",
  "journal_published_doi": null,
  "corresponding_institution": "University of Central Florida"
}