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Search indexed bioRxiv preprints in genomics, neuroscience, cell biology and bioinformatics. Read source abstracts and check manuscript versions; preprints are not peer reviewed.

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98 records · Page 3Linked to original sources

bioRxiv2026

Seed Microbiome Transfer Mitigates Intergenerational Dysbiosis, Modulates Plant Defenses and Suppresses Foliar Disease

Antibiotic-induced disruption of plant-associated microbiomes has the potential to alter host health beyond the directly exposed generation, yet whether the effects of dysbiosis are transmitted through the seed microbiome remains unknown. Here, we investigated the intergenerational impacts of streptomycin-induced dysbiosis in tomato (Solanum lycopersicum), demonstrated that seed microbiome transfer (SMT) restores progeny microbiome function and disease resistance, and characterized the underlying physiological and genetic mechanisms. Parental streptomycin exposure altered the composition of progeny rhizosphere bacterial communities, reduced expression of defense-associated genes, and increased susceptibility to Xanthomonas perforans. Suppression of immune gene expression was strongly associated with increased disease severity, indicating that parental dysbiosis impaired progeny plants ability to mount effective immune responses. Transfer of the seed microbiome from healthy plant donors partially restored rhizosphere community composition, reduced disease severity and recovered defense gene expression of three genes. Together, our findings demonstrated that antibiotic exposure microbiome disturbance generates intergenerational legacy effects that influence plant immunity and disease susceptibility and seed microbiome transfer can counteract this dysbiosis across generations.

plant biology↗

bioRxiv2026

Proteolytic Remodeling of Cargo Receptor Networks by RHBDL4 Tunes Secretory Pathway Flux

Cargo receptors are central organizers of the secretory pathway, yet the mechanisms controlling their abundance remain poorly understood. The endoplasmic reticulum (ER)-resident intramembrane protease RHBDL4 promotes substrate turnover via a non-canonical branch of ER-associated degradation and has recently been implicated in regulating secretory pathway components. We previously identified the p24 cargo receptor TMED7 as an RHBDL4 substrate, suggesting that cargo receptor turnover contributes to secretory pathway regulation. Here, quantitative proteomics identify members of the ER-Golgi intermediate compartment (ERGIC) cargo receptor family as endogenous RHBDL4 substrates, demonstrating that RHBDL4 targets multiple cargo receptor families within the early secretory pathway. Accordingly, RHBDL4 modulates multiple ERGIC-dependent transport pathways. In addition, unbiased secretome analysis reveals increased secretion of lysosomal precursor proteins upon RHBDL4 ablation. Mechanistically, we show that this phenotype is mediated, at least in part, by RHBDL4-dependent cleavage of the lysosomal cargo receptor sortilin/SORT1. Together, these findings identify cargo receptors as a major class of RHBDL4 substrates and establish proteolytic remodeling of cargo receptor networks as a mechanism for regulating secretory pathway flux.

cell biology↗

bioRxiv2026

Non-invasive forecasting of skin cancer evolution through longitudinal hair sampling

The ability to longitudinally track clonal evolution non-invasively would transform cancer interception strategies, long before late-stage disease when most cancer genomes are analysed. Here, we demonstrate that repeated hair sampling from the same individual followed by exome sequencing enables tracking of somatic evolution in vivo over several months after chemically induced skin carcinogenesis. We found that hair follicles accumulate a higher mutation burden than spatially-matched skin and harbour mutations that spread into surrounding epidermis and persist throughout tumour progression. DNA-damaged follicles enter sustained quiescence that delays replication and repair, creating a reservoir for long-lived mutations. During premalignant progression, carcinogen-associated mutations become enriched as follicular clones expand into adjacent skin. Mutation tracking identified genes that may govern tumour predisposition and initiation, many of which are mutated at high incidence in human cutaneous squamous cell carcinoma cohorts. Hair follicles therefore provide a non-invasive readout to forecast the early development of skin cancer, enabling patient risk stratification.

cell biology↗

bioRxiv2026

Scalable proxiloids enable human-relevant assessment of kidney proximal tubule toxicity

Drug-induced injury to the human proximal tubule (PT) is a leading cause of acute kidney injury and drug attrition, yet remains difficult to predict preclinically. PT toxicity arises from the coupling of transporter-mediated xenobiotic accumulation and high oxidative metabolic demand. Current models lack key aspects of PT physiology or are difficult to scale for toxicity testing. New Approach Methodologies (NAMs) address this challenge through human-relevant in vitro systems. Here we introduce proxiloids, a scalable suspension-based human induced pluripotent stem cell differentiation strategy. Within 14 days, proxiloids form lumenized, polarized tubular organoids enriched for PT identity, with functional transport and oxidative metabolic competence. Proxiloids are compatible with genetically encoded reporters and standard multiwell assays, enabling detection of defined stress responses. They recapitulate aminoglycoside nephrotoxicity with greater sensitivity than matched two-dimensional cultures and detect adefovir-induced mitochondrial toxicity not predicted in rodents. Together, proxiloids provide a scalable, human-relevant NAM for PT nephrotoxicity assessment.

cell biology↗

bioRxiv2026

The nuclear actin cytoskeleton supports DNA double-strand break repair via VCP-mediated extraction of the KU70/80 complex from damaged chromatin

Double-strand breaks (DSBs) are critical lesions in genomic DNA, and their accurate repair is essential for maintaining genome stability. The nuclear actin cytoskeleton has been implicated in homology-directed repair (HDR) of DSBs. However, the underlying mechanism remains poorly understood. Here, we report that Myosin VI (Myo6), an actin-based motor protein, cooperates with F-actin in end resection and DSB mobilization. Our findings reveal that Myo6 directly interacts with both KU70 and the ubiquitin-dependent segregase VCP to facilitate the extraction of the KU70/80 complex from chromatin. This process is supported by F-actin, revealing an interplay between nuclear actin dynamics and the DSB repair machinery. By elucidating the function of Myo6 and its direct interactions with key repair factors, our study provides mechanistic insight into how repair mechanisms rely on nuclear actin to safeguard genome integrity.

cell biology↗

bioRxiv2026

Germ granules act as repositories for RNA and protein molecules essential for zebrafish germline development

Germ granules are conserved, phase-separated ribonucleoprotein condensates enriched in germline determinants, yet their precise function remains unclear. Using quantitative live imaging, translational reporters, and targeted disruption of germ granule assembly in zebrafish primordial germ cells, we show that germ granules are dispensable for germ cell fate, migration, and gamete production. Instead, granules act as reservoirs, sequestering transcripts and releasing them gradually for cytoplasmic translation. Under heat stress or translational inhibition, granules further accumulate mRNAs and canonical stress granule factors, indicating a role in buffering RNA and regulatory protein availability rather than serving as sites of localized translation, as previously proposed. Consistent with this reservoir model, cytoplasmic expression of the germline determinants Nanos3 and Dead end is sufficient to direct somatic cells toward a germline fate even in the absence of germ granules. Correspondingly, germ cells lacking granules develop normally but show reduced persistence of germline RNA expression and impaired fertility. Together, these findings establish zebrafish germ granules as protective condensates that safeguard germline determinants and enhance developmental robustness by buffering the timing and rate of RNA translation.

cell biology↗

bioRxiv2026

Injury size regulates glucose allocation locally and systemically during vertebrate tissue regeneration

Tissue regeneration requires careful allocation of metabolic resources, yet how organisms adjust this allocation in response to varying amounts of tissue loss remains poorly understood. Here, we show that the regenerative metabolic response is not fixed: the size of an injury regulates how glucose is allocated at both local and organism-wide levels. We first demonstrate that tail regeneration requires glucose metabolism in the axolotl (Ambystoma mexicanum), a salamander capable of regenerating centimetre-scale tissues. We then mapped glucose uptake in axolotls regenerating from small or large tail injuries using positron emission tomography/magnetic resonance imaging (PET/MRI) and the radiolabelled glucose analogue [18F]FDG. Glucose uptake was elevated in regenerating tails compared to uninjured tails. During early regeneration, larger injuries induced higher glucose uptake than smaller injuries, correlating with faster regenerative outgrowth. Larger injuries also increased glucose uptake in distant organs, indicating a systemic metabolic response. Together, our findings suggest that metabolic responses tuned to injury size underlie faithful tissue regeneration and establish PET/MRI as a powerful approach for studying whole-body metabolic dynamics in large regenerating vertebrates.

developmental biology↗

bioRxiv2026

Predictability failure in glucose-insulin system for ICU patients

Modern medicine implicitly assumes that physiological responses to intervention are predictably determined by administered treatments. However, physiological systems containing intrinsic delays between the detection of a stimulus and the biological response may violate this assumption. We investigate the human glucose-insulin system as described by the Ultradian model and mathematically demonstrate that clinically relevant forcing protocols-such as pulsatile insulin delivery and step-wise glucose infusion, both commonly used in intensive care units (ICUs)-can induce sustained temporal chaos that may hamper accurate prediction of the physiological response. If not accounted for, these chaotic dynamics could create difficulties in achieving optimal dosing and timing when administering glucose and insulin in clinical or home care settings. This phenomenon, termed delay-induced uncertainty (DIU), arises from the interaction between physiological delay, intrinsic shear near a limit cycle, and external forcing. Using the Ultradian glucose-insulin model, we compute top Lyapunov exponents to quantify predictability. Across a range of pulsatile and step-wise forcing regimes, including stochastic amplitudes drawn from Markov processes, we observe positive Lyapunov exponents, indicating sustained chaos. Our results suggest that delayed endocrine regulation may fundamentally limit the predictive value of the models used to develop glycemic management strategies, with implications for clinical protocols in the ICU.

systems biology↗

bioRxiv2026

GDF15 contributes to inflammasome-associated excessive mechanoresponses of hyperlipidemic PdL fibroblasts

Orthodontic tooth movement relies on a tightly regulated pro-inflammatory and pro resorptive mechanoresponse of local periodontal ligament fibroblasts (PdLFs). Dysregulation is linked to complications such as root resorption and tooth loss. Hyperlipidemic conditions promote excessive PdL mechanoresponses, with growth differentiation factor 15 (GDF15) acting as potential regulator. This study examined the contribution of the inflammasome/pyroptosis pathway as underlying mechanism for dysregulated mechanoresponses. Human PdLFs were treated with palmitic acid (PA) or oleic acid (OA) for six days before 24 hours of compressive loading. PA increased CASP1, CASP4, and CASP3 activity, secretion of IL-1{beta}, IL-18, and HMGB1, and LDH release. Pharmacological blockade and siRNA-mediated knockdown of inflammasome- and pyroptosis-related targets revealed that NLRP3, CASP1, CASP4, and GSDMD partially contributed to monocyte and osteoclast overactivation. Silencing PA-increased GDF15, partially normalized the phenotype, at least in part by inflammasome/pyroptosis regulation. GDF15 acted through extracellular, and a nuclear signaling route, each accounting partially to this phenotype. Together, GDF15 partially regulates the PA-induced, pyroptosis-associated overactivated mechanoresponse alongside pyroptosis-independent mechanisms suggesting it as an interesting target for potential clinical interventions.

cell biology↗

bioRxiv2026

The trade-off between parsimony and model complexity for understanding biomedical mechanisms from mathematical models

Mechanistic mathematical models have been used extensively to provide a deeper understanding of biological mechanisms, including unveiling the regulation of tumour growth and its response to various treatments. However, given the breadth of biological regulatory mechanisms, these models are frequently large and thus prone to potential issues with parameter identifiability. Statistical metrics like the Akaike and Bayesian information criteria can help identify a parsimonious model by balancing goodness of fit against model complexity. Yet simple models may fail to provide sufficient biological insight if they do not adequately capture known physiological processes or mechanisms. A modeller must therefore balance hypothesis generation and biological learning with model tractability. Here, we illustrate this balance using models of ovarian cancer growth and treatment response to cisplatin and immune checkpoint blockade in homologous recombination (HR)-deficient and HR-proficient immunocompetent mouse models. We develop a hierarchy of mathematical models of increasing complexity to describe tumour growth, treatment response, and immune dynamics. Our results highlight the limits of relying purely on statistical metrics for model selection, particularly when the goal is to obtain biological insight and underscore the importance of balancing model complexity to avoid overfitting and parameter unidentifiability.

systems biology↗

bioRxiv2026

Rate of meristem initiation driven by the MADS-WUS axis contributes to floral survival and inflorescence evolution in grasses

Crop domestication has repeatedly shaped inflorescence architecture to improve floral production, but mechanisms coordinating the rate of floral initiation, maturation and survival remain unclear. Combining morphometry, modelling and molecular genetic analyses, we show that floral production in the indeterminate barley (Hordeum vulgare L.) inflorescence follows an "initiate fast-die young" strategy orchestrated by a main MADS-box gene, SPIKELET INITIATION AND FERTILITY (SIF). SIF accomplishes this duality by coordinately terminating the inflorescence meristem via WUSCHEL and activating the floral meristem via APETALA1 (Vrn-H1). Hereby, the ancestral SIF "slow" allele promotes a timely commitment to floral maturation, whereas the derived "fast" allele permits more floral initiations. Postdomestication selection of SIF alleles thus enables diversified reproductive strategies in barley populations to maintain yield traits in the field. Finally, we show that a lineage-specific SIF duplication contributed to meristem fate transition and inflorescence evolution during Triticeae cold adaptation. Our results establish developmental rate as a key driver of architectural innovation and reproductive success.

plant biology↗

bioRxiv2026

Heterogeneous and conserved radiation responses reveal FOXM1-dependent regulation of microcephaly genes in glioblastoma

Glioblastoma (GBM) is characterized by marked heterogeneity, glioma stem-like cells (GSCs), and resistance to therapy. Because GSCs share features with neural progenitor cells (NPCs), we investigated whether neurodevelopmental programs contribute to their response to irradiation. Transcriptional profiling of four patient-derived GSC lines revealed cell line-specific responses, with radiosensitivity correlating with the magnitude of p53 activation and basal expression of its negative regulator, MDM2. Despite this heterogeneity, radiation consistently activated p53-dependent pathways and suppressed cell-cycle programs. Among these, genes associated with primary hereditary microcephaly (MCPH) that regulate NPC proliferation were coordinately repressed. Single-cell RNA sequencing localized this response to G2/M-cycling cells. FOXM1 was similarly reduced following irradiation, emerged as a candidate regulator of a subset of MCPH genes, and correlated with their expression in GBM tumors. Pharmacological inhibition of FOXM1 reduced expression of selected MCPH genes and enhanced radiosensitivity in U251 cells. Together, these findings identify coordinated suppression of a FOXM1-associated MCPH program as part of the GBM radiation response, while suggesting that the radiosensitizing effects of pharmacological FOXM1 inhibition extend beyond this transcriptional axis.

cancer biology↗

bioRxiv2026

m1A58 acts as a conformational checkpoint coupling human initiator tRNA maturation to translation initiation

tRNAs are characterized by extensive chemical modifications that influence tRNA fate. N1-methyladenosine at position 58 (m1A58) is a widespread core tRNA modification linked to physiological and pathological processes. However, how m1A58 coordinate tRNA folding and processing to ensure translational efficiency in mammalian cells remains largely unknown. Using acute dTAG-mediated degradation and CRISPR-Cas9 knockout, we identified initiator methionine tRNA (tRNAiMet) as selectively vulnerable to m1A58 loss, lacking the isodecoder buffering observed for most other tRNA isoacceptors. NMR analysis of the tRNAiMet showed that m1A58 stabilizes D/T-loop interactions, consistent with a maturation-competent conformation. In vitro processing assays further demonstrated that m1A58 promotes RNase P-mediated 5'-leader removal and RNase Z-mediated 3'-trailer cleavage, while La/SSB protects accumulated precursors. Disrupting this checkpoint impaired the assembly of the eIF2-containing 43S pre-initiation complex and global protein synthesis, which was substantially rescued by adding m1A58-modified tRNAiMet. Acute TRMT6 degradation elicited temporally coordinated gene-expression responses involving proteostasis, transport and signaling. Together, these findings establish m1A58 as a conformational checkpoint coupling human initiator-tRNA maturation to translation initiation and stress responses.

molecular biology↗

bioRxiv2026

RSV competes with the host for translational machinery without a host shutoff strategy

RNA viruses often enhance ribosome recruitment to their own mRNAs through non-canonical sequence elements or by degrading host mRNA. Respiratory syncytial virus (RSV) produces mRNAs with host-like features, including 5'-cap and poly(A) tail. Therefore, the virus lacks an obvious mechanism to preferentially protect its own mRNAs or recruit ribosomes. Furthermore, it remains unknown how RSV interacts with antiviral defense pathways that would reduce cap-dependent translation. Using spike-in normalized sequencing of total and ribosome-associated RNA, we found that RSV does not appear to evoke any host shutoff mechanisms to limit the expression of host genes. These findings show that RSV manages to make use of available ribosomes by competing effectively with host mRNAs and any translational shutoff mechanism would be detrimental. Consistent with this, we found that following activation of antiviral host pathways that reduce cap-dependent translation, translation of RSV mRNAs is decreased to the same extent as host mRNAs. Furthermore, we found that RSV infection does not trigger the dsRNA-activated kinase PKR (which initiates the ISR) and OAS (activates endonuclease RNase L) pathways. These data support a model in which RSV achieves viral protein production, not though inhibiting the host, but by successfully competing with host mRNAs and avoiding activation of antiviral pathways.

molecular biology↗

bioRxiv2026

Arabidopsis Acyl-CoA Binding Protein 4, ACBP4, functions in developmentally programmed endoreduplication

Powdery mildew fungi induce localized endoreduplication, a variant of the cell cycle in which DNA is replicated but cells do not divide, in leaf mesophyll cells underlying the fungal feeding structure. Induced endoreduplication occurs concurrent with powdery mildew (PM) spore production and is associated with enhanced metabolic capacity and flux to lipids. The final ploidy of these cells is highly correlated with fungal spores produced and is the consequence of both basal (developmental) ploidy and PM-induced endoreduplication programs. Herein, we find the Arabidopsis lipid trafficking and regulatory protein ACYL-COA BINDING PROTEIN 4 (ACBP4) enhances PM spore production on Arabidopsis leaves. ACBP4 does not limit plant defense but instead supports basal mesophyll cell ploidy, with decreased final ploidy in cells underlying the fungal feeding structure in acbp4 mutants compared to wild-type (WT). Leaf epidermal cell size is decreased and stomatal density is increased in acbp4, consistent with a role for ACBP4 in developmentally programmed endoreduplication. Moreover, hypocotyl elongation in the dark, which is driven by programmed developmental endoreduplication, shows reduced hypocotyl length, cell length and ploidy in acbp4 versus WT. Together, our findings establish a novel means by which a plant ACBP promotes cell metabolism and development, with potential applications to agricultural productivity and quality.

plant biology↗

bioRxiv2026

Gene duplication of SNAPC1 generates transcription factors for snRNAs and sex-specific piRNAs

Piwi-interacting RNAs (piRNAs) are small non-coding RNAs essential for transposon silencing and germline integrity across metazoans. In many species, piRNA expression is sexually dimorphic, yet the molecular mechanisms underlying this sex specificity remain poorly understood. In Caenorhabditis elegans, sexually dimorphic piRNA expression is regulated at the transcriptional level. We previously identified SNPC-1.3, a paralog of the small nuclear RNA (snRNA) activating protein complex (SNAPc/SNPC) subunit SNAPC1, as a male-specific piRNA transcription factor. However, the factors governing female piRNA expression remained elusive. Here, we identify SNPC-1.2, a second SNPC-1 paralog, as a female-specific piRNA transcription factor. SNPC-1.2 interacts with the core piRNA transcriptional machinery, binds female piRNA loci, is required for female piRNA expression, and promotes hermaphrodite fertility. In contrast, a third paralog, SNPC-1.1, retains the ancestral SNAPc function in snRNA transcription and is dispensable for piRNA biogenesis. Together, these findings reveal how gene duplication and functional specialization within the snpc-1 gene family generate specificity factors that direct the core SNAP complex to distinct genomic targets, providing a molecular mechanism for sexually dimorphic piRNA expression while maintaining canonical snRNA transcription.

molecular biology↗

bioRxiv2026

Function-driven geometry directs human pilosebaceous unit development

Single-cell technologies have generated cell censuses of tissues, however, how tissue geometry reflects functional needs remains poorly characterized. The human pilosebaceous unit offers a tractable model, a prenatally-formed complex mini-organ combining hair and sebum production with a stem cell reservoir. Using histomorphology, spatial transcriptomics, and single-cell multiomics on the same human prenatal scalp skin samples (8-19 post-conception weeks), integrated and analyzed using machine learning approaches, we built a spatiotemporal map of pilosebaceous unit development. We demonstrate that epithelial-mesenchymal interactions coordinate cellular fate and organogenesis, using an in vitro hair-bearing skin organoid model to validate this tissue-patterning. In addition, we show sebaceous gland developmental programmes are overcome during tumor formation. Our large-scale multi-modal analysis provides a unique framework for understanding form and function of tissues with applications in tissue engineering and pathology.

developmental biology↗

bioRxiv2026

Lipogenic gene expression and substrate sensitivity in the bovine mammary gland shape milk fat composition

Milk fat is produced by mammary epithelial cells (MEC) through a conserved mechanism shared among all fat-producing cells across biological kingdoms. Although highly conserved, different tissues and organisms produce distinctive fat compositions. Notably, ruminant milk fat is characterized by enrichment in short and medium chain fatty acids. We hypothesized that this unique profile is driven by MEC-specific metabolic characteristics related to their response to lipogenic substrates. To study this, we compared bovine MEC and udder-derived fibroblasts in terms of their lipogenic capacity and fatty acid composition when exposed to lipogenic building blocks. When exposed to acetate, MEC showed coordinated upregulation of acyl-CoA short-chain synthetase 1 (ACSS1) and diacylglycerol transferase (DGAT), while expression of acyl-CoA synthetase long-chain 1 (ACSL1) decreased. Medium chain fatty acids were also elevated in acetate-treated MEC and not in fibroblasts. The role of ACSS1 in the production of medium chain fatty acids in MEC was confirmed by knockdown experiments. Metabolomics analysis showed that in MEC acetate treatment triggered a broad metabolic response, primarily amino acids catabolism, energy and polar lipid metabolism. Collectively, these findings demonstrate effective utilization of acetate for de novo fatty acid synthesis in MEC with preferred tendency to produce medium chain fatty acids.

cell biology↗