Biology subjects

Yu, X.

Publications and source records attributed to Yu, X..

At least 109 records · Page 6Linked to original sources

bioRxiv2026

A mediterranean-mimicking diet harnesses gut microbiota-derived 3-IAA to rejuvenate T cell

Diet profoundly shapes the tumor microenvironment through metabolite modulation, yet the mechanisms linking diet, gut microbiota, and antitumor immunity remain unclear. Here, we demonstrate that a mediterranean-mimicking diet (MedDiet) suppresses tumor growth by orchestrating a microbiota-metabolite-immune axis. MedDiet selectively enriched Bacteroides thetaiotaomicron (B. thetaiotaomicron) in the gut, whose administration recapitulated tumor suppression. Both MedDiet and B. thetaiotaomicron elevated plasma levels of the tryptophan metabolite indole-3-acetic acid (3-IAA). Mechanistically, 3-IAA enhanced CD8+ T cell cytotoxicity and alleviated exhaustion by inhibiting the integrated stress response, sustaining antitumor immunity in vivo. Importantly, 3-IAA synergized with anti-PD-1 therapy to further restrain tumor progression. Finally, we developed a MedDiet Score to predict patient survival and response to immunotherapy. These findings reveal that dietary modulation of gut microbiota can reshape systemic metabolites to potentiate T cell-mediated antitumor responses. Our study identifies 3-IAA as a metabolite-based adjuvant for immune checkpoint therapy and highlights the translational potential of diet-driven immunomodulation in cancer treatment.

cancer biology↗

bioRxiv2026

Dynamic control of Raf-ERK signaling modulates neuronal activity across biological scales

Neuronal activity robustly engages the extracellular signal-regulated kinase (ERK) signaling pathway through Ca2+-dependent mechanisms; however, whether ERK can acutely and causally modulates ongoing neuronal activity remains unsolved due to complex upstream regulation and diverse subcellular functions. Here, we directly address this question using an optogenetic ERK activator, opto-miniRaf, that enables selective, rapid, graded, and reversible control of ERK signaling. Combining this AAV-compatible system with calcium imaging and electrophysiology, we interrogate ERK functions across biological scales, from cultured neurons, acute brain slices, and the intact brain. Acute optogenetic activation of ERK enhances synchronized network burst activity in cultured rat cortical neurons and increases calcium activity of cortical pyramidal neurons in awake and moving mice following non-invasive light stimulation. Together, these results establish ERK signaling as an acute modulator of neuronal and network activity, positioning opto-miniRaf as a generalizable platform for precise spatiotemporal control of intracellular kinase signaling in complex biological systems.

neuroscience↗

bioRxiv2025

Dose-dependent NFI regulation of progenitor lifespan and output underlying human neocortical malformation

Nuclear Factor I (NFI) misexpressions in humans are associated with severe brain malformations, yet the underlying mechanisms remain poorly understood. Here we show that NFIs regulate the broad lineage progression and lifespan of radial glial progenitors (RGPs), and consequently neocortical development in a dose-dependent manner. Human cerebral organoids carrying patient-mimicking NFI mutations exhibit expression level-dependent bidirectional impairments in RGP temporal development, coinciding with patient phenotypes. In mouse models, selective removal of NFIs leads to a dramatic protraction of RGP lineage progression and lifespan, excessive progeny output, and neocortical overgrowth and abnormal folding, whereas overexpression of NFIs accelerates RGP lineage progression, resulting in developmental stage-dependent precocious productions of diverse neural progenies. Moreover, NFIs exhibit a positive auto-regulation and progressive increase in expression, and regulate distinct temporal-specific targets underlying RGP lineage progression. These results suggest that NFIs act as evolutionarily conserved key global temporal regulators of RGP lineage progression and neocortical development. HIGHLIGHTSO_LINFIs affect human RGP temporal development coinciding with patient phenotypes. C_LIO_LINFI removal protracts RGP lineage progression and lifespan with excessive progeny output. C_LIO_LINFI overexpression accelerates RGP lineage progression with precocious progeny output. C_LIO_LINFIs regulate distinct temporal-specific targets underlying RGP lineage progression. C_LI

neuroscience↗

bioRxiv2025

A MYC Family Switch: L-MYC Drives and Maintains Neuroendocrine Lineage Programs in Prostate Cancer

Neuroendocrine prostate cancer (NEPC) is an aggressive, therapy-resistant subtype that emerges through lineage plasticity following androgen receptor (AR) pathway inhibition. Although MYC family oncogenes are central to prostate cancer progression, the role of MYCL (L-MYC) in NEPC has remained unclear. Here, we show that MYCL is selectively and robustly upregulated in NEPC patient samples and cell line models, whereas MYC is downregulated and MYCN remains low, revealing a lineage-associated MYC family switch. MYCL expression strongly correlates with the neuroendocrine lineage regulators ASCL1 and INSM1 and inversely with adenocarcinoma-associated genes. Mechanistically, MYCL activation is not driven by genomic amplification but reflects a permissive epigenetic landscape. Functionally, MYCL overexpression suppresses AR signaling and induces neuroendocrine-like transcriptional reprogramming, whereas MYCL knockdown disrupts neuroendocrine lineage identity and restores adenocarcinoma-associated gene expression, including MYC. We further identify ASCL1 and INSM1 as upstream regulators of MYCL, establishing a conserved neuroendocrine transcriptional axis. Together, these findings define MYCL as a lineage-specific regulator that drives neuroendocrine identity and plasticity in advanced prostate cancer.

cancer biology↗

bioRxiv2025

Temporal boundary gating of auditory sensitivity

Perception unfolds over time, but whether continuous sounds are sampled with uniform sensitivity is unknown. We combine human psychophysics, EEG and rodent neurophysiology to show that local auditory change detection is strongly gated by stimulus boundaries. In humans, brief perturbations inserted at different temporal positions within 0.5-1-s tones revealed an inverted U-shaped sensitivity profile: detection was attenuated near sound onset and offset and maximal mid-epoch, with EEG change responses showing a closely matching dependence on change timing. Electrocorticography in awake rats exhibited homologous temporal weighting, and analogous profiles for amplitude changes and visual motion demonstrated cross-feature and cross-modal generality. To uncover circuit mechanisms, we recorded single units along the inferior colliculus-medial geniculate body-auditory cortex pathway together with laminar local field potentials in A1. Onset-locked suppression of change responses emerged in midbrain and was progressively amplified in thalamus and cortex, whereas the full start-end profile was expressed in granular-layer alpha-gamma power. A simple biophysically grounded model in which onset responses saturate and cortical populations integrate over finite temporal windows recapitulates this pattern, explaining how stimulus boundaries disrupt prospective and retrospective integration and thereby degrade change detection near the beginning and end of sounds.

neuroscience↗

bioRxiv2025

Neocortical temporal patterning by a two-layered regulatory network

In the developing neocortex, a diverse array of neurons with defined types and abundances are systematically generated by a limited population of radial glial progenitors (RGPs) as they undergo successive fate changes. The molecular regulation behind this intricate temporal patterning remains elusive. We undertook in-depth single-cell multi-omics analyses, discovering a two-layered regulatory framework at the core of this process. Central to this are global temporal regulators positioned above a temporal network, consisting of series of transcriptional factor (TF) hub groups under sequential state transitions. This temporal network operates not by restricting TF expressions to discrete temporal windows, but through coordinated transcriptional and chromatin-accessibility dynamics that modulate transient TF regulatory activity. Moreover, global temporal regulators specify the duration of each cascading stage and, consequently, the number of progenies generated at each stage. Loss of global temporal regulators protracts RGP lineage progression, whereas their increased activity accelerates it. These findings suggest a two-layer temporal regulatory system controlling RGP lineage progression and neural progeny output duality in mammalian neocortical development.

neuroscience↗

bioRxiv2025

Microgradients in porosity and canal diameter in femur bone

Bone exhibits hierarchical structural gradients that optimize mechanical performance and regenerative potential. Longitudinal and radial variations in cortical porosity and canal architecture influence load distribution, vascularization, and remodeling. Understanding these gradients is essential for designing scaffolds and implants that mimic native bone structure and function. This study quantified longitudinal and radial microgradients in cortical porosity and canal diameter along the rabbit femur and explored their implications for bone regeneration and repair implant design. Rabbit femora were divided into proximal, mid-shaft, and distal regions. High-resolution micro-computed tomography quantified cortical thickness, porosity, and canal diameter along radial and longitudinal axes in micron-scale resolutions. Compressive mechanical testing of cortical slices determined local moduli, which were correlated with microstructural parameters to establish structure-function relationships. Cortical thickness peaked at the mid-shaft and decreased toward both ends. Porosity and canal diameter increased radially toward the medullary cavity and longitudinally toward the bone ends. Upto 500 micron cortical thickness from the outer surface toward modullary cavity, porosity and canal diameter ranged, respectively, from ~5% and 40 {micro}m at the mid-shaft to ~40% and 110 {micro}m at the ends. At 750 micron cortical thickness, porosity and canal diameter ranged, respectively, from ~5% and 50 {micro}m at the mid-shaft to ~80% and 200 {micro}m at the ends. As expected, compressive moduli declined linearly with increasing porosity and canal size. The mid-shaft, with the lowest porosity and smallest canals, exhibited the highest modulus of around 15{square}MPa, which decreased to 5{square}MPa toward the ends. The rabbit femur displays distinct longitudinal and radial microgradients in porosity and canal architecture that govern local stiffness. These gradients define structural benchmarks for designing functionally graded tissue engineering scaffolds and bone implants that replicate native tissue structure and stiffness transitions to promote osteoconduction, osteoinduction, osteogenesis in bone regeneration and improve osseointegration of bone implants.

bioengineering↗

bioRxiv2025

Prolonged Loss of Oxidative Phosphorylation and Mitochondrial Mass Characterize CD66b+ Leukocytes from Patients with Sepsis

IntroductionSepsis leads to expansion of myeloid-derived suppressor cells (MDSC) and their subtypes. These normally transitory MDSCs suppress T cell activation and alter T cell cytokine production while simultaneously promulgating systemic low-grade inflammation. Immune metabolism can shape cell responses, regulate immune suppression, and enhance effector activity. Although MDSC metabolism has been extensively studied in cancer, the metabolic phenotype of this heterogeneous population in sepsis remains unclear. Our goal was to assess metabolic flux in blood MDSCs during and after sepsis and to stratify these patients clinical features and outcome with differences in metabolic flux that may guide treatment decisions. MethodsPeripheral blood mononuclear cells (PBMC) from healthy subjects and sepsis patients at 4 days, 2-3 weeks, and 6 months underwent CD66b+ or CD3+ enrichment, followed by assessment of metabolic flux, flow cytometry, mRNA sequencing, and chromatin accessibility. ResultsMitochondrial basal oxygen consumption rates (OCR) and maximal oxygen consumption rates (SRC, spare respiratory capacity) were decreased in MDSC from septic patients at 4 days after infection and persisted for up to 6 months after sepsis onset. Sepsis was not associated with differences in glycolysis. In contrast, oxidative metabolism in CD3+ T cells was similar between sepsis patients and healthy subjects. Reduced MDSC oxidative metabolism was linked to adverse clinical outcomes. The decline in oxygen consumption from MDSCs in septic patients was also associated with significant reductions in MDSC mitochondrial content. Transcriptomic analysis of CD66b+ cells isolated from PBMC of healthy participants and patients with sepsis at 4 days, 2-3 weeks, and 6 months revealed 19 differentially expressed genes and three long non-coding RNAs as potentially responsible for this decline in mitochondrial mass. Specifically, NR4A3, NR4A2, and TAMLIN/NR4A1 expression, all critical for mitochondrial biogenesis, were persistently decreased with reduced chromatin accessibility indicative of gene silencing. DiscussionAfter sepsis, blood CD66b+ cells present with reduced mitochondrial mass and oxidative metabolism that continue at least 6 months after sepsis. These changes in mitochondrial function result from a reduced content of these organelles. We have also identified gene silencing, reduced gene expression of key transcription factors that regulate mitochondrial biogenesis, as well as increased long non-coding RNA as potential drivers of this unique metabolic phenotype. These results highlight the potential benefit of targeting metabolism in sepsis to promote immune homeostasis and recovery.

immunology↗

bioRxiv2025

Echoes as Signal, Not Noise: Reverberation Sharpens Sensitivity to Temporal Structure

Sensitivity to temporal structure is fundamental to hearing, yet how natural reverberation shapes this sensitivity is unclear. Here we identify echo-facilitated temporal sensitivity (EFTS), a principle whereby the auditory system exploits echoes to selectively enhance responses to rapid temporal changes. Using transitional click trains with subtle inter-click-interval (ICI) shifts, we first show that increasing echo strength systematically enlarges the sound-level step at ICI transitions in both recorded and simulated stimuli, sharpening the physical boundary between segments of distinct temporal structure. In humans, psychophysical detection of ICI changes improves monotonically with echo level in both simulated and real free-field environments, while a late EEG change response scales with echo strength as onset responses remain comparatively stable. In awake rats, electrocorticography over auditory cortex reveals parallel echo-dependent enhancement of transition-evoked activity. Single units exhibit echo-level-dependent amplification of change-related firing and improved neurometric discriminability. Laminar local field potential and current source density analyses further show that echo-dependent divergence emerges first in granular and infragranular layers before propagating to supragranular cortex, consistent with thalamocortical drive followed by intracortical amplification. Together, these findings establish EFTS as a cross-species mechanism that reframes echoes as structured signals the brain uses to sharpen temporal integration in everyday listening.

neuroscience↗

bioRxiv2025

Structural Basis of Asymmetric Class C GPCR activation and distinct Gq coupling induced by force stimulation

Mechanosensation is essential for diverse physiological processes. While many G protein-coupled receptors (GPCRs) are known to be mechanosensitive, the underlying mechanism remains largely unknown. Here, we reveal that mechanical force induces Gq activation of mGlu2, a balance modulator residing in kinocilia, but not other 7 mGlu members. Force activates mGlu2 through a conserved N-terminal force transduction motif (FTM) via a unique cis mechanism. We engineered a potent FTM-derived peptide agonist that recapitulates force-induced activation and resolved cryo-EM structures of apo-mGlu2, FTM-mGlu2, LFTM-{Psi}EK-mGlu2 and LFTM-{Psi}EK-mGlu2-Gq. The structures reveal that an atypical FTM binding to a previously uncharacterized pocket induces asymmetric 7TM domain rearrangement, enabling Gq coupling via an ICL1-TM3/6/7 interface, fundamentally distinct from the glutamate-induced Gi coupling mode of mGlu2. Compared with Gi-coupled mGlu2, the 5 helix of Gq rotated by 180{degrees}, penetrating deeper (8 [A]) into a hydrophobic pocket. Disruption of the M7947.32-F7806.57-F7766.53 hydrophobic triad core and a conformational propagation path predominantly comprising TM6-7 residues are identified as key elements mediating force induced mGlu2 activation. Further In vivo rescue experiments support that mGlu2s mechanosensitivity is dependent on FTM and is required for vestibular function. This work establishes a paradigm for class C GPCR mechanotransduction, revealing unprecedented structural mechanisms underlying force-induced Gq coupling and offering a chemical toolset to modulate mechanical signaling of GPCR.

cell biology↗

bioRxiv2025

A Mechanosensitive GPCR at vestibular kinocilium is required for normal balance

Intracellular calcium increase and neurotransmitter release in vestibular hair cells (VHCs) play central roles in equilibrioception, which is one of the basic senses essential for daily life activities and movement in mammals. Independent of mechano-electrical transduction (MET), whether Gq protein-coupled receptor (GqPCR) signaling participate in the regulation of intracellular calcium dynamics and induce neuronal transmitter release in hair cells remains unknown. We screened mechanosensitive GqPCRs in VHCs and found that a Class C GPCR, metabotropic glutamate receptor 2 (mGlu2), is expressed in kinocilia and is essential for normal balance. Notably, the dispensable role of mGlu2 in normal hearing is consistent with absent of mature kinocilia in cochlea hair cells. Different from the conventional mGlu2-Gi signaling, the sensing of mechanical signals by mGlu2 activates the Gq-PLCD4 pathway, increases intracellular calcium concentration and promotes neurotransmitter release in VHCs. Hair cell-specific deficiency of either Grm2 or Gnaq, or knockdown of Plcd4 expression, but not deficiency of another GqPCR Gpr68, causes significant balance deficits. Reintroduction of mGlu2 into the VHCs of Pou4f3-CreER+/- Grm2fl/fl mice restore vestibular functions. Our study reveals a previously uncharacterized role of GPCR signaling in equilibrioception and provides important insight into kinocilia signaling in VHCs, which are absent in mature cochlear hair cells.

cell biology↗

bioRxiv2025

TAp73 mediates anti-tumor immunity through regulation of lipid metabolism in the lung tumor microenvironment

While immunotherapy has become the standard of care for lung adenocarcinoma (LUAD) patients without actionable genomic alterations, only a subset of patients benefits from a long-lasting response to immunotherapy. Activation of p53-related signals has emerged as a potential mediator of the lung tumor microenvironment (TME). Given that mutant-p53 interacts with p73 extensively and TAp73-deficient mice develop LUAD, we engineered a mouse model with conditional deletion of TAp73 to understand the interactions of the p53 family in the TME and in metabolic pathways that impact anti-tumor immunity. We demonstrated that TAp73 exerts a tumor-suppressive role in KrasG12D-driven LUAD by regulating lipid metabolism in the TME. We identified a TAp73-driven transcriptional signature involving genes in the arachidonic acid metabolism pathway operational in tumor-associated macrophages that favors T-cell activation and thus anti-tumor immunity. Similar transcriptional changes are seen in macrophages from LUAD patients with p53 mutations and in association with response to immunotherapy. SIGNIFICANCEThere is a need to understand how the LUAD TME impacts patient response to immunotherapy. We identified a transcriptional program enacted by TAp73 in tumor alveolar macrophages that supports T-cell activation. Transcriptional and metabolomic data from LUAD patients supports the relevance of this program in response to immune checkpoint inhibition.

cancer biology↗

bioRxiv2025

CDK7, CDK9, or CDK11 Inhibition Reduces Neutrophil-Driven Inflammation and Tissue Damage in Experimental Autoimmune Models

BackgroundCyclin-dependent kinases (CDKs) are involved in basic cellular processes like regulation of cell-cycle progression and transcription. However, recent data also indicate a specific role in terminally differentiated neutrophils by promoting reactive oxygen species (ROS) release, degranulation, neutrophil extracellular trap formation, or apoptosis. Since these mechanisms are implicated in multiple autoimmune diseases, we aimed to delineate the role of CDKs in IC-mediated autoimmune diseases both in vitro and in vivo. MethodsWe analyzed CDK gene expression in unstimulated and immune complex (IC)-stimulated neutrophils. Subsequently, we investigated the effect of pharmacological CDK inhibition on IC-activated neutrophil functions. To analyze the inhibitors in a more translational approach, we proceeded with the systemic and topical application of the effective inhibitors in a murine antibody transfer-induced local epidermolysis bullosa acquisita (EBA) model. The most efficient inhibitor, MC180295, was validated in two other IC-mediated models of autoimmune disease: Serum-transfer arthritis (STA), which also, but not exclusively, depends on neutrophils and immune thrombocytopenia (ITP), which is considered less neutrophil-dependent. ResultsWe found 14 CDKs expressed in unstimulated cells, while the IC-stimulation showed an upregulation of CDK2 and CDK4 expression. Inhibitors selectively targeting CDK1, CDK2, CDK4/6, CDK7, CDK9, CDK11, and CDK12 showed effects on different neutrophil functions (surface activation marker expression, ROS release, adhesion, apoptosis) in vitro. In the predominantly neutrophil-driven EBA model, we observed a reduction of disease severity upon treatment with CDK7, CDK9, or CDK11 inhibitors. Inhibiting these CDKs with topical THZ2, MC180295, or OTS964, respectively, also improved the clinical phenotype. In line with our hypothesis, MC180295 impaired the development of STA, but not ITP. ConclusionsCDK7, CDK11, and especially CDK9 inhibition show therapeutic potential in IC-driven neutrophil-mediated diseases such as rheumatoid arthritis and EBA.

immunology↗

bioRxiv2025

ERK5 is required for neutrophil-mediated ROS release and essential in epidermolysis bullosa acquisita

Neutrophils are key effector cells in antibody-mediated autoimmune diseases, contributing to inflammation via the release of reactive oxygen species (ROS). Extracellular signal-regulated kinase 5 (ERK5), a member of the MAPK family, is expressed in neutrophils but its role in autoimmune disease pathogenesis remains unclear. We investigated the functional relevance of ERK5 in antibody-mediated autoimmune diseases by comparing neutrophil-dependent (epidermolysis bullosa acquisita, EBA; serum transfer arthritis, STA) and neutrophil-independent (immune thrombocytopenia, ITP) murine models using the small-molecule ERK5 inhibitor XMD8-92. In vitro, pharmacological ERK5 inhibition specifically reduced neutrophil ROS release and CD62L shedding without affecting adhesion, chemotaxis, or CD18 expression. No major effects on viability were observed. In vivo, ERK5 inhibition with XMD8-92 significantly ameliorated antibody transfer-induced EBA, supporting a critical role of neutrophil-derived ROS in disease pathogenesis. In STA and ITP, ERK5 inhibition did not affect clinical outcomes. Together, these findings highlight ERK5 as a regulator of neutrophil ROS release and a potential therapeutic target in ROS-driven autoimmune diseases such as EBA.

immunology↗

bioRxiv2025

High-salt diet disturbs the physiological uterine endothelial junction remodeling during pregnancy

A high-salt diet (HSD) induced excessive sodium intake is a major risk factor for various diseases. However, its specific effects on uterine endothelial cell and pregnancy outcomes remain poorly understood. In this study, we demonstrated that HSD induces gestation specific hypertension and adverse pregnancy outcomes in murine models. The proper spiral artery remodeling, which involved the decidual vascular endothelia, is thought to be essential for normal regulation of gestational blood pressure. We explored the molecular basis for the adaptation of vascular endothelial cell based on the transcriptome data, and uncovered the significant changes for the cell junction in the endothelia during this process. Furthermore, it was revealed that HSD induced more salt accumulation in the uteri and triggered the disturbed vascular endothelium cytoskeletal remodeling, which was associated impaired trophoblast cell invasion and incorporation into the vascular wall. Overall, our study identifies unique roles of decidual endothelium for pregnancy vascular remodeling, and demonstrates that HSD disrupts physiological spiral artery remodeling through endothelial maladaptation, which may concurrently induce systemic endothelial damage in maternal systemic vascular.

physiology↗

bioRxiv2025

Ultra-High Field 31P functional Magnetic Resonance Spectroscopy Reveals NAD+ Dynamics in Brain Energy Metabolism during Visual Stimulation.

We investigated dynamic changes in nicotinamide adenine dinucleotide (NAD{square}) metabolism in the human occipital lobe using ultra-high field 31P functional magnetic resonance spectroscopy (fMRS) at 7 Tesla. Twenty-five healthy volunteers (mean age 24 {+/-} 4 years, 10 female) performed a visual task alternating between fixation and flashing checkerboard stimuli. 31P MRS spectra were acquired from a visual cortex voxel functionally localized by prior fMRI. Linear mixed-effects modelling revealed a significant reduction in NAD{square} concentrations during the first stimulation block, while no significant change was observed during the second block. No significant changes were observed for other high-energy phosphate metabolites (ATP, phosphocreatine, and inorganic phosphate), indicating specificity in the NAD{square} response. Exploratory analyses, dividing the blocks in two halves, suggested further reductions in NAD{square} and tNAD in the second halves of both stimulation blocks, though these trends were not statistically significant. Our findings demonstrate the feasibility of using fMRS at 7T to detect stimulus-induced dynamics in cerebral NAD{square} metabolism in vivo, providing insights into the interplay between glycolysis and oxidative phosphorylation during neural activation.

neuroscience↗

bioRxiv2025

Clair-Mosaic: A deep-learning method for long-read mosaic small variant calling

Mosaic variants, defined as postzygotic mutations occurring during an organisms development from zygote to adult, play critical roles in developmental biology, aging, and diseases such as cancer and neurological disorders. However, their accurate detection remains challenging due to low abundance in the genome and low variant allelic fractions (VAF). While current mosaic variant callers are primarily designed for short-read sequencing, no method is available for long-read sequencing, which can generate tens of kilobase-long reads to cover complex genomic regions inaccessible to short reads. To fill the gap, we present Clair-Mosaic, a deep-learning-based method for detecting mosaic small variants from long-read data. Clair-Mosaic was trained on hundreds of millions synthetic variants encompassing diverse read coverages and allelic fractions, enabling it to detect low-VAF mosaic variants with high sensitivity in paired-sample and single-sample modes. In addition to neural network prediction, Clair-Mosaic distinguishes genuine mosaic variants from sequencing artifacts by leveraging their inherent haplotype relationship in phased long reads. Furthermore, a Bayesian mosaic-germline discriminator is introduced to distinguish mosaic variants from germline variants. It also employs multiple post-calling filters, including a mosaic variant database and multiple germline population resources, to tag common germline and mosaic variants. Comprehensive benchmarking on synthetic datasets and real samples demonstrated Clair-Mosaics outstanding performance in ONT and PacBio. Clair-Mosaic is also applicable to short-read data and outperforms methods like MosaicHunter, MosaicForecast, DeepMosaic, and DeepSomatic. Clair-Mosaic is open-source and available at https://github.com/HKU-BAL/Clair-Mosaic.

bioinformatics↗

bioRxiv2025

Arabidopsis DXO1 is an evolutionarily diverged homolog that impacts ribosome loading and mRNA surveillance

The Rai1/Dxo1/DXO protein family are involved in eukaryotic 5'-end RNA quality control by hydrolyzing non-canonical mRNA cap structures, such as the NAD+ 5'-cap. The plant DXO1 ortholog shows distinct biochemical properties, compared to its fungal and mammalian counterparts, and only minor phenotypic traits can be attributed to its NAD+-decapping (deNADding) activity. On the other hand, the chloroplast and growth defects observed in dxo1 null mutants appear linked to the presence of a serine-rich domain at its N-terminus. Here, we report that plant DXO1 is a distinct ortholog that likely diverged earlier than its fungal and mammalian counterparts. We attribute this to the presence of a serine-rich N-terminal domain, which is found almost exclusively in plants and likely arose during the emergence of angiosperms. Degradome profiling revealed that Arabidopsis DXO1 contributes to mRNA surveillance, via examination of exon junction complex and ribosome footprints, and this activity is reliant on the presence of the serine-rich N-terminal domain in Arabidopsis. Furthermore, polysome profiling revealed that plants lacking DXO1 have severe ribosome loading defects, which may explain the loss of mRNA surveillance and alterations in pre-rRNA processing. Taken together, our data leads us to propose a model whereby Arabidopsis DXO1 is involved in 5'-end RNA quality control, which is critical for ribosome loading that impacts translational fidelity and translation-dependent mRNA surveillance.

plant biology↗