Biology subjects

Ma, Y.

Publications and source records attributed to Ma, Y..

At least 127 records · Page 7Linked to original sources

bioRxiv2025

Hexavalent Chromium Inhibits Nitrate-Dependent Anaerobic Methane Oxidation While Enriching Denitrifiers: Insights into Microbial Interactions for Simultaneous Methane, Nitrate and Chromate Removal

Chromate (Cr(VI)) is a widely distributed heavy metal known for its toxicity and adverse effects on human health. Due to its extensive industrial use, Cr(VI) is commonly detected in municipal and industrial wastewater, often co-occurring with other contaminants such as nitrate (NO3-). Nitrate-dependent anaerobic methane oxidation (N-DAMO) is a promising microbially driven process that enables the simultaneous removal of methane (CH4) and NO3-, potentially lowering the carbon footprint of wastewater treatment plants (WWTPs). Given that Cr(VI) can act as an alternative electron acceptor, its presence may influence the N-DAMO process either by supporting CH4 oxidation or, conversely, by exerting toxic effects that inhibit microbial activity. In this study, we investigated the impact of Cr(VI) on an N-DAMO enrichment culture composed of Candidatus Methanoperedens and Candidatus Methylomirabilis, using NO3- as the electron acceptor and 13C-CH4 as the sole electron donor. Cultures were exposed to varying concentrations of Cr(VI), and microbial activity was assessed through GC-MS, 16S rRNA gene sequencing and qPCR. Here we found that while Cr(VI) was reduced within the culture, this process was not coupled to CH4 oxidation. In fact, CH4 oxidation was significantly inhibited, and the relative abundances of Ca. Methanoperedens and Ca. Methylomirabilis declined under increasing Cr(VI) concentrations. Cr(VI) reduction was likely mediated by the flanking microbial community via two possible pathways: (i) enzymatically, through nitrate reductase activity in denitrifying bacteria, and (ii) abiotically, through chemical reaction with nitrite (NO2-), an intermediate of denitrification. These findings highlight the potential of N-DAMO microbes to confer functional resilience in contaminated environments. However, the sensitivity of methanotrophic organisms to Cr(VI) underscores a limitation in applying this process to wastewater treatment systems containing heavy metals.

microbiology↗

bioRxiv2025

The representation of emotion knowledge in hippocampal-prefrontal systems

Emotional experiences involve more than bodily reactions and momentary feelings--they depend on knowledge about the world that spans contexts and time. Although it is well established that individuals conceptualize emotions using a low-dimensional space organized by valence and arousal, the neural mechanisms giving rise to this configuration remain unclear. Here, we examine whether hippocampal-prefrontal circuits--regions implicated in forming cognitive maps--also support the abstraction of emotional experiences. Using functional MRI data collected as participants viewed emotionally evocative film clips, we found that activity in hippocampal and prefrontal cortex predicted self-reported emotion across schematically distinct videos, consistent with a role in structural learning. Computational modeling of emotion transitions revealed that hippocampal responses to films and emotion self-reports could be predicted based on the statistical regularities of emotion transitions across different temporal scales. These findings demonstrate that hippocampal-prefrontal systems represent emotion concepts at multiple levels of abstraction, offering new insight into how the brain organizes emotion knowledge.

neuroscience↗

bioRxiv2025

Central nervous system atlas of larval zebrafish constructed using the morphology of single excitatory and inhibitory neurons

Single-neuron morphology mapping is fundamental for deciphering brain architecture and function, yet in vertebrates it remains limited in spatial coverage and cell-type information. Here we present a nervous system-wide single-neuron morphology atlas of larval zebrafish with annotated excitatory/inhibitory identity and dendrite-axon polarity. The atlas comprises >20,000 reconstructed neurons from >13,400 animals, spanning the central and peripheral nervous system and representing [~]24.5% of the total excitatory and inhibitory neurons in the brain, all integrated into a common physical space with neuroanatomical parcellations. We define >500 excitatory and inhibitory neuronal morphotypes and construct putative inter-cell-type and interregional connectomes. Projection and morphotype analyses reveal distinct laterality and directionality biases and modular innervation patterns in excitatory and inhibitory neurons, while network analyses uncover fundamental connectivity motifs, hubs, and sensorimotor pathways. Accessible through custom-built interactive platform ZExplorer, this atlas provides a foundational resource for multimodal data integration, circuit analysis, computational modeling, and hypothesis-driven research.

neuroscience↗

bioRxiv2025

Towards Unified Neural Decoding with Brain Functional Network Modeling

Recent achievements in implantable brain-computer interfaces (iBCIs) have demonstrated the potential to decode cognitive and motor behaviors with intracranial brain recordings; however, individual physiological and electrode implantation heterogeneities have constrained current approaches to neural decoding within single individuals, rendering interindividual neural decoding elusive. Here, we present Multi-individual Brain Region-Aggregated Network (MIBRAIN), a neural decoding framework that constructs a whole functional brain network model by integrating intracranial neurophysiological recordings across multiple individuals. MIBRAIN leverages self-supervised learning to derive generalized neural prototypes and supports group-level analysis of brain-region interactions and inter-subject neural synchrony. To validate our framework, we recorded stereoelectroencephalography (sEEG) signals from a cohort of individuals performing Mandarin syllable articulation. Both real-time online and offline decoding experiments demonstrated significant improvements in both audible and silent articulation decoding, enhanced decoding accuracy with increased multi-subject data integration, and effective generalization to unseen subjects. Furthermore, neural predictions for regions without direct electrode coverage were validated against authentic neural data. Overall, this framework paves the way for robust neural decoding across individuals and offers insights for practical clinical applications.

neuroscience↗

bioRxiv2025

The Cell Wall Controls Stem Cell Fate in the Arabidopsis Shoot Apical Meristem

At the basis of plant developmental plasticity are continuously active pluripotent stem cells, which fuel the life-long post-embryonic formation of new organs. Since plant cells are encased in cell walls and thus immotile, their individual fate-specification program is dependent on their relative position within the organism. It is assumed that the cell wall and its mechanical properties are under surveillance, linking cell wall state to intracellular gene-regulatory networks. However, the role of these cell wall signalling pathways in plant development and the contribution of cell wall properties to cell behaviour and identity are unclear. Here, we show that control of cell wall properties is essential for the perpetuation of stem cell populations and pattering in the shoot apical meristems. The expression of pectin methylesterases (PMEs), which modify homogalacturonan methylesterification and thereby modulate cell wall mechanics, is maintained at low levels in stem cells by the stem cell specifying transcription factor WUS. Low PME expression is required for stemness, auxin patterning and stem cell-specific mechanical properties. Conversely, WUS depletion reduces wall stiffness in the meristem centre, reinforcing its role in maintaining mechanical homeostasis. Together, our findings show that WUS-mediated control of cell wall-modifying enzymes is essential for sustaining stem cell identity and SAM organization. These results demonstrat that the plant cell wall is not only involved in cell differentiation, but also exerts feedback control on developmental transitions, contributing to our understanding how the immediate physical environment is able to guide cell fate decisions in plants.

plant biology↗

bioRxiv2025

A luminescent attenuated SARS-CoV-2 for the identification and validation of drug-resistant mutants

The emergence of SARS-CoV-2 variants has necessitated continuous updating of vaccines. In contrast, antivirals remained effective as they target conserved viral proteins that are essential for the viral life cycle. However, several mutations in SARS-CoV-2 that may affect the efficacy of United States (US) Food and Drug Administration (FDA)-approved antivirals have been recently identified. Detecting drug-resistant SARS-CoV-2 mutants and investigating their escape mechanism(s) are critical to guide the selection of effective antiviral therapies. In this study, we constructed an attenuated recombinant (r)SARS-CoV-2 lacking the open reading frame (ORF) proteins 3a and 7b but expressing nanoluciferase (Nluc), rSARS-CoV-2 {Delta}3a7b-Nluc, to facilitate tracking viral infection. Using this virus, we selected drug-resistant mutants to the main viral protease (Mpro) inhibitor nirmatrelvir. After passaging {Delta}3a7b-Nluc 10 times in the presence of increasing concentrations of nirmatrelvir, a virus population with enhanced resistance was selected. We identified two non-synonymous mutations (L50F and R188G) in Mpro, encoded by the non-structural protein 5 (NSP5) gene. Using reverse genetics, we generated rSARS-CoV-2 {Delta}3a7b-Nluc containing the identified L50F and R188G mutations, individually or in combination, and assessed their contribution to nirmatrelvir resistance. Our results indicate that both mutations are involved in escaping from nirmatrelvir. Altogether, our results demonstrate the feasibility of using rSARS-CoV-2 {Delta}3a7b-Nluc variant to identify and validate mutations that confer resistance to FDA-approved antiviral drugs without the concern of conducting gain of function (GoF) experiments with wild-type (WT) forms of SARS-CoV-2. IMPORTANCESmall-molecule antiviral drugs have been used for the treatment of SARS-CoV-2 infections. However, drug-resistant SARS-CoV-2 mutants to currently US FDA-approved Mpro targeting antivirals have been identified. Information on SARS-CoV-2 escape mutants and mutations affecting the antiviral activity of licensed antivirals remain limited. In this study, we developed a nanoluciferase (Nluc)-expressing attenuated recombinant (r)SARS-CoV-2 lacking the ORF 3a and 7b proteins ({Delta}3a7b-Nluc) to identify nirmatrelvir resistant mutants without the biosafety concerns associated with gain-of-function (GoF) research using wild-type (WT) SARS-CoV-2. Using {Delta}3a7b-Nluc, we have selected variants with reduced sensitivity to nirmatrelvir that were validated by the generation of rSARS-CoV-2 {Delta}3a7b-Nluc containing the candidate L50F and R188G mutations in Mpro. These results demonstrate the feasibility of using rSARS-CoV-2 {Delta}3a7b-Nluc to safely identify and validate drug-resistant mutants overcoming concerns originating from adaptation studies using WT SARS-CoV-2.

microbiology↗

bioRxiv2025

P3ANUT: An enhanced DNA sequencing analysis platform for uncovering and correcting errors in peptide phage display library screening

Display technologies are used extensively in the discovery of peptides and antibodies towards the development of new medicines and diagnostic tools. Phage display technology enables the filtering of <1010 random peptides/antibodies down to and enriched pool of candidates with favourable binding affinities. In recent years, next-generation DNA sequencing technologies have increased the precision and accuracy with which the peptide sequences of phage display library clones are identified. Inaccuracies in DNA sequencing such as substitutions, insertions and deletions in the library oligonucleotide region have the potential to result in the identification of erroneous candidate sequences. Here, we describe a Python Pipeline for Phage Analysis through a Normative Unified Toolset (P3ANUT) which employs Levenshtein distance, k-mer approaches and a novel encoding scheme on paired-end sequencing outputs to correct sequencing errors from next-generation sequencing outputs of display library screens. We introduce an easy-to-use and highly customisable computational tool with graphical user- and command line interfaces to process entire datasets within a single input, as well as visualisation tools for candidate analysis and data generation. P3ANUT shows significant improvements in read recovery, overall read quality, and runtime compared to a previously published pipeline. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=96 SRC="FIGDIR/small/648809v1_ufig1.gif" ALT="Figure 1"> View larger version (17K): org.highwire.dtl.DTLVardef@15e1172org.highwire.dtl.DTLVardef@cb9097org.highwire.dtl.DTLVardef@81cabcorg.highwire.dtl.DTLVardef@1253865_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioinformatics↗

bioRxiv2025

Metabolic modulation of intratumoral cholesterol with gut microbiota for the treatment of colorectal cancer

Excess cholesterol is positively correlated with colorectal cancer (CRC). Current therapeutic strategies for modulating cholesterol levels in CRC are limited and often come with complications. Here, we demonstrated that microbiome shunting of intestinal cholesterol to anticancer metabolites is a safe and applicable therapeutic approach for CRC. By screening major microbial metabolic products of cholesterol, we found that 4-cholesten-3-one (4-C-3) was selectively depleted in fecal samples and tumor tissues of patients with CRC. 4-C-3 exhibits strong antitumor effects on human CRC cell lines, patient-derived organoids, and patient-derived xenograft (PDX) models. Mechanistically, 4-C-3 suppresses CRC tumorigenesis by dually targeting the epidermal growth factor receptor (EGFR) and Kirsten rat sarcoma viral oncogene homologue (KRAS). 4-C-3 directly binds to EGFR, blocking its signal transduction by inhibiting the binding of EGFR ligands. Additionally, 4-C-3 inhibits oncogenic KRAS variants, such as KRASG12D, by suppressing nucleotide exchange activity and effector engagement. By targeting both EGFR and KRAS, 4-C-3 reduces primary resistance to anti-EGFR therapies caused by KRAS mutations in CRC. As a proof-of-concept study, we showed that delivery of 4-C-3 by Oscillibacter ruminantium, a 4-C-3- producing commensal bacterium that is reduced in CRC patients, or a nonpathogenic Escherichia coli strain engineered to specifically convert intestinal cholesterol into 4-C-3, removed intratumoral cholesterol and led to rapid tumor regression in multiple models of CRC. These results suggest that microbial therapies for restoring intestinal cholesterol homeostasis represent a new therapeutic avenue for CRC.

cancer biology↗

bioRxiv2025

Neural signature underlying the effect of intranasal vasopressin on emotional responses to spontaneous social comparison

Vasopressin, a key molecular regulator of social behavior, is implicated in promoting self-protective responses to threats against physical safety and resources. However, its role in defending against self-view threats--common in social interactions and critical to well-being--remains unclear. This study investigates the neural mechanisms through which vasopressin modulates self-protective responses to spontaneous social comparison. In a double-blind, placebo-controlled neuroimaging experiment, participants rated their satisfaction with social evaluations and monetary outcomes assigned to a stranger, friend, or themselves. Compared to placebo, vasopressin selectively intensified contrastive emotional responses to social evaluations of the stranger, decreasing satisfaction with positive evaluations and increasing satisfaction with negative evaluations, relative to those of the self or friend. At the neural level, vasopressin reduced the distinctions between the stranger and the self/friend in the medial prefrontal cortex activity, multivariate response patterns, and functional connectivity with the temporoparietal junction and precuneus, with this effect being especially pronounced among socially dominant individuals. These converging neuroimaging findings support the hypothesis that vasopressin alters the neural representation of the stranger, shifting it from a socially irrelevant figure under placebo to a psychologically salient competitor, thereby triggering self-protective emotional processes. These findings elucidate novel neuropsychological mechanisms through which vasopressin amplifies emotional defense against social threats and offer insights into potential clinical applications for psychiatric conditions characterized by impaired self-protection.

neuroscience↗

bioRxiv2025

Integrated single cell spatial multi-omics landscape of WHO grades 2-4 diffuse gliomas identifies locoregional metabolomic regulators of glioma growth

Diffuse infiltrating gliomas are aggressive tumors of the central nervous system driven by intra-tumoral heterogeneity and aberrant normal-tumor cell-cell interactions. Grade specific and locoregional metabolic dependencies driving aberrant cell-states linked to treatment resistance, seizures and infiltration of gliomas remain elusive. Here, we applied spatial transcriptomics (stRNAseq), imaging mass cytometry (IMC) and mass spectrometry imaging (MSI; metabolites, peptides and glycans) to the core and edge tumor tissue from patients with World Health Organization (WHO) grades 2-4 diffuse infiltrating gliomas including isocitrate dehydrogenase (IDH) mutant oligodendrogliomas (WHO Grades 2 and 3) and IDH wildtype astrocytomas including anaplastic astrocytoma (prior 2016 WHO histological grade 3) and glioblastoma (GBM, WHO grade 4) stRNAseq identified regions-specific differentially expressed genes with significant overall survival implications particularly in IDH wildtype GBM. Integration of stRNA seq and MSI-derived metabolite expression demonstrated enrichment of L-glutamine in SOX4+ Neural progenitor-like (NPC-like) cells and DL-dopamine in GPNMB+ Mesenchymal-like (MES-like) GBM cells at the tumor edge relative to the core. Our results uncover clinically relevant and locoregional cell state-specific metabolites that may contribute to GBM proliferation, infiltration and seizures. This comprehensive pan-diffuse infiltrating glioma multi-omics study could serve as a resource for uncovering region-specific metabolic vulnerabilities encompassing metabolites, glycans and peptides within transcriptionally defined cell states across WHO 2-4 diffuse glioma.

cancer biology↗

bioRxiv2025

Pervasive phenotypic effects of Fbxo42 controlled by regulation of PP4 phosphatase

F-box proteins are the substrate recognition modules of the SCF (SKP1-Cullin- F-box) E3 ubiquitin ligase complex. FBXO42, an understudied member of this family, has recently emerged as a modulator of key cellular processes, including cell cycle progression, DNA damage response and glioma stem cell survival. In this study, we define the function of FBXO42 as a major regulator of the protein phosphatase PP4. Phosphoprotein phosphatases (PPPs) have a broad array of substrates, hence necessitating tight regulation. We observe that FBXO42 ubiquitinates the PP4 complex to govern the assembly of regulatory and catalytic subunits with the net effect of restraining the latters phosphatase activity. FBXO42 depletion unleashes PP4 activity with broad cellular effects highlighting FBXO42 as a novel regulatory node in ubiquitin-mediated signalling for future therapeutic exploitation. Impact StatementFBXO42 is a major regulator of PP4 phosphatase impacting multiple cellular phenotypes.

biochemistry↗

bioRxiv2025

PhysDock: A Physics-Guided All-Atom Diffusion Model for Protein-Ligand Complex Prediction

Accurate prediction of protein-ligand complexes remains a central challenge in structural biology. Traditional methods are computationally inefficient and prone to local minima, whereas deep learning approaches struggle to capture structural flexibility and physical plausibility. We introduce PhysDock, a physics-guided diffusion model that uniquely integrates (i) all-atom diffusion to model ligand flexibility and protein precision-flexibility (i.e., subtle conformational adjustments); (ii) physical priors as diffusion conditioning, alongside two-phase physics guidance during the denoising diffusion to ensure physical plausibility. PhysDock demonstrates state-of-the-art performance in redocking benchmarks and excels in the more challenging cross-docking assessments. For practical utility, PhysDock (i) resolves cannabinoid receptor selectivity across diverse molecules, achieving accuracy comparable to experiments; (ii) distinguishes most drug candidates from weak binders in virtual screening of NTRK3 kinase, while uncovering novel candidates with structural insights. PhysDock serves as a versatile tool for protein-ligand complex prediction, with substantial potential to accelerate structure-based drug discovery.

bioinformatics↗

bioRxiv2025

Robust Bayesian Integrative Modeling of Single Cell and Spatially Resolved Transcriptomics Data

A recent technology breakthrough in spatially resolved transcriptomics (SRT) has enabled comprehensive molecular characterization at the cellular level while preserving spatial information. However, many SRT technologies (e.g., spatial transcriptomics) cannot achieve single-cell resolution. Instead, they measure the average gene expression of a mixture of cells within a spot arranged on a lattice. Here, we introduce iMOSCATO, a fully Bayesian model that integrates single-cell RNA sequencing (scRNA-seq) data and SRT data to simultaneously decompose cell-type compositions of spots and identify the underlying spatial domains. We incorporate the lattice structure by employing a Markov random field prior, improving the accuracy of both cell-type deconvolution and spatial domain detection. Moreover, we use a zero-inflated Dirichlet distribution to capture cell-type sparsity. Finally, iMOSCATO shows competitive performance in accuracy compared to existing methods in both simulation studies and two real data applications.

bioinformatics↗

bioRxiv2025

Deciphering the Sequence Basis and Application of Transcriptional Initiation Regulation in Plant Genomes Through Deep Learning

Transcription initiation is a critical regulatory step in plant gene expression, yet its sequence determinants remain largely elusive. Here we introduce GenoRetriever, an interpretable deep learning model that deciphers the sequence basis of transcriptional initiation regulation across plant genomes. Trained on STRIPE-seq data from 16 soybean tissues and six other crop species, GenoRetriever identifies 27 core sequence motifs that govern transcription start site (TSS) selection and usage. The model predicts TSS locations and usage levels with high accuracy, as validated by in silico motif insertions, saturation mutagenesis, and CRISPR-Cas9 promoter editing. It further reveals that 31.85% of natural variation between wild and domesticated soybean drives shifts in promoter motif usage during domestication, and uncovers lineage-specific motif effects between monocots and dicots. This interpretable model and its user-friendly web server for promoter analysis and design make GenoRetriever both a methodological innovation and practical tool for plant functional genomics and crop improvement.

plant biology↗

bioRxiv2025

Catastrophic drought effects on water quality and phytoplankton biomass in Nanwan Reservoir (Xinyang, China)

Climate change has led to increasingly frequent and unpredictable droughts and high-temperature events, creating extreme conditions that profoundly impact the productivity of freshwater ecosystems. This study investigates the Nanwan Reservoir, a large and deep reservoir in Xinyang, China, to evaluate the effects of extreme drought events on water quality and phytoplankton production. Field investigations were conducted during both high-temperature and drought (HTD) conditions in 2019, and during non-high-temperature and drought (NHTD) conditions in 2020. Results showed that HTD conditions significantly disrupted the thermocline and oxycline structures, leading to prolonged stratification during the HTD period. Although phosphorus concentrations remained relatively stable across both periods, nitrogen levels were markedly lower during HTD events--likely due to uptake by phytoplankton--indicating a shift in nutrient limitation from phosphorus to nitrogen. Additionally, a complex relationship between environmental variables and phytoplankton biomass was observed under HTD conditions. These findings advance our understanding of primary production responses to extreme weather events in the Nanwan Reservoir and highlight the importance of incorporating such knowledge into water resource management and ecological conservation strategies.

ecology↗

bioRxiv2025

Rare codon translation regulates growth factor-dependent cell proliferation

In animal cells, growth factor signaling promotes both cell cycle progression and cell growth, but the connection between these two processes is not well understood. Here, we investigated whether cell cycling and cell growth are coupled through protein translation. Using ribosome profiling and mRNA sequencing we examined changes in translational activities in human Retinal Pigment Epithelial (RPE-1) cells as they entered the cell cycle in response to serum growth factor stimulation. We found that, in addition to mRNAs encoding factors in ribosome biogenesis and translational initiation, mRNAs encoding many DNA replication factors were translationally upregulated by serum. We also noted increases of snoRNAs and tRNAs, which facilitate translation. By analyzing the distribution of 21nt mRNA ribosome footprints, produced by stalled ribosomes that lack amino-acyl-tRNAs, we found that growth factor withdrawal promoted ribosome stalling preferentially at specific rare codons. DNA replication factor genes that were translationally upregulated by serum and essential for cell cycle progression were enriched in many of these rare codons, and the cognate tRNAs that read these codons were induced by growth signaling. The serum-dependent induction of translation was more mTOR-dependent than MEK-dependent. Our results support a novel regulatory mechanism wherein growth factor signaling promotes cell proliferation by inducing tRNAs that decode rare codons, which in turn promote translational elongation of mRNAs encoding DNA replication factors to accelerate G1/S progression. Significance StatementWe present a mechanistic explanation for the longstanding question of how cell cycle progression is coupled to cell growth. Our findings emphasize the role of translation machinery and reveal a "growth checkpoint" that ensures that DNA replication gene translation occurs only when growth signaling has activated the protein translation machinery. Our work complements the textbook model of the Growth Factor-Cyclin D-Rb-E2F transcriptional mechanism for cell cycle entry and is a fundamental advance for the fields of cell proliferation and growth factor signaling.

cell biology↗

bioRxiv2025

The role of mating systems in postzygotic reproductive isolation between two recently divergent Aquilegia Species

Mating systems play a crucial role in plant speciation. In particular, hybrid seed inviability is prevalent among species with different mating systems due to parental conflict for resource allocation to offspring. However, whether such a postzygotic barrier can be rapidly established in recently diverged species remains poorly understood. In this study, we integrate population genomic and ecological approaches to address this question using recently diverged species pairs Aquilegia kansuensis and A. ecalcarata, which diverged approximately 0.256 Ma, in a sympatric population from Qinghai, China. Population structure and demographic history results reveal clear genetic differentiation between the two species, corroborating their recent divergence. The results of outcrossing rate estimation based on microsatellite markers indicated that A. kansuensis and A. ecalcarata exhibit high selfing and mixed mating systems, respectively. We performed reciprocal crosses between A. kansuensis and A. ecalcarata and found that A. ecalcarata yielded a very small number of small-sized seeds when selfed A. kansuensis was used as pollen donors, resulting in strong asymmetric reproductive isolation. An approximate Bayesian computation framework identified that approximately 4.6% of genomic loci are associated with reproductive isolation, and gene ontology analyses of these loci highlighted key pathways involved in seed maturation and post-embryonic development. Therefore, our findings provide evidence that A. ecalcarata and A. kansuensis represent a novel case of parental conflict and postzygotic isolation driven by divergent mating systems, suggesting mating systems can play a critical role in rapid plant speciation.

evolutionary biology↗

bioRxiv2025

Disturbing immune homeostasis by neutrophil loss of Uba1 induces VEXAS-like autoinflammatory disease in mice

ObjectiveVEXAS (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic) syndrome is an identified haemato-rheumatoid disease caused by somatic UBA1 mutations in hematopoietic stem cells. We report Uba1 loss in various mouse hematopoietic cell types leads to diverse effects, with approximately 70% Uba1 depletion in neutrophils inducing non-lethal VEXAS-like symptoms. MethodsUsing nine different Cre/flox-mediated conditional-knockout (CKO) models, we interrogated the phenotypes caused by hematopoietic loss of Uba1. Neutrophil-specific depletion of Uba1 were validated and VEXAS-like phenotypes were examined. ResultsUba1 loss in HSCs induces extensive hematopoietic cell death while in B or T cells, or megakaryocytes induces corresponsive cell death but these mutants appear normal. Uba1 loss in monocytes and neutrophils failed to induce cell death and the mutants are viable. Among the models, only Uba1 loss in neutrophils manifests autoinflammatory symptoms including increased counts and percentage of neutrophils, increased proinflammatory cytokines, vacuoles in myeloid cells and dermatitis. Residual Uba1 is about 30% in the mutant neutrophils, which manifest disturbed cellular hemostasis. Genetic loss of Morrbid partially mitigated the VEXAS-like symptoms. ConclusionOur study reveals diverse effects of Uba1 loss in hematopoietic cells and establishes a VEXAS-like murine model, facilitating understanding and potential treatments for this syndrome prevalent in aged men. HIGHLIGHTSO_ST_ABSWHAT IS ALREADY KNOWN ON THIS TOPICC_ST_ABSVEXAS syndrome is a recently identified hematological and immunological disease prevalent in adult man but rarely in adult woman. Somatic mutations in the E1-enzyme encoding gene UBA1 in hematopoietic stem cells is the driver on the top of the genetic etiology of the disease. However, the major pathogenic cell type(s) for VEXAS syndrome has not been experimentally examined and mouse models recapitulating the disease are lacking. WHAT THIS STUDY ADDSO_LIUsing nine different conditional-knockout (CKO) murine models, we interrogated the pleiotropic phenotypes caused by loss of the ubiquitin activation enzyme Uba1 in different hematopoietic cell types; C_LIO_LIOur results demonstrated that among the nine tested CKO mutants, only neutrophil loss of Uba1 results in VEXAS-like autoinflammatory disease; C_LIO_LIThe VEXAS-like symptoms in the S100a8Cre-CKO mutant mice include: increased counts of white blood cells and neutrophils, increased percentage of neutrophils, increased serum level of proinflammatory cytokines (IL-1{beta}, IL-6 and TNF), observation of vacuoles, increased survival, and increased phagocytosis in mutant neutrophils; C_LIO_LIPharmacological treatments with IL-1 inflammatory pathway inhibitors Anakinra or Canakinumab or genetic loss of the myeloid pro-survival regulator Morrbid partially mitigated the VEXAS-like symptoms in the S100a8Cre-CKO mutants; C_LI HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICYThe study reports a technical strategy of developing the murine models for VEXAS syndrome. In addition, the study dissects cellular and molecular mechanisms, especially the cell-type-dependent tolerance and pathogenicity of loss of function of Uba1, for the occurrence of the autoinflammation diseases in mice. The study provides translational implications in etiology and potential treatment choices for the newly-identified haemato-rheumatoid syndrome in clinical management.

immunology↗