Biology subjects

Deng, Y.

Publications and source records attributed to Deng, Y..

At least 73 records · Page 4Linked to original sources

bioRxiv2025

Natural killer cell TGF- signaling regulates senolytic activity and vascular patterning in the postnatal lung

BackgroundBronchopulmonary dysplasia (BPD) is a disease of neonatal lung development that is linked to impaired pulmonary vascularization, dysregulated transforming growth factor-{beta} (TGF-{beta}) signaling and the accumulation of senescent cells. Despite the established role for TGF-{beta} signaling in promoting vascular remodeling and suppressing the senolytic activity of natural killer (NK) cells, the contribution of NK cell TGF-{beta} signaling to postnatal lung patterning and the pathogenesis of BPD remains unclear. MethodsMice bearing an NK cell-selective deletion of the type-II TGF-{beta} receptor (Tgfbr2NK-/-) were analyzed for vascular and alveolar structure, lung NK cell infiltration, senescence markers and lung function testing across neonatal and adult timepoints. Single-cell RNA sequencing of lung tissue from both neonatal mice and human infants with BPD was performed. The effect of enhanced NK cell activity in a hyperoxia-induced model of BPD was assessed in Tgfbr2NK-/-neonates, as well as pharmacologically, using the TGF-{beta} ligand trap/IL-15 superagonist, HCW9218. ResultsNeonatal Tgfbr2NK-/- mice exhibited a baseline reduction in distal arteriolar density, impaired alveolarization, and sex-specific deficits in long-term lung function. Single-cell RNA sequencing identified the excessive clearance of senescent endothelial cells by TGF-{beta} insensitive NK cells in the lungs of Tgfbr2NK-/- neonates, which served as a contributor of the BPD-like phenotype observed in naive animals. Tgfbr2NK-/- mice were protected from impaired lung development in the hyperoxia model. Sequencing from lung tissue from infants with BPD confirmed excessive TGF-{beta} signaling and cytotoxic impairment in NK cells. Treatment with HCW9218 prevented senescent cell accumulation and rescued lung development in the hyperoxia mouse model. ConclusionsThese findings identify TGF-{beta} as a tunable regulator of NK cell senolytic activity that is essential to normal postnatal lung development. Excessive NK cell TGF-{beta} signaling contributes to impaired lung development following exposure to neonatal hyperoxia and may serve as a viable therapeutic target for human BPD.

developmental biology↗

bioRxiv2025

Bioinspired Geometry-Encoded Rheotactic Navigation of Sound-Driven Microrobots

Imitating the shape-encoded tactics of natural microswimmers--organisms that flip, roll, and rheotaxis through viscous fluids--could transform microfluidics, micromanufacturing, and targeted therapy. However, translating those geometric navigation cues into actively driven microrobots is an open, largely unexplored challenge. Here, inspired by the structure of sperm cells, we introduce a sound-propelled head-helix microparticle ("microrobot") featuring an elliptical head and a spiral tail. This asymmetrical design interacts with the incident acoustic field, generating complex secondary flows that induce a torque, enabling the particle to reorient around its cross-section. The microparticle exhibits a preferred direction of propulsion and orientation when exposed to a traveling sound wave, reorienting if its initial alignment deviates from this preference. Both the preferred direction and orientation can be modulated by adjusting the sound frequency, and they further adapt to background flow fields in the environment. Furthermore, the microparticle exhibits rheotaxis-like motion, exhibiting wall-following motion with frequency-dependent sliding behavior. By moving towards the channel wall, it enters the region with the smallest flow velocities, allowing it to move antiparallel to the fluid. These findings contribute to the engineering of the trajectories of sound-propelled microparticles and to the development of next-generation microrobots for medical and other innovative applications.

bioengineering↗

bioRxiv2025

Identification and quantification of alternative polyadenylation sites in single cell RNA-seq data using scPAISO

AbstractsAlternative polyadenylation (APA) is a critical posttranscriptional mechanism that generates transcriptomic diversity through the production of mRNA isoforms with distinct 3 UTRs or coding sequences. Current APA analysis based on single-cell RNA sequencing (scRNA-seq) for establishing cell type-specific APA landscapes primarily rely on Read2 data, which lacks precise cleavage site (CS) information. This limitation restricts their ability to achieve precise de novo mapping of polyadenylation sites (PASs). Here, we present single-cell PolyAdenylation ISOform quantification (scPAISO), a computational pipeline designed for de novo identification of PAS and quantification of PAS isoforms in scRNA-seq data, by leveraging the often-discarded Read1 from 3 tag-based scRNA-seq protocols. Unlike existing tools, scPAISO directly captures mRNA 3 end cleavage sites, enabling superior performance in motif enrichment (stronger AAUAAA signal) and peak precision (sharper PAS peaks). Moreover, the smaller peak widths enhance the spatial resolution, enabling more accurate detection of closely spaced PASs in the genome. By integrating Read1 and Read2 data, scPAISO achieves isoform-level quantification with an assignment accuracy exceeding 95%. We demonstrate the robustness of scPAISO in identifying PASs and quantifying APA events across diverse biological contexts, including hematopoiesis, systemic sclerosis (SSc), and mouse tissues. We identified stage-specific 3 UTR lengthening in hematopoietic progenitors, global 3 UTR remodeling in SSc and tissue-specific polyadenylation (PA) preference along with RNA-binding proteins in mice. Overall, scPAISO represents a significant advancement in the analysis of APA at single-cell resolution and provides a powerful tool for exploring the regulatory landscape of APA, offering new insights into transcriptome complexity and gene regulation in both health and disease.

bioinformatics↗

bioRxiv2025

Hypobaric hypoxia drives citrate cycle reprogramming to suppress tumor progression

High altitude residents present lower tumor incidence and mortality than plain residents, suggesting that hypobaric hypoxia displays protective effect against tumor development. The results of our studies showed that hypobaric hypoxia exposure significantly suppressed tumor progression in subcutaneous bearing and lung metastasis tumor models. With single-cell transcriptome analysis, we identified HIF-1 pathway was significantly downregulated in tumor tissues with high altitude hypoxia, leading to decreased glycolysis and angiogenesis and improved antitumor immune response. Mechanistically, systemic hypoxia rewired citric acid cycle, with enhanced CS and IDH2 expression and reduced OGDH and SUCLG2 expression, to induce -ketoglutarate accumulation and succinate decline in tumor microenvironment, further mediating HIF-1 pathway inhibition. Moreover, hypobaric hypoxia treatment significantly improved the antitumor effects of adjuvant therapies (including chemotherapy, anti-angiogenic therapy and immunotherapy). Our findings reveal the role and mechanism of hypobaric hypoxia for tumor regression and yield new insights into tumor therapy.

cancer biology↗

bioRxiv2025

Three-dimensional spatial transcriptomics at isotropic resolution enabled by generative deep learning

Mapping the complete three-dimensional (3D), transcriptome-wide spatial architecture of tissues and organs remains a fundamental challenge in biology. Typically, studies approximate 3D structures by profiling serial two-dimensional (2D) tissue sections, resulting in incomplete and anisotropic reconstructions. Here, we demonstrate that organ-wide, isotropic-resolution 3D gene expression landscapes can be effectively inferred from sparse 2D spatial transcriptomics data using artificial intelligence. Our framework, isoST, leverages stochastic differential equations (SDEs) to model the intrinsic biological continuity of gene expression along tissue depth, enabling the integration of discrete 2D measurements into coherent 3D transcriptomic maps. isoST is applied across diverse biological systems, including the brain, kidney, spinal cord, and gastrulating embryos, accurately reconstructing anatomical structures and molecular patterns that are only partially resolved in 2D analyses. isoST enables the comprehensive characterization of tissue niches at full 3D resolution, uncovering radial and spherical gene expression gradients associated with disease progression that are often distorted or missed in 2D approaches. Furthermore, isoST is extended to integrate histological imaging for reducing experimental complexity and to reconstruct high-resolution developmental spatial trajectories over time. Together, isoST provides a practical and scalable solution toward comprehensive high-resolution 3D spatial transcriptomic atlases.

bioinformatics↗

bioRxiv2025

Inhibition of Clostridioides difficile-specific DNA adenine methyltransferase CamA by analogs of S-adenosyl-L-methionine

Epigenetically-targeted therapies, especially those inhibiting S-adenosyl-L-methionine (SAM)- dependent methylations of DNA, mRNA and histones, have advanced rapidly in cancer treatment. However, these therapies remain underexplored for antibiotic development, despite the growing threat of antimicrobial resistance. Here, we screened a focused library of SAM analogs against the DNA adenine methyltransferase CamA specific to the enteric pathogen Clostridioides difficile. At the same time, we examined six other adenine methyltransferases, including two bacterial DNA methyltransferases, and four human RNA methyltransferases having distinct RNA substrates. Compound 113 selectively inhibited CamA (IC50 = 0.15 M). In addition, compound 67 inhibited Caulobacter crescentus CcrM (IC50 = 1.8 M), which has orthologs present in pathogens such as Brucella; while compounds 77 and 37 inhibited the human DNA methyltransferase complexes MettL3-MettL14 and MettL5-Trm112, respectively, at 7-8 M concentrations. These results provide chemical probes for exploring the role of CamA in sporulation and colonization, with potential as antivirulence agents against C. difficile infection. Our study also introduces the first chemical probes for inhibiting bacterial CcrM and human MettL5, each of which plays key roles in their respective hosts. Table of Contents Graphic (TOC) O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=163 SRC="FIGDIR/small/670177v1_ufig1.gif" ALT="Figure 1"> View larger version (15K): org.highwire.dtl.DTLVardef@f7d56org.highwire.dtl.DTLVardef@edbd09org.highwire.dtl.DTLVardef@15abc9org.highwire.dtl.DTLVardef@c12ca7_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

bioRxiv2025

Glycemia Shift Pancreatic Islets Rhythmicity via δ-α Cell in vivo, Impairment in Diabetes

Blood glucose homeostasis relies on the well-coordinated rhythmic activity of millions of islets throughout the pancreas. Islet rhythmicity is triggered by glucose elevation and mediated by paracrine interactions. However, the dynamics of islet population rhythmicity in healthy and diabetic pancreases in vivo remain poorly understood. Using simultaneous multi-islet Ca2+ imaging (20-100 islets per experiment) in both live mice and pancreatic tissue slices, we systematically studied how glycemia fluctuations and intra-islet paracrine signaling collectively shape the islet rhythmicity. In this study, we report that a transition from Hyperglycemia to Euglycemia induces a coordinated shift from slow to fast islet Ca2+ oscillations (HESF) in vivo. HESF is conserved in pancreatic tissue slices and isolated islets, however, not dispersed single cells in vitro, suggesting a mechanistic link with paracrine interactions. We found HESF arises from -cell activation, which is inhibited by {delta} cells upon glucose elevation. The autonomous islets mostly differ in phase and period at high glucose level. Diabetic mice with disrupted glycemic stability lost HESF both in vivo and in vitro. Interestingly, HESF is preserved in {beta}-cell knockout Gcgr transgenetic mice, both in vivo and in vitro, suggesting HESFs dependence on Glp1r. Indeed, HESF was restored in semaglutide-treated diabetic mice with stabilized glycemic stability. These findings offer a comprehensive understanding of how {delta} and cells influence islet rhythmicity and precisely maintain the stability of blood glucose.

physiology↗

bioRxiv2025

Localization of Mutant Huntingtin with HTT Exon1 P90 C-terminal Neoepitope Antibodies in Relation to Regional and Neuronal Vulnerability in Forebrain in Q175 Mice and Human Huntington's Disease

BackgroundRecent evidence suggests that accumulation of mutant exon 1 protein (HTT1a) may be critical to HD pathogenesis, but the relation of this to differential regional and cellular vulnerability in HD is unknown. ObjectiveWe assessed the contribution of the accumulation of the mutant huntingtin HTT1a to the regional and cellular variation in HD brain pathology by determining if more vulnerable regions and neuron types were relatively enriched. MethodsWe performed immunolabeling using the novel monoclonal antibodies 11G2 and 1B12 against the C-terminal proline 90 (P90) neoepitope of huntingtin HTT1a, which detect accumulation of monomeric, oligomeric and aggregated mutant HTT1a, on forebrain of Q175 and R6/2 mice and human HD cases. ResultsDiffuse nuclear and aggregate immunolabeling increased in abundance in Q175 with age, with striatal projection neurons showing immunolabeling earlier than cortical neurons, and only neuropil immunolabeling prominent in pallidal regions. Nonetheless, some regions less affected in HD, such as hippocampus, were rich in mutant HTT1a as well. In humans, striatal immunolabeling was sparser than in mouse, and mainly in the neuropil, but sparser in striatal target areas. In human HD cortex, the P90 antibodies detected predominantly neuropil aggregates, which appeared to, in part, localize to dendrites. Immunostaining in mouse and human could be blocked with HTT1a target peptide, demonstrating antibody specificity. ConclusionsOur results indicate that mutant HTT1a burden appears to partly account for overall differential forebrain regional vulnerability in HD, but additional factors may contribute to vulnerability differences among forebrain regions and between specific neuron types. Plain Language SummaryHuntingtons disease (HD) is caused by a mutant gene that is passed from one generation to the next. The mutant gene causes production of a mutant variant of an otherwise valuable protein called huntingtin. This mutant protein is thought to gradually damage neurons in the brain, leading to such extensive loss in a part of the brain called the basal ganglia that movement is impaired. The disability is eventually so severe, it proves fatal. It has been a mystery as to why the mutant protein might cause brain damage, but more so to some brain areas than others. One important recent clue has emerged from studies of the abnormal huntingtin protein that cells with the mutation make. Namely, rather than make a huntingtin protein of full size, as occurs normally, cells instead make only an abbreviated form of the huntingtin protein, but one that contains the abnormality. We hypothesized that if this mutant fragment is particularly toxic and the cause of the neuron damage in HD, then those brain regions that are most injured in the disease should accumulate more of this mutant fragment early in disease. We evaluated this hypothesis by examining accumulation of this mutant fragment, using a staining method selective for the fragment, in histological specimens from the brains of humans with HD and mice engineered to possess the same mutant gene as in the human disease. We found to a large extent that it is the case that those brain regions that showed the most disease-related damage, such as the basal ganglia, also accumulated the mutant huntingtin protein fragment the most. This fragment thus does appear to be toxic for neurons. Our work suggests that therapeutic efforts for HD should be directed at preventing its production or accumulation.

neuroscience↗

bioRxiv2025

CIAdex: Single-Cell FTIR Spectral Fingerprinting for Cell Identity Verification and Aging Quantification in Therapeutic Cell Manufacturing

Ensuring the identity and optimal aging state of cell products is critical for the efficacy and safety of cell therapies. Despite rapid iterations, there remains an urgent need for robust and easy-to-implement tests to characterize cell products. Here, we present CIAdex (Cell Identification and Aging Index), an analytical framework that utilizes single-cell Fourier-transform infrared (FTIR) spectral fingerprints and machine learning to achieve precise label-free cell identity assessment and aging quantification. CIAdex employs a Feature Extraction Processor to automatically extract FTIR spectral variables corresponding to distinct cellular biomolecular features, enabling reliable distinction of lineage-, donor-, and batch-specific cell populations using linear discriminant analysis. Through application of the XGBoost algorithm, a quantitative aging index (trPDL/trPN) was further generated for tracking cellular aging dynamics along culture expansion. Notably, trPDL/trPN quantitatively represent subtle age-related shifts among different batches and drug-induced senescence or rejuvenation effects which are unmeasurable by existing methods. Together, our work demonstrates that CIAdex, by simultaneous label-free identity verification and aging quantification of cell populations, offers a transformative approach to interpret single-cell FTIR spectral fingerprints and provides novel metrics for quality control in cell manufacturing with significant potential for optimization and assurance of cell therapies safety and efficacy.

cell biology↗

bioRxiv2025

scDIAGRAM: Detecting Chromatin Compartments from Individual Single-Cell Hi-C Matrix without Imputation or Reference Features

Single-cell Hi-C (scHi-C) provides unprecedented insight into 3D genome organization, but its sparse and noisy data pose challenges in accurately detecting A/B compartments, which are crucial for understanding chromatin structure and gene regulation. We presented scDIAGRAM, a data-driven method for annotating A/B compartments in single cells using direct statistical modeling and graph community detection. Unlike existing approaches, scDIAGRAM operates without relying on external information, such as the CpG density or imputation techniques, and preserves cell-to-cell heterogeneity. Accuracy and robustness of scDIAGRAM were illustrated through simulated scHi-C datasets and a human cell line. We applied scDIAGRAM to real scHi-C datasets from the mouse brain cortex, mouse embryonic development, and human acute myeloid leukemia (AML), demonstrating its ability to capture compartmental shifts associated with transcriptional variation. This robust framework offers new insights into the functional roles of chromatin compartments at single-cell resolution across various biological contexts.

bioinformatics↗

bioRxiv2025

Distinct antibody-based signatures and functionality distinguish latent and active pediatric tuberculosis

BackgroundTuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is among the leading causes of death from an infectious agent among children worldwide. Children represent a particularly vulnerable population due to the greater challenges in diagnosis and the higher risk of progression to severe forms of the disease. However, whether different pediatric outcomes relate to distinct immunologic responses remains incompletely understood. Emerging data suggest that Mtb-specific humoral immune responses represent a correlate of protection against Mtb both following natural infection and vaccination. MethodsTo determine if immune profiles can distinguish children across the spectrum from Mtb infection to TB disease, as well as children with TB from non-TB lower respiratory tract infection, we mapped the humoral immune response across a panel of 4 dozen Mtb antigens across children presenting with symptoms of active TB (ATB), children with evidence of latent TB infection (LTBI) and children exhibiting non-TB lower respiratory tract infection (non-TB LRTI). Using a custom Luminex assay, Mtb-specific antibody subclass/isotype, Fc receptor (FcR) binding profiles, and functions were profiled across the pediatric groups. FindingsA robust humoral immune response was observed in children with active TB compared to non-TB LRTI, marked by a strong IgA response, that exhibited high FcR binding. Conversely, children with LTBI uniquely elicited Mtb-specific antibodies with enhanced opsinophagocytic Fc{gamma}R2A binding, as well as a higher capacity to activate NK cells and neutrophils. InterpretationThere are significant differences in humoral immune profiles across the landscape of pediatric TB, potentially contributing to differential mycobacterial control, and highlighting biomarkers that could guide both diagnostic and therapeutic approaches. FundingUS National Institutes of Health.

immunology↗

bioRxiv2025

A novel, high-density CRISPR activation platform for mapping cancer dependencies and resistance pathways ex vivo and in vivo

CRISPR activation (CRISPRa) enables precise, locus-specific upregulation of gene expression, offering potential for both ex vivo and in vivo applications. However, the lack of scalable, high-coverage tools has limited its use in comprehensive genetic screens, particularly in murine models. Here, we introduce Partita, a next-generation, whole-genome CRISPRa sgRNA platform designed for unparalleled efficiency and depth in gene activation studies. Partita employs a high-density targeting strategy, deploying 10 sgRNAs per transcription start site, structured into five gene family-specific sub-libraries to maximize transcriptional induction. To demonstrate its capabilities, we performed a series of large-scale screens: an in vitro enrichment/depletion screen in iBMDMs, whole-genome CRISPRa screens in a double-hit lymphoma model to uncover genes driving resistance to pro-apoptotic drugs (venetoclax, nutlin-3a, etoposide), and an in vivo whole-genome screen identifying accelerators of Myc-driven lymphomagenesis. Each experiment revealed both expected and novel regulators of cellular phenotypes, with a high validation rate in secondary assays. By enabling robust, high-throughput gain-of-function screening, Partita unlocks new avenues for functional genomics and expands the toolkit for discovering key drivers of biological processes across diverse research fields.

cancer biology↗

bioRxiv2025

Historical Contingency Shapes Toxin Resistance in a Specialist Avian Predator

Adaptations to toxic diets can cascade through ecosystems, altering physiology, species interactions, and trophic dynamics. To uncover the molecular basis of toxin resistance in the black-headed grosbeak (Pheucticus melanocephalus), a specialist predator of cardiotonic steroid-defended monarch butterflies (Danaus plexippus), we investigated the evolution of target-site insensitivity in the toxins molecular target - the Na,K-ATPase. Functional assays of engineered Na,K-ATPases revealed that resistance in grosbeaks arises from a non-additive interaction between a substitution at position 111 (Q111E) and up to six nearby amino acid changes in the first extracellular loop of the protein. Using resurrected ancestral proteins, we show that the earliest of these six substitutions to evolve (V113L) altered the functional effects of Q111E, such that Q111E alone became maladaptive. Only after the accumulation of additional permissive substitutions could Q111E confer resistance, highlighting how intramolecular epistatic interactions and historical contingency constrained the evolutionary path to adaptation. Our phylogenetic analysis of Na,K-ATPase sequences from 360 birds further revealed that several of the specific grosbeak substitutions--particularly at sites 112, 114, and 116--show strong signatures of co-evolution with changes at site 111 across the avian tree, supporting the hypothesis that resistance evolves through repeated, interacting changes. Together, these results reveal the molecular mechanisms of convergent evolution of toxin resistance and demonstrate how genetic background can shape evolutionary outcomes across trophic levels.

evolutionary biology↗

bioRxiv2025

Spatial joint profiling of DNA methylome and transcriptome in mammalian tissues

The spatial resolution of omics dynamics is fundamental to understanding tissue biology. Spatial profiling of DNA methylation, which is a canonical epigenetic mark extensively implicated in transcriptional regulation, remains an unmet demand. Here, we introduce a method for whole genome spatial co-profiling of DNA methylation and transcriptome of the same tissue section at near single-cell resolution. Applying this technology to mouse embryogenesis and postnatal brain resulted in rich DNA-RNA bimodal tissue maps. These maps revealed the spatial context of known methylation biology and its interplay with gene expression. The two modalities concordance and distinction in spatial patterns highlighted a synergistic molecular definition of cell identity in spatial programming of mammalian development and brain function. By integrating spatial maps of mouse embryos at two different developmental stages, we reconstructed the dynamics of both epigenome and transcriptome underlying mammalian embryogenesis, revealing details in sequence, cell type, and region-specific methylation-mediated transcriptional regulation. This method extends the scope of spatial omics to DNA cytosine methylation for a more comprehensive understanding of tissue biology over development and disease.

genomics↗

bioRxiv2025

MassNet: billion-scale AI-friendly mass spectral corpus enables robust de novo peptide sequencing

Breakthroughs in artificial intelligence (AI) for natural language processing and computer vision have been largely driven by high-quality, large-scale datasets such as OpenWebText and ImageNet. Inspired by this, we present MassNet, a foundational resource for proteomics designed to accelerate deep learning applications. MassNet is the largest known corpus of data-dependent acquisition (DDA) mass spectrometry (MS) data, derived from ~30 TB of raw files and comprising 1.54 billion MS/MS spectra, resulting in 558 million peptide-spectrum matches (PSMs) across 35 species, including animals, plants, and microbes. Within the human subset, MassNet includes more than 1.7 million precursors and 19,966 proteins, covering 98% of annotated human proteins. To enable efficient AI training, we developed the Mass Spectrometry Data Tensor (MSDT), a structured format based on Parquet that enables standardized, high-performance batch access and seamless integration with GPU and TPU platforms for distributed training. We further extended MassNet to support de novo peptide sequencing, which infers peptide sequences directly from MS/MS spectra without reference databases, and is critical for discovering novel proteins, characterizing non-model organisms, and identifying post-translational modifications (PTMs). We introduce XuanjiNovo, a non-autoregressive Transformer model that leverages a curriculum learning strategy to enhance training stability. By dynamically adjusting learning difficulty based on model performance, XuanjiNovo achieves smooth convergence on complex, multi-distributional data without manual hyperparameter tuning. Trained on 100 million PSMs from the MassNet, it consistently outperforms state-of-the-art methods across diverse benchmarking tasks. Peptide recall exceeds 0.8 on the Bacteroides thetaiotaomicron and Zea mays datasets. On human data acquired using the Orbitrap Astral platform, XuanjiNovo achieves achieves 38.8% to 144.3% improvement over existing models. MassNet represents the first large-scale, standardized foundational dataset in proteomics, marking a critical milestone in the integration of artificial intelligence into proteomics research.

bioinformatics↗

bioRxiv2025

Agropyron cristatum genome provides a new insight for wheat improvement with wild relatives

Exploring novel genetic variation for target traits is crucial for advancing wheat breeding and genetic improvement. Since 1990, we have been transferring genes from Agropyron cristatum, a promising wild relative genetic resource featuring robust spike morphology and stress tolerance, into common wheat by distant hybridization. To efficiently harness A. cristatum genes, we de novo assembled a 25.62-Gb high-quality genome of an autotetraploid accession Z559 with 28 chromosomes, and uncovered its specific genome features and an extensive repertoire of genes associated with yield and resistance to abiotic and biotic stresses. We systematically characterized A. cristatum genome introgressions by resequencing 431 wheat-A. cristatum derivatives and cloned the gene AcGNS1, which functions in the regulation of grain number per spike in wheat. Subsequently, we developed an optimized genome-selection model for wheat-A. cristatum breeding derivatives, enabling the rapid selection of new potential varieties. These findings demonstrate a genomic breeding strategy for leveraging novel genetic resources of wild relatives and advancing wheat improvement.

genomics↗

bioRxiv2025

ASC contributes to sustained glial reactivity and mild cognitive impairment after closed-head injury

Mild brain traumatic brain injury (mTBI) from closed-head injuries (CHI) can lead to prevalent neuropsychiatric disorders, including an increased risk for neurodegenerative diseases and dementia. Inflammasomes are molecular complexes crucial for neuroinflammation and secondary damage after trauma, however their role in mild CHI is poorly understood. In this study, we investigate the cellular expression of inflammasome-related genes and their functional significance in CHI models. Single-cell RNA sequencing of cortical tissue revealed selective expression of Pycard (PYD and CARD domain containing), also known as Asc (apoptosis-associated speck-like protein containing a caspase recruitment domain), which encodes the inflammasome adaptor ASC, predominantly in microglial clusters. Sustained upregulation of inflammasome-related proteins persisted up to 21 days in a model for mTBI, with this pattern significantly reduced in Asc-/- mice. Importantly, mild cognitive impairment induced after mild CHI was largely abrogated in Asc-/- mice. These findings suggest that ASC, as the primary inflammasome adaptor, plays a critical role in sustaining neuroinflammation and contributes to cognitive deficits after mild CHI. This study provides insights into the molecular neuroinflammatory mechanisms underlying CHI, potentially informing future therapeutic strategies.

neuroscience↗

bioRxiv2025

HSV-1 orchestrates host RAP80 ubiquitination by ICP0 and UL36USP to promote viral survival

Herpes simplex virus 1 (HSV-1) is a widespread human pathogen that establishes lifelong infections, ubiquitination is crucial for HSV - 1 to interact with the host and regulate its life activities. But the mechanisms of how HSV-1 dynamically modulates host proteins at different infection stages to promote its own survival remains challenging. Here we identified DNA damage response protein RAP80 as a critical target of HSV-1 ubiquitination enzymes ICP0 and UL36USP throughout HSV-1s infection cycle. In early stages, RAP80 inhibits HSV-1 transcription by directly binding to the viral genome, blocking viral protein ICP4 binding to transcription factors. This interaction is regulated by phase separation via an intricate interplay between RAP80 and ICP0/ICP4. As infection progresses, the viral E3 ligase ICP0 degrades RAP80, dissolving phase separation, and allowing the formation of a mature viral replication compartment. In late infection stages, RAP80 is deubiquitinated by the viral deubiquitinase UL36USP, which restores cellular homeostasis and promotes HSV-1 survival. This process involves modulating the R-loop-cGAS-apoptosis pathway. These findings underscore the dynamic interplay between viral and host factors and the complex mechanisms used by HSV-1 to subvert host defenses, offering practical implications for the future development of antiviral strategies.

molecular biology↗