Biology subjects

Peng, G.

Publications and source records attributed to Peng, G..

At least 19 recordsLinked to original sources

bioRxiv2026

Cross-Tissue Inflammatory Convergence Supports a Putative Muscle-Brain Axis in Alzheimer's Disease

Background Reduced muscle strength is associated with cognitive decline and Alzheimer's disease (AD), suggesting that skeletal-muscle aging and AD-related neurodegeneration may share biological mechanisms. Vascular dysfunction, immune activation, and extracellular-matrix remodeling have been implicated in both tissues, but the extent of shared cellular and molecular programs remains unclear. We investigated cross-tissue transcriptional programs in aging skeletal muscle and AD-related brain tissue and evaluated whether related signals are detectable in peripheral blood. Methods We analyzed independent, unpaired human transcriptomic datasets from skeletal muscle (23 donors), the SEA-AD middle temporal gyrus atlas (84 donors), and peripheral blood. Donor-aware models identified age-associated changes in muscle and transcriptomic changes across continuous pseudoprogression score (CPS) in brain. Cross-tissue comparisons focused on 30 brain donors within an early CPS window. Shared tissue-derived programs were assessed in peripheral blood mononuclear cells and independently tested in frailty bulk-blood and Alzheimer's Disease Neuroimaging Initiative (ADNI) whole-blood datasets. CellOracle simulations were used to prioritize candidate transcriptional regulators. Results Aging muscle showed increased inflammatory, extracellular-matrix, and stromal communication programs. During early AD-related brain progression, vascular and immune populations showed increasing inflammatory and matrix-associated activity together with shifts in intercellular communication. Cross-tissue analysis identified six concordantly enriched pathways comprising 109 leading-edge genes in endothelial populations and four pathways comprising 51 genes in myeloid populations. Related peripheral-blood signatures varied across cohorts and cell types. However, in independent frailty and ADNI mild cognitive impairment and AD datasets, 23 of 30 predefined tissue-derived pathway-subset tests showed significant positive enrichment after false-discovery-rate correction, whereas individual gene-level bulk-blood associations did not survive correction. CellOracle analyses prioritized ETS2 and BHLHE40 as exploratory endothelial regulators whose simulated perturbation consistently reduced selected shared program scores across tissues. Conclusions Aging skeletal muscle and AD-related brain tissue exhibit convergent endothelial and myeloid inflammatory programs, with related pathway-level signals detectable in peripheral blood. These cross-tissue programs and candidate endothelial regulators provide testable hypotheses for mechanisms linking systemic aging, muscle dysfunction, and AD-related neurodegeneration.

neuroscience↗

bioRxiv2026

Bexobrutideg: A Selective, Catalytic Degrader of Bruton's Tyrosine Kinase Overcomes Inhibitor Resistance and Suppresses Autoantibody-Mediated Disease

Brutons tyrosine kinase (BTK) transduces B-cell receptor (BCR), Toll-like receptor (TLR), and Fc receptor (FcR) signaling, and overactivation of these pathways drives B-cell malignancies and antibody-mediated autoimmune disease. Small molecule inhibitors block the enzymatic functions of BTK, but this inhibition is undermined by resistance mutations, several of which abolish BTKs kinase activity yet promote oncogenic signaling through BTK scaffolding functions. We report the discovery and characterization of bexobrutideg (NX-5948), a heterobifunctional degrader that recruits cereblon (CRBN) to selectively degrade BTK while sparing molecular glue neosubstrates. We demonstrate that bexobrutideg acts catalytically, degrading thousands of copies of BTK per molecule per hour, and this event-driven pharmacology renders it resilient to mutations that confer resistance to both covalent- and noncovalent-inhibitors. Bexobrutideg is orally bioavailable, driving deep and durable BTK degradation across species. Bexobrutideg demonstrates strong efficacy in wild-type and ibrutinib-resistant lymphoma models and robustly suppresses pathway activation in models of autoimmune disease.

cancer biology↗

bioRxiv2026

Single-cell lineage tracing of human neuromesoderm organoids reveals TBX6-mediated posterior mesoderm fate diversification

Neuromesodermal progenitors (NMPs) drive vertebrate posterior axis elongation, but the lineage hierarchy of human NMP derivatives remains poorly defined. Here, we integrated a CRISPR/Cas9-based single-cell lineage tracing system with paired multiomics profiling--including scRNA-seq and scATAC-seq--in human pluripotent stem cell-derived neuromesodermal organoids (NMOs) to reconstruct high-resolution lineage relationships spanning 50 days of differentiation. Our data analysis reveal that intermediate mesoderm (IM) and paraxial mesoderm (PM) originate from a shared presomitic mesoderm (PSM) progenitor downstream of NMPs, whereas lateral plate mesoderm (LPM) segregates early from committed mesodermal progenitors. Notably, TBX6 ablation disrupts both IM and somite development, demonstrating that TBX6 functions as an upstream regulator of these two lineages. Mechanistically, TBX6 loss arrests PSM at the progenitor stage and abolishes activation of development programs required for IM maturation. We further delineate neural crest differentiation pathways from NMPs, identifying pre-bifurcation molecular signatures that predict neural crest fate. This work provides a clonal-resolution lineage map of human NMP differentiation and advances our understanding of human posterior trunk development and the etiology of TBX6-associated congenital disorders affecting both the spine and the kidney.

developmental biology↗

bioRxiv2026

Homeostatic control of stem cell activity during intestinal regeneration.

Stem cells proliferate rapidly to maintain fast tissue turnover during regeneration. However, the feedback mechanisms in stem cells that prevent hyperproliferation remain unclear, and their dysregulation can lead to organ failure and cancer. Here, we identified nuclear factor-Y (NF-Y) as the transcriptional repressors to maintain the stem cell quiescence during intestinal homeostasis. We found that NF-Y negatively regulates intestinal stem cell (ISC) proliferation through preferentially occupying the promoters of EGFR signaling pathway components Egfr/Mkp3/Raf/Ras/pointed, via the action of histone acetyltransferase Nejire (Nej)/p300 dependent transcription regulation. While the loss of NF-Y enhances ISC proliferation, cell death and sensitivity to stress and tumor induced mortality. Moreover, NF-Y acts together with Nej to restrict Egfr expression and suppress ISC hyperproliferation. Together, these results demonstrate NF-Y acts with Nej serve as a key negative feedback module to orchestrate transcription initiation and termination of growth signaling in the control of stem cell activity in homeostatic and disease conditions.

cell biology↗

bioRxiv2026

Steller: a high-resolution platform for spatial clonal tracing of mammalian brain development

Resolving both lineage history and spatial position at single-cell resolution is essential for understanding how tissue assemble, yet simultaneously interrogation of both dimensions remains technically challenging. Here, we present Steller (Spatio-temporal cell lineage tracker), an integrated experimental and computational framework that overcomes the sensitivity bottleneck limiting lineage barcode detection in high-resolution spatial transcriptomics (ST). By co-depositing capture probes alongside conventional poly(T) oligonucleotides on high-density spatial arrays, Steller achieves targeted enrichment of lineage barcodes at spatial single cell resolution. Applied to clonally labeled embryonic day 12.5 (E12.5) mouse forebrain development harvested at postnatal day 4 (P4), Steller increased the proportion of barcode-detectable cells and recovered higher clonal diversity compared with poly(T) chip. Leveraging this enhanced sensitivity, we resolved distinct spatial clonal architectures across three forebrain regions: horizontal or radial-to-horizontal transitions in hippocampal pyramidal neurons, dorsoventrally restricted yet multi-nuclei spread in thalamus, and fate-restricted spiny projection neuron lineages. Steller establishes a generalizable strategy for lineage-enhanced spatial profiling compatible with existing high-resolution spatial transcriptomics platforms and adaptable to diverse biologic process, providing a framewrok for investigating lineage-dependent tissue organization. HighlightsO_LISteller integrates targeted lineage-barcode enrichment with high-resolution spatial transcriptomics C_LIO_LISteller substantially improves clonal detection sensitivity at single-cell resolution C_LIO_LISteller reveals region-specific spatial clonal architectures across the developing mouse forebrain C_LI

Developmental Biology↗

bioRxiv2026

AEGIS reveals epitope- and clone-resolved convergence of CNS B and T cell autoreactivity in ROHHAD

Autoimmune diseases arise when B and T lymphocytes lose tolerance to self. Yet in most disorders, the underlying molecular determinants, including autoantibodies, epitopes and lymphocyte clones that drive tissue injury remain undefined. Rapid-onset obesity with hypothalamic dysfunction, hypoventilation and autonomic dysregulation (ROHHAD) is a rare and often fatal pediatric neuroendocrine syndrome with strong evidence of antigen-driven paraneoplastic autoimmunity, including association with the intracellular autoantigen ZSCAN1. However, the effector immune circuit and the epitope-level determinants operating within the hypothalamus and brainstem have remained unknown. To address this challenge in ROHHAD and more broadly in autoimmune disease, we developed the Autoimmune Epitope and immunoGlobulin/Immune-receptor identification System (AEGIS), an integrated framework that links immune repertoires to their cognate self-epitopes. AEGIS combines B cell and T cell receptor profiling from sites of tissue injury with high-resolution epitope mapping, direct sequencing of antigen-specific autoantibodies, in silico antibody-antigen folding, selection, and T cell antigen discovery. Applied to a deeply phenotyped child with ROHHAD, AEGIS revealed a compartmentalized, clonally restricted immune response in which brain-deposited IgG and expanded cerebrospinal fluid B cell and CD4 T cell clonotypes converged on shared ZSCAN1 epitopes, resolved to minimal determinants and peptide-MHC ligands. These findings provide a clone- and epitope-linked mechanistic map of ROHHAD autoimmunity and establish a generalizable framework for identifying candidate pathogenic clones and antigens across diverse autoimmune diseases.

immunology↗

bioRxiv2026

ARID1A deficiency unleashes centromeric RNA transcription to drive chromosomal instability and boosts PKMYT1 inhibitor efficacy via RNA sensing

Cancer gene-associated mutations and molecular hallmarks of chromosomal instability (CIN) are unexpectedly common in histologically normal cells and tissues. These emerging findings challenge the binary distinction between "normal" and "cancerous" cells and suggest that early tumorigenesis may commence against a background of widespread yet largely tolerated genomic instability. However, it remains largely unexplored how a cancer gene-associated mutation can initiate the development of CIN-like states in non-malignant cells and drive tumor evolution. ARID1A, a chromatin remodeling factor, was identified as the most frequently mutated gene in both gastric normal epithelium and tumors. This distinctive molecular convergence presents an opportunity to elucidate the mechanisms by which a cancer-associated gene facilitates the initiation of early CIN phenotypes and develop effective antitumor strategies. In the present study, using primary human gastric organoids, we employed optical genome mapping (OGM) and live-imaging technologies to demonstrate that ARID1A depletion induced a wide spectrum of structural variants (SVs), copy number variants (CNVs), and chromosomal segregation errors, characteristic features of CIN at a very early stage of gastric tumorigenesis. Mechanistically, ARID1A bound centromere repetitive satellite DNA (satDNA) sequences. Its SWI/SNF-associated chromatin remodeling activity was required for suppressing satDNA transcription and the production of -SatRNA, through restricting RNAPII elongation. Consequently, ARID1A depletion led to overexpression of -SatRNA, and a higher incidence of sister chromatid exchange (SCE), a sensitive indicator of CIN. Importantly, the elevated -SatRNA expression in ARID1A-deficient cells further established a dual therapeutic vulnerability for G2/M checkpoint blockade, such as PKMYT1 inhibitor (PKMYTi), by concurrently aggregating CIN-induced cell death and activating self-dsRNA sensing-mediated innate immune response. Notably, PKMYTi markedly promoted -SatRNA expression, aberrant release of these self-derived dsRNAs into the cytosol and a robust activation of the RIG/MDA5-MAVS-depenent type-I interferon response in ARID1A-depleted cells. As expected, PKMYTi potentiated the efficacy of immunotherapy in ARID1A-deficient gastric tumors. Together, our findings reveal that ARID1A deficiency unleashes centromeric -SatRNA transcription, which sets the molecular stage for tumor evolution and targeted therapy by coordinately inducing CIN and self-dsRNA-induced innate immune responses.

cancer biology↗

bioRxiv2026

A Hierarchical Spatial Graph Neural Network Resolves Immunogenic and Tolerogenic Tertiary Lymphoid Structures in Renal Cell Carcinoma

Tertiary lymphoid structures (TLS) in the tumour microenvironment span a functional spectrum from immunogenic -- driving germinal centre reactions and anti-tumour immunity -- to tolerogenic, harbouring regulatory T cells and suppressive myeloid populations. Distinguishing these states is clinically critical: immunogenic TLS predict ICI response whereas tolerogenic TLS may promote immune evasion. Bulk transcriptomics conflates productive TLS with exhausted immune infiltrates, masking this distinction. We present a hierarchical graph neural network (GNN) that operates directly on 10x Visium spatial transcriptomics graphs to classify TLS functional state at the cluster level. Using a three-scale architecture combining graph attention (GAT) and differentiable pooling (DiffPool), the model hierarchically aggregates spot-level signals into niche- and region-level representations before predicting immunogenic versus tolerogenic state. Trained on 915 TLS clusters from 24 renal cell carcinoma (RCC) Visium samples (GSE175540), the model achieves a validation AUC-ROC of 0.718 and a clinical AUC of 0.908 on IgG-validated samples from the BIONIKK cohort. Zero-shot transfer to an independent multi-cancer Visium cohort (GSE203612; breast, liver, ovarian, pancreatic, uterine) correctly identifies hepatocellular carcinoma as harbouring the most tolerogenic TLS, consistent with the known immunosuppressive liver tumour microenvironment. Spatial decomposition of CXCL13 across TLS and non-TLS compartments reveals that 85% of tissue CXCL13 signal originates from non-TLS parenchyma, where it co-expresses primarily with exhaustion markers (mean Spearman rho = 0.233) rather than Tfh markers (CXCR5 rho = 0.039) -- a pattern consistent with the paradoxical association of bulk CXCL13 with worse overall survival in TCGA-KIRC (HR = 1.38, p < 0.001). Code and processed data are deposited at GitHub and Zenodo.

cancer biology↗

bioRxiv2026

Deriving functional network topology from in vivo two-photon calcium imaging: state-dependent graph features in mouse mesoscale motor cortical network

Mesoscale neuronal networks represent an intermediate organizational level linking single-neuron activity to large-scale brain networks. Here, we used in vivo two-photon calcium imaging and graph-theoretical analysis to characterize functional network topology in the primary motor cortex across behavioral states. Motion networks exhibited the largest functional connectivity architectures, whereas anesthesia networks showed reduced network scales together with stronger modular segregation and more pronounced small-world topology. Network sign further shaped topology, with negative associations associated with reduced modularity and weakened small-world structure. Hub analyses revealed additional state-dependent differences: anesthesia networks exhibited stronger hub connectivity despite reduced neuronal activity, whereas motion networks showed higher hub activity with weaker connectivity structure. These findings demonstrate that mesoscale neuronal networks exhibit structured and state-dependent organization and provide a framework for studying cortical network dynamics in normal brain function and brain disorders.

neuroscience↗

bioRxiv2026

Empagliflozin alleviates doxorubicin-induced cardiotoxicity by suppressing oxidative stress via modulation of the JNK/Nrf2 signaling pathway

Doxorubicin (DOX) treatment increases the risk of myocardial dysfunction and heart failure, in which oxidative stress plays a central role. Empagliflozin (EMPA) has been shown to benefit heart failure patients, yet its underlying mechanism remains unclear. In this study, we showed that EMPA treatment improved cardiac function, ameliorated structural remodeling, and increased survival in DOX-treated mice. Furthermore, EMPA reduced DOX-induced reactive oxygen species (ROS) overproduction and myocardial injury. Through functional analysis overlapping DIC- and EMPA-regulated genes, we identified the involvement of JNK signaling in addition to redox pathways. Subsequent investigations demonstrated that EMPA restored redox homeostasis by inhibiting JNK activation, reactivating NRF2 and its downstream antioxidant proteins HO-1, NQO1, GPX4, and SOD2 both in vivo and in vitro. These protective effects were abolished by the Nrf2 inhibitor ML385 or the JNK activator anisomycin. Collectively, our findings indicate that EMPA protects against DOX-induced cardiotoxicity by modulating the JNK/Nrf2 signaling and attenuating oxidative stress. This study provides a rationale for further investigation of EMPA as a potential therapeutic strategy for chemotherapy-associated cardiac injury. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=135 SRC="FIGDIR/small/697595v1_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@16743d4org.highwire.dtl.DTLVardef@96495borg.highwire.dtl.DTLVardef@aa343dorg.highwire.dtl.DTLVardef@4ba18c_HPS_FORMAT_FIGEXP M_FIG C_FIG

pharmacology and toxicology↗

bioRxiv2025

The transcriptional regulatory circuit as a driver and therapeutic target in CML blast crisis

Patients with blast crisis in chronic myeloid leukemia (CML) exhibit an extremely poor prognosis, with median survival of only a few months and limited therapeutic options. Dysregulated transcriptional regulation plays a pivotal role in driving blast crisis progression. In this study, we performed histone modification and transcriptomic high-throughput sequencing on bone marrow cells derived from chronic and blast-phase CML patients, identifying a CML blast-specific transcriptional regulatory circuit comprising MEF2C, MYB, MEIS1, and ZEB2. These transcription factors (TFs) form protein complexes that co-bind to shared enhancers or promoters, reciprocally enhancing each others transcriptional activity and that of their downstream targets. Mechanistically, this circuit synergistically reprograms chromatin accessibility and transcriptional landscapes in blast cells, parallel activation of purine metabolism and Rho GTPase signaling pathways which exhibit functional crosstalk. Functional validation demonstrated that silencing components of this circuit or its downstream core targets significantly suppressed CML blast progression in vitro and in vivo. Notably, mebendazole (MBZ), a clinically approved inhibitor targeting MYB protein stability, recapitulated these inhibitory effects. Our findings establish the MEF2C-MYB-MEIS1-ZEB2 transcriptional circuit as a central driver of CML blast crisis and position MBZ as a high-potential translational strategy for targeting this lethal phase of the disease. Key PointsO_LIMEF2C, MYB, MEIS1, and ZEB2 form the CML blast-crisis transcriptional circuit, synergistically reprogramming chromatin and transcription. C_LIO_LIMebendazole inhibits CML blast progression by impairing the circuit, offering a rapid translational strategy for this lethal phase. C_LI

cancer biology↗

bioRxiv2025

Brain-derived neurotrophic factor supports pericyte and vascular homeostasis in the aging brain

Microvascular circulation in the brain is often impaired in connection with the loss of pericytes in old age. The neurotrophic factor BDNF also decreases in the aging brain. We hypothesized that BDNF regulates the homeostasis of cerebral pericytes and microvasculature. We used differently aged C57BL/6J mice, and C57BL6 mice with conditional knockout of Bdnf gene. Collagen IV-positive microvessels and PDGFR{beta}-positive pericytes in the brain were counted after immunological staining. Pericytes were also quantified by Western blot of PDGFR{beta} and CD13 in isolated cerebral microvessels. The level of BDNF and TrkB phosphorylation was determined in brain homogenates. To demonstrate the direct effect of BDNF on pericytes, TrkB and pericytes were co-stained in brain tissue, single-cell sequencing and transcriptomic analysis were used to identify and characterize Ntrk2-expressing pericytes, and TrkB was also detected in the pericyte cell line by Western blot. Cultured pericytes were further treated with recombinant BDNF in the presence and absence of an Akt inhibitor and examined for PDGFR{beta} expression. The length and branching of microvessels and pericytes decreased in conjunction with the reduction in mature BDNF and TrkB phosphorylation in aging brains. Deficiency of BDNF in neurons or astrocytes was sufficient to reduce cerebral microvessels, PDGFR{beta} and CD13 concentrations and Akt and Erk1/2 phosphorylation in isolated blood vessels. A subset of pericytes in the brain and cultured pericytes expressed TrkB. BDNF treatment increased PDGFR{beta} expression along with Akt and Erk1/2 phosphorylation in cultured cells. The effect of BDNF on PDGFR{beta} expression was abolished by treatment with Akt inhibitor. Therefore, BDNF induces the expression of PDGFR{beta} and CD13 by activating Akt signaling in pericytes, promoting the homeostasis of pericytes and microvasculature in the aging brain. Our study identified a BDNF-mediated mechanism that regulates microvascular integrity in the aged brain.

neuroscience↗

bioRxiv2025

Identification of biomarkers for ulcerative morphology in carotid atherosclerosis plaques through single-cell RNA sequencing data

BackgroundCarotid atherosclerotic stenosis (CAS) is a major risk factor for stroke, particularly when associated with ulcerative plaque morphology. However, the molecular mechanisms underlying ulceration remain inadequately defined. In this study, we aimed to construct single-cell atlases of ulcerative and non-ulcerative CAS plaques to identify biomarkers associated with ulcerative lesions. MethodsPlaque tissues from four ulcerative and three non-ulcerative CAS samples were collected and subjected to single-cell RNA sequencing (scRNA-seq). Cell types were identified through scRNA-seq analysis, and differential cell types were determined by comparing their proportions between the 2 groups. Candidate genes were identified by intersecting differentially expressed genes (DEGs) within these differential cell populations. Subsequently, the Molecular Complex Detection (MCODE) plugin in Cytoscape was employed to confirm the biomarkers. Functional annotation and regulatory network analysis were then performed to investigate underlying biological mechanisms. ResultsscRNA-seq analysis identified 7 cell types, of which 6 showed differential proportions, leading to the identification of 61 candidate genes and 7 key biomarkers (KLF2, JUNB, FOS, HSPA1A, DUSP1, JUND, and ZFP36). Enrichment analysis indicated that these biomarkers may influence ulcerative CAS plaques via RNA polymerase II-mediated transcription and stress-response pathways. Regulatory network analysis revealed complex interactions, with RBMX, STAT3, YTHDF3, DDX3X, and ELAVL1 identified as potential upstream regulators. ConclusionsKLF2, JUNB, FOS, HSPA1A, DUSP1, JUND, and ZFP36 were identified as biomarkers, offering novel insights into the molecular mechanisms underlying ulcerative morphology in CAS.

pathology↗

bioRxiv2025

Effects of Ambient Temperature During Pregnancy on Newborn Birthweight

This study evaluates the association between ambient temperature exposure during pregnancy and newborn birthweight, using a penalized generalized additive model (GAM) framework with distributed lag non-linear models (DLNM) to identify sensitive windows of exposure. The analysis includes 238 participants from the SHIP study with complete temperature exposure and birthweight data. Weekly maximum temperatures during pregnancy were estimated using Daymet data, and the impact of temperature on birthweight was assessed, adjusting for maternal age, pre-pregnancy BMI, gestational age, race, smoking, diabetes status, and infant biological sex. The model incorporated a crossbasis function for temperature exposure across 42 gestational weeks and allowed penalization for smoother, data-driven lag estimation. Results from the combined-sex model indicated that higher ambient temperatures during the third trimester, particularly in the final weeks of pregnancy, were associated with increased birthweight. Stratified analyses suggested that this association was more pronounced in male infants. These findings highlight the importance of considering prenatal temperature exposures and timing when evaluating determinants of newborn health.

developmental biology↗

bioRxiv2025

Divergent stem cell mechanisms governing the primary body axis and appendage regeneration in the axolotl

Exploring the fundamental mechanisms of organ regeneration is crucial for advancing regenerative medicine. The axolotl tail represents a unique opportunity to study regeneration of the primary axis including segmented muscle, vertebrae and skin. During tail development, muscle stem cells (MuSCs) displayed expected specificity to the muscle lineage. Tail amputation, however, induced expansion of MuSC potential yielding clonal contribution to muscle, connective tissue including cartilage, pericytes, and fibroblasts. This expanded potential was not observed during limb regeneration, and cross-transplantation showed these differences in potential are intrinsic. ScRNA-Seq profiling revealed that tail MuSCs revert to an embryonic mesoderm-like state. Through genetic manipulation involving the over-expression of constitutively active TGF-{beta} receptors or Smad7 (antagonist of TGF-{beta} signaling) in MuSCs, we demonstrated that the levels of TGF-{beta} signal determine the fate outcome of MuSCs to connective tissue lineage or muscle respectively. Our findings illustrate a fundamental difference between regeneration of primary axis versus limb and offers a novel stem cell source for regeneration of axial skeletal tissues.

developmental biology↗

bioRxiv2024

Age-Related Patterns of DNA Methylation Changes

Epigenetic clocks have achieved significant success in aging research, but they often assume linear methylation changes with age and lack biological interpretability. Using data from 4,641 samples across 23 GEO datasets, we analyzed 1,557 CpGs from nine widely used clocks with minimal overlap, and identified consistent age-associated methylation patterns. We then identified 19,432 age-associated CpGs (aaCpGs) that were strongly correlated with age and showed high consistency between sexes, with faster methylation changes observed in males. Most aaCpGs were identified during early and late life stages, indicating accelerated epigenetic changes during development and aging. No specific genomic enrichment was observed. Clustering analysis revealed four distinct, non-linear age-related methylation trajectories. These findings underscore the complexity of epigenetic aging and suggest that current clocks may overlook important dynamic patterns, particularly after age 65. Incorporating these insights could improve the accuracy and biological relevance of future epigenetic clocks, especially for use across diverse age ranges and populations.

molecular biology↗

bioRxiv2024

A new stegosaur (Dinosauria: Ornithischia) from the Upper Jurassic Qigu Formation of Xinjiang, China and a revision on Chinese stegosaurs phylogeny

Stegosaurs are a small but iconic clade of ornithischian dinosaurs. They and their sister taxa, the ankylosaurs, formed the clade Eurypoda which means broad-footed. Here, we describe a stegosaur from the Upper Jurassic Qigu Formation of Xinjiang, China, based on an associated partial skeleton that includes axial, pectoral girdle, pelvic girdle, limb and armor elements. It can be diagnosed as a new taxon, Angustungui, based on numerous autapomorphies. Some morphologies of Angustungui are more similar to the taxa from Europe, Africa and North America than to those from Asia. Our phylogenetic analysis recovers it as the sister taxon of Loricatosaurus. More importantly, the narrow and claw-shaped ungual of Angustungui proves that Eurypoda, at least stegosaur, has claw-shaped unguals. Besides, we revised the character scores for Chinese stegosaurs based on observations of the specimens.

paleontology↗

bioRxiv2024

Loss of PMR4 callose synthase results in salicylic acid-independent and broad-spectrum resistance to clubroot in Arabidopsis and Brassica napus

The clubroot disease caused by protist Plasmodiophora brassicae is one of the most important diseases of Brassica crops. Growing clubroot-resistant cultivars remains the most effective and practical approach to managing clubroot disease. However, resistance gene-mediated immunity is rapidly overcome in the field when new pathotypes arise. In this study, we identified PMR4 as a potential gene target for creating a novel clubroot-resistant source. Recessive PMR4 mutations in Arabidopsis thaliana conferred broad-spectrum resistance to multiple P. brassicae pathotypes, independent of salicylic acid-mediated plant immunity. CRISPR/Cas9-mediated gene-editing was employed to create mutations in two PMR4 orthologs in the B. napus genome, and resulting homozygous mutants exhibited dual resistance to powdery mildew and clubroot. PMR4 is required for the callose deposition at wound and powdery mildew infection sites in leaves. This study reveals that callose deposition in roots is induced by P. brassicae infection and requires PMR4. It appears that the clubroot disease progression is arrested at the primary-to-secondary infection phase in pmr4-1 mutants. Together, this study demonstrates that PMR4-encoded callose synthase is a host susceptibility factor required for P. brassicae to complete its life cycle, and that PMR4 can be targeted against both powdery mildew and clubroot diseases in Brassica crops.

plant biology↗