Biology subjects

Jin, W.

Publications and source records attributed to Jin, W..

At least 37 records · Page 2Linked to original sources

bioRxiv2025

Arousal-Driven Serial Dependence: Internal States Modulate Perceived Duration

Emotional experiences shape not only how we perceive the present but also how recent experiences inform our current judgments. This study examined whether emotional arousal and valence modulate serial dependence in time perception--the tendency for prior stimuli to bias ongoing estimates. Participants viewed affective images that induced high-arousal (positive or negative) or low-arousal (neutral) states and then reproduced each images duration. High arousal reliably lengthened perceived durations. More critically, it strengthened serial dependence, with the strongest biases emerging when high-arousal trials followed other high-arousal trials, showing a state-dependent amplification of temporal integration. Emotional valence, by contrast, exerted no measurable influence on either temporal distortion or sequential bias. These findings show that emotional arousal tunes how the brain weighs past against present, highlighting internal emotional states as a key driver of temporal continuity in perception.

neuroscience↗

bioRxiv2025

CNVPipe: An enhanced pipeline for accurate analysis of copy number variation from whole-genome sequencing

Copy number variations (CNVs) are critical contributors to the genetic architecture of complex diseases, yet many existing pipelines for whole-genome sequencing (WGS) data exhibit persistently high false discovery rates (FDR). Here, we introduce CNVPipe, an enhanced workflow that integrates widely used CNV-calling tools with a novel machine-learning framework to achieve lower FDR and higher sensitivity. CNVPipe also provides a specialised module for single-cell CNV analysis, featuring a new model that accurately estimates the ploidy of single cells to get integer copy number profile. Benchmark evaluations demonstrate that CNVPipe outperforms current pipelines in various genomic contexts. In addition to detecting recurrent CNVs in paediatric developmental disorders, CNVPipe enables large-scale functional genomics applications involving stem cell technologies. Moreover, its application to sparse single-cell DNA sequencing data provides a new aspect of research in cancer evolution. Collectively, these findings underscore the versatility and reliability of CNVPipe as a comprehensive solution for CNV detection in WGS-based research.

systems biology↗

bioRxiv2025

Triple-N Dataset: Non-human Primate Neural Responses to Natural Scenes

Understanding the neural mechanisms of visual perception requires data that encompass both large-scale cortical activity and the fine-grained dynamics of individual neurons. While the Natural Scenes Dataset (NSD) has provided substantial insights into visual processing in humans (Allen et al., 2022), its reliance on functional magnetic resonance imaging (fMRI) limits the exploration of individual neuron contributions. To bridge this gap, we present a new dataset: the Triple-N (Non-human Primate Neural Responses to Natural Scenes) dataset, which extends the NSD framework to non-human primates, incorporating single-neuron activity and fMRI recorded from the inferotemporal (IT) cortex. Using Neuropixels probes, we recorded neural responses from five macaques as they passively viewed 1,000 shared NSD images. The dataset includes 59 sessions across 27 sub-regions, capturing over 30,000 visual responsive units. Many recordings were obtained from fMRI-defined category-selective regions, such as face-, body-, scene-, and color-selective areas. Our dataset enables in-depth exploration of neural responses at multiple levels - from population dynamics to single-neuron activity, providing new insights into various aspects of visual processing, including the heterogeneity of object selectivity within functional regions and the temporal dynamics of responses to natural images. Furthermore, the dataset enables joint cross-species analyses, by integrating the macaque neural recordings with human fMRI data, offering a framework for comparing and aligning visual representations across primate species. Overall, our dataset provides a valuable resource for advancing our understanding of visual perception, bridging the gap between large-scale neuroimaging and fine-grained electrophysiological signals, while also facilitating the development of computational models of the high-level visual system.

neuroscience↗

bioRxiv2025

spRefine Denoises and Imputes Spatial Transcriptomics with a Reference-Free Framework Powered by Genomic Language Model

The analysis of spatial transcriptomics is hindered by high noise levels and missing gene measurements, challenges that are further compounded by the higher cost of spatial data compared to traditional single-cell data. To overcome this challenge, we introduce spRefine, a deep learning framework that leverages genomic language models to jointly denoise and impute spatial transcriptomic data. Our results demonstrate that spRefine yields more robust celland spot-level representations after denoising and imputation, substantially improving data integration. In addition, spRefine serves as a strong framework for model pre-training and the discovery of novel biological signals, as highlighted by multiple downstream applications across datasets of varying scales. Notably, spRefine enhances the accuracy of spatial ageing clock estimations and uncovers new aging-related relationships associated with key biological processes, such as neuronal function loss, which offers new insights for analyzing ageing effect with spatial transcriptomics.

genomics↗

bioRxiv2025

STPath: A Generative Foundation Model for Integrating Spatial Transcriptomics and Whole Slide Images

Spatial transcriptomics (ST) has shown remarkable promise in pathology applications, shedding light on the spatial organization of gene expression and its relationship to the tumor microenvironment. However, its clinical adoption remains constrained due to the limited scalability of current sequencing technologies. While recent methods attempt to infer ST from whole slide images (WSIs) using pretrained image encoders, they remain restricted by limited gene coverage, organ-specific training, and the need for dataset-specific fine-tuning. In light of this, we introduce STPath, a generative foundation model pretrained on a large-scale collection of WSIs paired with ST profiles. This extensive pretraining enables STPath to directly predict gene expression across 38,984 genes and 17 organs without requiring downstream fine-tuning. STPath integrates multiple data modalities, including histological images, gene expressions, organ type, and sequencing technology information, within a novel geometry-aware Transformer architecture. Unlike previous methods that directly map WSIs to gene expression, STPath is trained using a masked gene expression prediction objective guided by tailored noise schedules, effectively balancing between capturing gene-gene dependencies and performing high-quality predictions. We evaluate STPath across 6 tasks spanning 23 datasets and 14 biomarkers, including gene expression prediction, spot imputation, spatial clustering, biomarker prediction, gene mutation prediction, and survival prediction. These results demonstrate STPaths strong ability to infer spatially resolved gene expression and reveal crucial pathological structures within tissue samples, underscoring its promise for scalable ST-based pathology applications.

pathology↗

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↗

bioRxiv2025

Graph-based Contrastive Learning Enables Unified Integration and Niche Transfer Across Single-Cell and Spatial Multi-Omics

The rapid growth of single-cell and spatial omics has outpaced computational methods capable of unifying these data into a cohesive framework for tissue atlas construction and cross-sample analysis. A critical bottleneck lies in the inability of existing tools to co-embed cells from diverse technologies--spanning transcriptomics, epigenomics, and proteomics--into a shared reference space while preserving spatial architecture and molecular specificity. Here, we present Garfield (Graph-based Contrastive Learning Enables Fast Single-Cell Embedding), a geometric deep-learning framework that addresses these challenges through spatially or molecularly aware cell embedding. Leveraging a graph contrastive learning framework, Garfield learns a shared embedding space for data generated by diverse technologies, enabling seamless construction and querying of spatial reference atlases. Our results show that Garfield consistently outperforms state-of-the-art benchmark models in identifying spatial niches across multiple datasets. We further demonstrate Garfields versatility by applying it to multi-modal spatial data, including gene expression and chromatin accessibility, where it successfully identifies distinct niches in the mouse brain. Notably, Garfield reveals tumor microenvironment heterogeneity in non-small cell lung cancer and breast cancer, uncovered conserved, barrier-like immune niches at tumor margins orchestrating CD80-mediated T cell-B cell-dendritic cell interactions and IFN-/B cell activation pathways, forming spatially coordinated immune surveillance hubs. These findings underscore Garfields potential to advance spatial omics research by offering a robust, scalable solution for integrating and interpreting complex spatial data across diverse tissue types and modalities.

bioinformatics↗

bioRxiv2024

Gene Conversion Directed Successive Engineering of Modular Polyketide Synthases

Modular polyketide synthases (PKSs) can produce various secondary metabolites in a collinearity fashion. Although rational engineering of modular PKS can ultimately create a diverse array of novel compounds, de novo generation of defined structures usually results in the loss or remarkable decline of productivity due primarily to the incompatibility of different elements. Here, we present a modular PKS engineering strategy driven by an evolutionary event of gene conversion to accomplish successive engineering of the modular PKS in cinnamomycin biosynthetic gene cluster (cmm BGC). By simulating the gene conversion process, cmm BGC is consecutively reprogrammed to generate a novel macrolide with predicted structural features. Moreover, in contrast to previous notion, the intra-module KS domain is demonstrated to associate with the selectivity of extender units. Collectively, the coordination between evolutionary consequence and functional manipulation of assembly line may shed a new light on modular PKS engineering. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=104 SRC="FIGDIR/small/630704v1_ufig1.gif" ALT="Figure 1"> View larger version (17K): org.highwire.dtl.DTLVardef@11bd249org.highwire.dtl.DTLVardef@18af1a9org.highwire.dtl.DTLVardef@ffa287org.highwire.dtl.DTLVardef@10756cf_HPS_FORMAT_FIGEXP M_FIG Gene conversion process, typically occurred in KS (purple squares) and AT (blue squares), plays an integral role of structural diversity of polyketides. In this study, an unusual gene conversion was observed in cmm BGC. Subsequently, a homologous BGC was obtained through genome mining by a gene conversion-associated KS domain. Under the direction of gene conversion, the modular PKS in cmm BGC was successively reprogrammed, resulting in de novo biosynthesis of a new-to-nature polyketide. C_FIG

bioengineering↗

bioRxiv2024

Temporally overlapping mechanisms diversify clonal B cell responses in vivo.

Naive B cells amplify and diversify their responses when activated by cognate antigen, via Myc-dependent clonal expansion, immunoglobulin class switch recombination (CSR), phenotypic variation, and somatic hypermutation (SHM). Whether these mechanisms act combinatorially in vivo to diversify clonal responses to a single pathogen remains unclear. Since diversity in the antigenic targets, functional classes, and production kinetics of parasite-specific antibodies influences immunity to malaria, we test here whether individual B cell clones diversify over time during Plasmodium infection and treatment. During the first week of infection, amid widespread Type I Interferon (IFN)-mediated bystander activation, CSR initiates soon after Myc up-regulation, and overlaps partially with clonal expansion, resulting in isotype variegation amongst clones. During the second week of infection, expanded clones that seed germinal centres (GC) bifurcate into extra-follicular plasmablasts, exhibit isotype variegation, and initiate SHM, revealing substantial intra-clonal diversification. Over the following month, GC clones exhibit SHM at approximately four mutations per week, with IgG mutational diversity and IgM+ cells also preserved in GCs over time. Anti-malarial intervention does not impede SHM, but instead exerts quantitative limits on GC size, plasma cell emergence, circulating IgG levels, and protection against re-infection. Finally, contemporaneous B cell development relocates from bone marrow to spleen during infection and treatment. Thus, multiple temporally overlapping mechanisms combine in vivo to amplify, diversify, and safeguard humoral immune responses. We present this data as a temporal, multi-parameter atlas of B cell differentiation in vivo: https://bcell-dynamics.science.unimelb.edu.au Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=130 SRC="FIGDIR/small/628863v2_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@c57890org.highwire.dtl.DTLVardef@6e5936org.highwire.dtl.DTLVardef@a2e872org.highwire.dtl.DTLVardef@14abbac_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIPartial temporal overlap of CSR with clonal expansion leads to isotype variegation in clones. C_LIO_LIClones seeding GCs bifurcate into plasmablasts and exhibit isotype variegation. C_LIO_LIGC B cells accrue [~]4 mutations/week, a rate unaffected by anti-malarials. C_LIO_LIPlasmodium infection triggers antigen-independent Type I IFN-mediated bystander activation. C_LIO_LIB cell development is preserved in malaria by shifting from bone marrow to spleen. C_LI

immunology↗

bioRxiv2024

Optimisation of a multiplexed, high throughput assay to measure neutralising antibodies against SARS-CoV-2 variants.

A multiplexed, lentivirus-based pseudovirus neutralisation assay (pVNT) was developed for high-throughput measurement of neutralising antibodies (nAbs) against three distinct SARS-CoV-2 spike variants. Intra-assay variability was minimised by optimising the plate layout and determining an optimal percentage transduction for the pseudovirus inoculum. Comparison of monoclonal antibody EC50 titres between single and multiplexed pVNT assays showed no significant differences, indicating reliability of the multiplexed assay. Evaluation of convalescent human sera confirmed assay validity, with consistent fold drops in EC50 for variant pseudoviruses relative to the ancestral strain observed across single and multiplexed assays. This multiplexed pVNT provides a reliable tool for assessing nAb responses against SARS-CoV-2 variants and could be used to accelerate preclinical vaccine assessment in preparation for the next coronavirus pandemic.

immunology↗

bioRxiv2024

Refining gene delivery to skeletal muscle with a dual-strategy approach of muscle-tropic AAV capsids and muscle-specific promoters.

Viral vector technologies based on adeno-associated virus (AAV) have demonstrated promising ability to deliver genetic cargo to a range of organs in vivo, with several novel candidates showing clinical efficacy in human trials over the past decade. However, naturally occurring AAV serotypes are limited in their ability to target skeletal muscle, an important gene therapy target for many neuromuscular disorders. This means that high doses of AAV are often required to achieve therapeutically effective doses in muscle. To overcome this, novel AAV vector capsids have been engineered by inserting targeting peptides into the AAV9 capsid variable region VIII (VRIII) to achieve greater muscle transduction efficiency. Here we describe investigation of a newly reported capsid, called MyoAAV1A combined with clinically validated muscle-specific promoters. We profiled the efficiency of in vivo delivery to murine skeletal muscle and found that the optimal combination of MyoAAV1A capsid with MHCK7 promoter maintains transgene expression in skeletal muscle, and reduces expression in off-target tissues, particularly the liver. This highlights a promising capsid-promoter combination to progress in further preclinical research for skeletal muscle gene therapy. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=143 SRC="FIGDIR/small/605568v1_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@10bbe78org.highwire.dtl.DTLVardef@5e2e0org.highwire.dtl.DTLVardef@71f4a7org.highwire.dtl.DTLVardef@1750d81_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioengineering↗

bioRxiv2024

Genetic diversity and evolution of rice centromeres

AbstractUnderstanding the mechanisms driving centromere evolution is crucial for deciphering eukaryotic evolution and speciation processes. Despite their widely recognized characteristics of conserved function in cell division, the centromeres have showed high diversity in composition and structure between species. The mechanism underlying this paradox remain poorly understood. Here, we assembled 67 high-quality rice genomes from Oryza AA group, encompassing both Asian and African rice species, and conducted an extensive analysis of over 800 nearly complete centromeres. Through de novo annotation of satellite sequences and employing a progressive compression strategy, we quantified the local homogenization and multi-layer nested structures of rice centromeres and found that genetic innovations in rice centromeres primarily arise from internal structural variations and retrotransposon insertions, along with a certain number of non-canonical satellite repeats (sati). Despite these rapid structural alterations, the single-base substitution rate in rice centromeres appears relatively lower compared to the chromosome arms. Contrary to the KARMA model for Arabidopsis centromere evolution, our model (RICE) suggests that centrophilic LTRs contribute to the decline of progenitor centromeres composed of satellite repeats, and facilitate the formation of evolutionary neo-centromeres, which are enriched with extended CENH3 binding regions beyond the native satellite arrays in plant genomes. In summary, this study provides novel insights into genomic divergence and reproductive barriers among rice species and subspecies, and advances our understanding of plant centromere evolution.

genetics↗

bioRxiv2024

In silico generation and augmentation of regulatory variants from massively parallel reporter assay using conditional variational autoencoder

Predicting the functional consequences of genetic variants in non-coding regions is a challenging problem. Massively parallel reporter assays (MPRAs), which are an in vitro high-throughput method, can simultaneously test thousands of variants by evaluating the existence of allele specific regulatory activity. Nevertheless, the identified labelled variants by MPRAs, which shows differential allelic regulatory effects on the gene expression are usually limited to the scale of hundreds, limiting their potential to be used as the training set for achieving a robust genome-wide prediction. To address the limitation, we propose a deep generative model, MpraVAE, to in silico generate and augment the training sample size of labelled variants. By benchmarking on several MPRA datasets, we demonstrate that MpraVAE significantly improves the prediction performance for MPRA regulatory variants compared to the baseline method, conventional data augmentation approaches as well as existing variant scoring methods. Taking autoimmune diseases as one example, we apply MpraVAE to perform a genome-wide prediction of regulatory variants and find that predicted regulatory variants are more enriched than background variants in enhancers, active histone marks, open chromatin regions in immune-related cell types, and chromatin states associated with promoter, enhancer activity and binding sites of cMyC and Pol II that regulate gene expression. Importantly, predicted regulatory variants are found to link immune-related genes by leveraging chromatin loop and accessible chromatin, demonstrating the importance of MpraVAE in genetic and gene discovery for complex traits.

bioinformatics↗

bioRxiv2024

Advancing the genetic engineering toolbox by combining AsCas12a knock-in mice with ultra-compact screening

Cas12a is a gene-editing tool that simplifies multiplexed gene targeting through its RNase activity, enabling maturation of individual crRNAs from a pre-crRNA-encoding RNA. Here, we present a mouse model that constitutively expresses enhanced Acidaminococcus sp. Cas12a (enAsCas12a) linked to an mCherry fluorescent reporter. We demonstrate efficient single and multiplexed gene-editing in cells from enAsCas12aKI mice. To test in vivo activity, we transduced haematopoietic stem cells from E-MycT/+;enAsCas12aKI/+animals with Trp53-targeting pre-crRNAs followed by transplantation into irradiated recipient animals. Tumour development was accelerated and TRP53 protein lost. We generated compact, genome-wide Cas12a knockout libraries targeting each gene with four guide RNAs encoded on two (Menuetto) or one (Scherzo) vector. Introducing these libraries into E-MycT/+;enAsCas12aKI/+lymphoma cells followed by treatment with an MCL-1 inhibitor (S63845) or TRP53-inducer (nutlin-3a) identified known and novel drug resistance genes. Finally, we demonstrate simultaneous gene knockouts (Trp53 or combined Bax/Bak) and activation (Cd19) in primary T cells and mouse dermal fibroblasts from crosses of our enAsCas12a and CRISPR activation models (dCas9a-SAM). Our enAsCas12a mouse model and accompanying libraries enhance genome engineering capabilities and complements current CRISPR technologies.

molecular biology↗

bioRxiv2024

MPRAVarDB: an online database and web server for exploring regulatory effects of genetic variants

SummaryMassively parallel reporter assay (MPRA) is an important technology to evaluate the impact of genetic variants on gene regulation. Here, we present MPRAVarDB, an online database and web server, for exploring regulatory effects of genetic variants. MPRAVarDB harbors 18 MPRA experiments designed to assess the regulatory effects of genetic variants associated with GWAS loci, eQTLs and various genomic features, resulting in a total of 242,818 variants tested across more than 30 cell lines and 30 human diseases or traits. MPRAVarDB empowers the query of MPRA variants by genomic region, disease and cell line or by any combination of these query terms. Notably, MPRAVarDB offers a suite of pretrained machine learning models tailored to the specific disease and cell line, facilitating the genome-wide prediction of regulatory variants. MPRAVarDB is friendly to use, and users only need a few clicks to receive query and prediction results. Availabilityhttps://mpravardb.rc.ufl.edu Supplementary informationSupplementary data are available at Bioinformatics online.

bioinformatics↗

bioRxiv2024

Synchronization of Circadian Clock Gene Expression in Arabidopsis and Hyaloperonospora arabidopsidis and its Impact on Host-Pathogen Interactions

Organisms across all kingdoms have an internal circadian clock running in 24h cycles. This clock affects a variety of processes, including innate immunity in plants. However, the role of pathogen circadian clocks had not been extensively explored. We previously showed that light can influence infection of the oomycete Hyaloperonospora arabidopsidis (Hpa, downy mildew disease) on its natural host Arabidopsis thaliana. Here, we identified Hpa orthologs of known circadian clock genes (CCGs) Drosophila TIMELESS (TIM) and Arabidopsis Sensitive to Red Light Reduced 1 (AtSRR1) genes. Expression of both HpaTIM and HpaSRR1 showed a circadian rhythm when Hpa was exposed to constant light. Contrastingly, these two genes were negatively regulated by constant dark exposure. Furthermore, the expression patterns of HpaTIM and HpaSRR1 correlate with those of AtCCA1 and AtLHY, indicating a synchronisation of biological clock genes between the host and the pathogen. In addition, screening mutants of Arabidopsis Clock Regulated Genes (AtCRGs) with three virulent Hpa isolates revealed that mutations in AtCRGs influenced HpaTIM and HpaSRR1 expression and Hpa development, indicating a functional link between the plant biological clock and virulence. Moreover, sporulation of Hpa was reduced by targeting HpaTIM and HpaSRR1 with short synthesized small interfering RNAs, indicating that the pathogen clock is also relevant to virulence. We propose that plant and pathogen clocks are synchronized during infection and that proper regulation of both clocks are genetically necessary for pathogen virulence.

plant biology↗

bioRxiv2024

Mapping chromatin remodelling in glioblastoma identifies epigenetic regulation of key molecular pathways and novel druggable targets.

Analysis of chromatin remodelling in neoplastic stem cells as compared to ontogenetically related neural stem cells, reveals multifactorial epigenetic regulation of signalling pathways known to contribute to glioblastoma development. It also identifies novel epigenetically regulated druggable target genes on a patient-specific level, including SMOX and GABBR2 which could be further developed for future translational approaches to more effectively treat this neoplasm.

cancer biology↗

bioRxiv2024

A universal molecular mechanism driving aging

How cell replication ultimately results in aging and the Hayflick limit are not fully understood. Here we show that clock-like accumulation of DNA G-quadruplexes (G4s) throughout cell replication drives conserved aging mechanisms. G4 stimulates transcription-replication interactions to delay genome replication and impairs DNA re-methylation and histone modification recovery, leading to loss of heterochromatin. This creates a more permissive local environment for G4 formation in subsequent generations. As a result, G4s gradually accumulate on promoters throughout mitosis, driving clock-like DNA hypomethylation and chromatin opening. In patients and in vitro models, loss-of-function mutations in the G4-resolving enzymes WRN, BLM and ERCC8 accelerate the erosion of the epigenomic landscape around G4. G4-driven epigenomic aging is strongly correlated with biological age and is conserved in yeast, nematodes, insects, fish, rodents, and humans. Our results revealed a universal molecular mechanism of aging and provided mechanistic insight into how G-quadruplex processor mutations drive premature aging.

molecular biology↗