Biology subjects

Zhang, W.

Publications and source records attributed to Zhang, W..

At least 91 records · Page 5Linked to original sources

bioRxiv2026

An EpCAM-Targeted Mirror-Image DNA Nanostructure for Precise Drug Delivery in Triple-Negative Breast Cancer

Triple-negative breast cancer (TNBC) remains a major therapeutic challenge due to the lack of effective molecular targets and the dose-limiting off-target toxicity of conventional chemotherapy. Here, we design and construct a mirror-image DNA (L-DNA) nanostructure functionalized with an epithelial cell adhesion molecule (EpCAM)-specific aptamer for targeted delivery of doxorubicin (DOX) to TNBC cells. The L-DNA nanostructure retains thermodynamic properties comparable to natural D-DNA while exhibiting substantially enhanced resistance to nuclease and serum-mediated degradation due to its mirror-image chirality. Thermal melting and serum stability assays confirmed superior structural stability of the L-DNA nanostructure compared to D-DNA counterparts. In vitro cytotoxicity studies demonstrated that the EpCAM-targeted L-DNA nanostructure has the potential to selectively inhibit the growth of EpCAM-positive TNBC cells while reducing cytotoxicity in normal cells. These findings demonstrate that combining aptamer targeting with mirror-image DNA nanotechnology provides a stable and selective nanoplatform for chemotherapeutic delivery, which can potentially improve the precision and therapeutic efficacy of treatment for aggressive breast cancers.

biochemistry↗

bioRxiv2026

A multimodal foundation model linking histopathology and DNA methylation

Hematoxylin and eosin (H&E) slides are routinely available in cancer care, but molecular profiling often requires additional tissue processing and turnaround time. We introduce HistoMethyl, a DNA methylation-aware pathology foundation model that aligns whole-slide histopathology with matched genome-scale methylation beta-value profiles during pre-training while requiring only an H&E slide at inference. We evaluated HistoMethyl across four task groups: gene mutation prediction, morphology-associated classification, overall survival prediction, and direct DNA methylation beta-value recovery. Evaluation spanned TCGA cross-validation, a disease-held-out lower-grade glioma cohort, and external cohort validation in CPTAC glioblastoma and SurGen rectal adenocarcinoma, totaling 14 cancer cohorts and 81 gene mutation tasks. The best-performing configuration improved mean mutation AUROC by 5.03 percentage points. By converting DNA methylation supervision into an H&E-only representation, His-toMethyl could support an early molecular triage layer that helps prioritize cases for confirmatory sequencing, methylation profiling, immunohistochemistry, and molecular tumor board review. These image-only predictions are intended to accelerate downstream molecular testing and tissue allocation while leaving final diagnosis and treatment selection anchored in validated molecular assays.

Cancer Biology↗

bioRxiv2026

Architecture of a portal complex embedded in the poxvirus core

Gene transcription within the viral core is a unique feature of poxvirus replication. Following entry into the cytoplasm, the poxvirus core dissociates from the lateral bodies and undergoes expansion, functioning as a compartment for early transcription. However, the mechanisms governing molecular exchange between the viral core and the host cytoplasm remain poorly understood. Here, we determine the structures of the portal complex and its pore on the poxvirus core at 7.1 [A] and 4.9 [A] resolution, respectively, using cryo-electron tomography and sub-tomogram averaging. The pore is assembled from three viral proteins, E8, E6, and L3, for which we constructed an atomic model. Structural and channel analyses reveal that the pore satisfies the geometric and electrostatic requirements for the transport of RNA and smaller negatively charged molecules, while excluding double-stranded DNA and cytosolic DNA sensors. Together, our findings establish a structural framework for understanding the assembly and function of the poxvirus portal complex and identify potential targets for antiviral intervention.

biophysics↗

bioRxiv2026

Genome Assembly of the Green Revolution Wheat Cultivar Pavon 76 Establishes a Reference for CIMMYT-Derived Wheat

Common wheat (Triticum aestivum L.) is a cornerstone of global food security. However, the standard reference genome, IWGSC RefSeq v2.1, is derived from wheat cultivar Chinese Spring, a historically important lineage that is not representative of modern cultivated wheat. In contrast, Pavon 76 is a CIMMYT Green Revolution wheat cultivar grown worldwide and is present in the pedigrees of numerous elite wheats, as well as in the genetic background of over 600 cytogenetic stocks used in studies ranging from recombination to male sterility. As no Pavon 76 reference has been reported, interpretation of these Pavon 76-derived stocks has relied on the genetically distant IWGSC RefSeq v2.1. To address this gap, we generated PacBio HiFi reads and Hi-C read pairs to assemble Pavon 76s genome. The final assembly comprises the expected 21 chromosomes, spans 15 Gb, and has an N50 of 710 Mb. Annotation identified 167,201 genes, of which 89.5% were functionally annotated. Comparative sequence and gene synteny analysis between Pavon 76 and IWGSC RefSeq v2.1 revealed significant structural divergence, establishing that IWGSC RefSeq v2.1 is not fully representative of modern wheats. This robust Pavon 76 assembly establishes the first chromosome-scale de novo assembly of a CIMMYT-derived wheat and provides a foundation for future genetic and genomic studies.

genomics↗

bioRxiv2026

Chronic Mild Stress Impairs Hippocampal Myelination through SOX6-Dependent Dysfunction of Oligodendrocyte Lineage Cells

Chronic stress induces structural and functional changes in the brain, increasing susceptibility to major depressive disorder and other mental illnesses. Myelination deficits are a key pathological feature of stress-related disorders, yet the molecular mechanisms linking chronic stress to oligodendrocyte dysfunction remain poorly understood. Here, we used single-nucleus multiome sequencing to map gene expression and chromatin-accessibility remodeling in the hippocampus of mice exposed to chronic unpredictable mild stress (CUMS), a model that simulates key features of human daily stressors. CUMS induced broad molecular reprogramming across hippocampal cell populations, with stress-responsive gene networks significantly enriched for depression-associated genes. The oligodendrocyte lineage showed heightened vulnerability, with CUMS preferentially disrupting immature OPC/intermediate states and impairing OPC migration, OPC-to-ODC lineage progression, intercellular communication, and myelination. Integrated multiomic analysis identified stage-specific cis-regulatory elements and stress-sensitive gene regulatory networks, converging on SOXD transcription factors, particularly SOX5 and SOX6, as key regulators of OPC dysfunction. SOX6 ChIP-seq confirmed direct SOX6 binding at regulatory elements associated with genes controlling OPC morphogenesis, migration, and glutamatergic signaling. CUMS reduced SOX6 protein levels and SOX6-associated regulatory network activity in OPCs, whereas OPC-specific enhancer-driven restoration of SOX6 rescued stress-induced defects in OPC migration and myelination. Together, these findings define a stress-sensitive SOXD/SOX6 regulatory mechanism linking chronic stress to oligodendrocyte lineage dysfunction and myelination deficits, identifying SOX6 as a functional regulatory node with therapeutic potential for stress-related brain pathology.

neuroscience↗

bioRxiv2026

Rapid in vitro synthesis of DNA templates via Sidewinder for polyadenylated Hantavirus mRNA vaccine candidates

As the recent COVID-19 pandemic illustrated, zoonotic viruses and other pathogens pose a credible threat to public health. Recent advancements in vaccine technology, particularly mRNA vaccines, provide key tools for an effective and swift public health response. Although mRNA vaccines can be developed more quickly than traditional vaccines, fast and accurate construction of DNA templates for these vaccines remains a critical bottleneck. Using our novel DNA assembly technology, Sidewinder, we rapidly designed and built multiple mRNA vaccine candidates to guard against a potential outbreak of Hantavirus (ANDV). We successfully constructed the DNA templates from oligo pools and produced the mRNA for three vaccine candidates in just 2 days after delivery of the synthetic DNA oligos.

biochemistry↗

bioRxiv2026

Activating adaptor-like sequences in pericentrin mediate its transport by dynein

Right before a cell divides, the centrosome rapidly increases its size and microtubule organizing activity through a process termed centrosome maturation. PCNT, a coiled-coil centrosomal protein, is synthesized and transported to the centrosome simultaneously by dynein. This dynein-mediated co-translational transport of PCNT facilitates centrosome maturation and mitotic spindle formation. How dynein engages and transports PCNT, however, remains unclear. Here we find that PCNT residues 1393-1525 are required for mediating dynein-dynactin interaction. PCNT (1393-1525) also shares similar sequence features with canonical dynein cargo adaptors. PCNT is predicted to interact with dynein heavy chains through similar contact sites used by canonical dynein cargo adaptors. Introducing point mutations at those contact sites abolishes dyneinmediated transport in a peroxisome motility assay. Our results suggest that PCNT contains adaptorlike sequences to bind and activate dynein directly during its transport to the centrosome. Our data also suggest that dynein may engage with some of its cargoes directly without an adaptor.

cell biology↗

bioRxiv2026

Efficient and accurate near telomere-to-telomere haplotype reconstruction of diploid genomes

Telomere-to-telomere (T2T) and haplotype-resolved assembly are crucial for understanding eukaryotic genomes. For diploid species, this resolution is critical to uncover allelic variations, inheritance patterns, and functional genomic traits. Current scaffolding methods typically employ either sequence-based or graph-based strategies. Sequence-based approaches rely on proximity signals to yield high contiguity, but underutilize assembly graph information, resulting in more structural errors and chromosomal misassignments. Graph-based methods leverage graph topology for higher accuracy but frequently struggle to achieve chromosome-scale contiguity. However, neither strategy alone can overcome its inherent limitations to simultaneously achieve high contiguity and accuracy. To address these challenges, we introduce HapFold, the first hybrid scaffolding framework that synergistically leverages the complementary strengths of both graph-based and sequence-based approaches. By integrating the topological accuracy of assembly graphs with the proximity-guided contiguity of sequence models, HapFold achieves highly accurate, chromosome-scale or near-T2T haplotype reconstructions for diploid genomes. Compared to existing methods, HapFold achieves superior assembly quality while accelerating computation by an order of magnitude. Furthermore, in the haplotype reconstruction of diploid genomes using standard Oxford Nanopore Technologies simplex reads, HapFold enables the reconstruction of a greater number of near-T2T assemblies. Our approach provides a robust and scalable solution for the high-fidelity reconstruction of haplotype-resolved diploid genomes.

bioinformatics↗

bioRxiv2026

Decoding Immune Reconstitution Failure in People Living with HIV through Single-cell Genomics

Immune non-responders (INRs), a subset of people living with HIV (PLWH), fail to achieve full immune reconstitution and remain at increased risk of morbidity, mortality, and non-AIDS-related illnesses. As the mechanisms underlying this impaired immune recovery remain poorly understood, we performed single-cell multi-omics profiling on peripheral blood mononuclear cells from 43 INRs, 47 immune responders and 53 healthy donors. Our dataset comprises 2,744,009 transcriptomes and 1,226,658 chromatin-accessibility profiles across 58 identified immune cell types. INRs exhibited markedly elevated inflammatory signaling, increased apoptotic activity, and dysregulation of immune-activating ligand-receptor interactions. Additionally, we identified 2,996 interaction cis-eGenes and 5,938 cis-caPeaks, and validated key cell type-specific cis-xQTL effects associated with immune reconstitution failure. Furthermore, we identified 3,551 sc-eQTLs and 872 cell-state interaction eQTLs (ieQTLs) in CD4+ T cells. A genotype-specific upregulation of OAS3 in INRs, likely regulated by STAT1, was identified based on these results. We developed scPRISM (single cell Predictive Reconstitution Immune Status Model), a multi-modal framework that integrates scRNA-seq and scATAC-seq data to perform the dual tasks of differentiating disease states and predicting gene expression from chromatin accessibility, thereby deciphering the cell type-specific cis-regulatory basis of the disease. Our study delineates the transcriptional and epigenomic landscape of immune dysregulation in INRs and provides new genetic insights into HIV-associated immune reconstitution failure. These findings offer a foundation for developing biomarkers and precision therapies to restore immune function in PLWH.

genetics↗

bioRxiv2026

Mirror-Image L-DNA Nanocubes for Stable and Targeted Multimodal Drug Delivery

Nucleic acid nanostructures provide programmable architectures for molecular delivery but remain limited by rapid nuclease degradation, poor in vivo persistence and inefficient intracellular cargo release. Here we report a mirror-image L-DNA nanocube as a biologically persistent and modular therapeutic delivery platform. The nanocube self-assembles from synthetic L-DNA oligonucleotides into a structurally defined architecture that exhibits substantially enhanced resistance to enzymatic degradation and prolonged stability under physiological conditions compared with the corresponding D-DNA nanostructure. Surface functionalization with folic acid enables selective tumour targeting in vitro and in vivo. The L-DNA nanocube supports the delivery of chemically distinct therapeutic cargos, including doxorubicin, a bortezomib prodrug and MCL1-targeting small interfering RNA (siRNA). In tumour-bearing mice, L-DNA nanocube-mediated delivery improves therapeutic efficacy while reducing systemic toxicity relative to free drug and D-DNA nanocube controls. For siRNA delivery, we engineer a pH-responsive release mechanism that promotes endosomal escape and cytosolic cargo localization, as visualized by cryo-electron tomography, resulting in efficient gene silencing. Together, these results establish mirror-image nucleic acid nanostructures as a class of biologically functional nanomaterials for programmable intracellular therapeutic delivery.

biochemistry↗

bioRxiv2026

Robust lesion network mapping reveals genuine symptom-specific networks

Lesion network mapping (LNM) and its derivatives successfully integrate anatomically distributed brain loci into common symptom-associated functional networks, however, their statistical validity and specificity have recently become topics of debate. Here, we introduce a null model-based robust LNM (rLNM) framework to perform sensitivity and symptom-specificity testing. Across multiple lesion-based (10 conditions, 333 lesions) and task-based (4 conditions, 706 experiments) datasets, rLNM reveals biologically meaningful and symptom-specific networks while effectively controlling for false positives.

neuroscience↗

bioRxiv2026

Methodological pitfalls in plant pangenome gene family identification may lead to biased evolutionary inferences

Pangenome-level gene family identification often applies sequence similarity clustering without phylogenetic or synteny information, which risks biologically misleading evolutionary inferences. Using five transcription factor families (bHLH, MYB, NAC, WRKY, MADS-box) across 401 rice pangenome accessions, we compared clustering strategies: OrthoFinder alone, cd-hit alone, MMseqs2 alone, and OrthoFinder-informed refinement by cd-hit or MMseqs2. Methods solely based on sequence similarity merged distinct orthogroups and generated fewer orthogroups than approaches incorporating graph-based orthology. Conflicting cluster assignments, measured against OrthoFinder, varied strongly among families, from approximately 14% in MADS-box to approximately 57% in MYB, and were associated with protein length differences. Core, shell, and cloud gene classifications shifted substantially depending on the method, especially in MYB, NAC, and WRKY families. Critically, Ka/Ks distributions for core genes were highly method-sensitive, with orthology-aware methods yielding more convergent and less variable estimates of selective pressure, whereas noncore gene estimates remained robust. These findings demonstrate that neglecting graph-based orthogroup inference inflates methodological artifacts. We recommend a two-step strategy: initial graph-based orthogroup delineation followed by sequence similarity refinement to balance evolutionary accuracy and resolution in pangenome-scale gene family studies.

genomics↗

bioRxiv2026

Cell-type-resolved RNP topologies reveal dynamic structural mechanisms of splicing and therapeutic targets

Resolving RNA conformations in native ribonucleoprotein (RNP) complexes remains a fundamental challenge. Here, we introduce spatial hydroxyl acylation reversible crosslinking with immunoprecipitation (SHARCLIP) to simultaneously capture RNA-RNA, RNA-protein and protein-protein contacts in cells. SHARCLIP profiling of HNRNPC-associated RNA conformations established a global phased map of ribonucleosomes, resolving a decades-old debate on heterogenous nuclear (hn)RNP assembly. We built a dynamic structural atlas across seven cell lineages for >10,000 RNAs, generating ~200 million contacts, and identifying millions of dynamic loops, steric blockers and conformational switches that control splicing outcome. Deciphering the structural logic of mutually exclusive exons (MXEs) enabled rational design of structure-breaking and stabilizing antisense oligonucleotides (ASOs). We demonstrate effective isoform swapping in 12 genes linked to genetic disorders. SHARCLIP provides a comprehensive roadmap for cellular RNA structural biology and structure-guided RNA therapeutics.

molecular biology↗

bioRxiv2026

Rhythmic motor activity alleviates auditory attentional blinks

Effective sensory processing relies on both attention and the motor system, yet whether motor activity could provide attention-like functions to regulate perception remains unknown. We hypothesized that rhythmic motor signals could provide phasic regulation of prioritizing and sampling perceptual targets. Using an auditory attentional blink paradigm that created a temporal deficit in selective attention, we found that temporally aligned finger tapping improved the probe detection during the attentional blink window but impaired performance when attentional resources were abundant. Furthermore, transcranial alternating current stimulation (tACS) over the right sensorimotor cortex alleviated attentional blink when the probe was close to the peak of the stimulation, whereas stimulation over the left aggravated attentional blink when the probe was close to the trough. These results suggest that the motor system is a resource-dependent rhythmic regulator of attentional sampling. Motor signals can override attentional bottlenecks, suggesting the motor system as an active shaper of cognitive processes.

neuroscience↗

bioRxiv2026

Eleven deep-sea coral genome assemblies unveil insights into evolution, adaptation, and coral biodiversity

Deep-sea corals are vital in maintaining coral ecosystem biodiversity, yet their genetic characteristics remain largely unexplored. Here, we present 11 deep-sea coral genome assemblies, including four Hexacorallia and seven Octocorallia species, significantly contributing new genomic information across two orders. Our analysis reveals the historical dynamics of coral speciation and the influence of environmental factors on the evolution of coral reef ecosystems.Total of 126 horizontal gene transfer (HGT) events were detected, among which genes from the ancestor of symbiodiniaceae indicate that the ancestors of deep-sea corals may have inhabited shallow-sea environments. Notably, several of these HGTs are involved in phosphorus (PhnX/PhnW) and cholesterol (DHCR7) metabolisms within corals, indicating that HGTs may serve as an adaptive survival strategy for the coral holobionts. Deep-sea corals also rely on symbiotic bacteria to synthesize 10 essential amino acids (such as valine and tyrosine), retaining only partial amino acid synthesis capacity. In addition, we investigated the evolution of key biological rhythm genes and temperature adaptation in corals. The loss of key rhythm genes (e.g., clock and cry) in deep-sea corals and copy number difference of genes related to heat stress (e.g., Cbl-b and Rchy) revealed genetic difference between deep-sea and shallow-sea corals. Our new genome assemblies enhance the understanding of deep-sea coral evolution, biodiversity, and adaptation, providing a genetic foundation for coral conservation.

genomics↗

bioRxiv2026

From Representation to Action: A Unified Laplacian Framework for Spatial Representation and Path Planning

Navigation in complex environments relies on internal spatial representations that guide action. While the brain employs a diverse repertoire of spatial tuning cells--including grid, place, and head-direction cells--a normative theory linking these static neural codes to the dynamic process of navigation remains elusive. In this work, we propose a Unified Laplacian Framework derived from first principles of representational smoothness and efficiency. We first demonstrate that diverse spatial codes emerge naturally as spectral decompositions of the Laplace operator. Crucially, bridging the gap from representation to action, we derive a biologically plausible navigation policy based on the Greens function potential. We show that this potential encodes the environments intrinsic geometry to enable simple, trap-free gradient ascent, achieving improved sample efficiency and generalization in goal-reaching tasks. Furthermore, we demonstrate that these spectral representations can be learned directly from high-dimensional visual inputs, confirming their plausibility in realistic environments. Our results suggest that the "cognitive map" can be viewed as a spectral embedding of the Laplacian, providing a rigorous foundation for spatial cognition in both biological and artificial agents.

neuroscience↗

bioRxiv2026

The Structural Code of Breast Cancer Proteoform: Alternative Splicing-driven Protein Isoform Variation and Functional Diversification

Alternative splicing generates extensive transcript diversity, but the extent to which this diversity contributes to the translated proteome and reshapes protein function remains unclear. Here, we develop 3DisoGalaxy, an atlas integrating transcript reconstruction, ribosome profiling, structural modelling and regulatory annotation in breast cancer. We find that 58,292 of 90,929 transcripts are linked to translation-supported ORFs, 71.9% of which arise from non-canonical transcript structures. These products are broadly accommodated within established protein fold space, indicating that alternative isoforms frequently preserve recognizable protein architectures despite substantial sequence variation. Functional divergence is instead concentrated in domains, intrinsically disordered regions, localization determinants and regulatory motifs. Motif remodelling is biased towards gains and is more extensive in cancer-driver genes than in other genes, linking isoform-associated regulatory variation to cancer-relevant proteins. As an example of domain remodelling, we identify an AKT1-{Delta}PH isoform that lacks the N-terminal PH domain while retaining the kinase core, with immunoblotting revealing a lower-molecular-weight AKT1 species consistent with this isoform. Together, our results show that alternative transcript diversity extensively enters translation-supported proteoform space and establish a systematic link between transcript variation and protein functional diversification.

cancer biology↗

bioRxiv2026

Colocalization and discordance between plasma and brain protein quantitative trait loci

Studies of protein quantitative trait loci (pQTLs) provide opportunities to interpret complex trait genetics and identify potential biomarkers and therapeutic targets. Circulating proteins are commonly used in pQTL studies due to the accessibility of blood-based measurements, but their levels may not always reflect regulation in disease-relevant tissues. We assessed colocalization and discordance between plasma and dorsal prefrontal cortex cis-pQTLs using data from four large-scale studies and investigated their implications for downstream analyses. Across the proteins examined, at most 80% of the cis-pQTLs showed evidence of colocalization. Among the colocalized loci, approximately 20% exhibited opposite directions of genetic effects. We characterized tissue-specific gene expression profiles based on data from the Genotype-Tissue Expression project. Proteins with colocalized cis-pQTLs were more likely to have high gene expression levels in systemic tissues and immune cells, whereas the remaining proteins were more likely to have high expression in brain tissues. We conducted Mendelian randomization (MR) analyses using neuroticism as an illustrative outcome to compare effect estimates derived using instruments from different pQTL studies. MR analyses identified 13 proteins significantly associated with neuroticism, including six with opposite effect directions between plasma and dorsal prefrontal cortex, highlighting the importance of tissue context. Overall, circulating pQTLs remain informative for proteins from systemic and immune pathways, while incorporating tissue-specific data may provide additional insight for proteins with more localized expression. Considering multiple tissue contexts may refine the interpretation of protein-trait associations and may improve the prioritization of candidate targets.

genetics↗