Biology subjects

Wu, D.

Publications and source records attributed to Wu, D..

At least 19 recordsLinked to original sources

bioRxiv2026

In Utero MRI of Radial Glial Fibers Highlights Their Role in Modulating Fetal Cortical Folding

The process of cortical folding is fundamental to early human brain development. While the differential growth of the cortical layers is a known driver, the biomechanical contribution of key cellular microstructures remains unclear, and there is a lack of direct in vivo markers of cortical microstructures for time-resolved observations. Using a multimodal approach combining in utero and ex vivo fetal brain MRI, histology, and computational mechanical simulation, we investigated whether developmental reorganization of cortical radial microstructures, particularly the radial glial cell (RGC)-associated scaffold, is linked to cortical folding and may modulate its mechanical progression. We characterized this radial organization noninvasively using diffusion MRI-based radial fiber density (FDrad). ex vivo fetal brain MRI and histology supported that regional variations in FDrad were strongly associated with vimentin-labelled radial architecture. Our in utero MRI data revealed closely coordinated developmental changes in cortical FDrad and curvature, with their regional timings and spatial patterns significantly coupled across the cortex. Longitudinal in utero MRI data further supported the synchronized within-individual co-development of FDrad and curvature. Furthermore, biomechanical simulations showed that reducing radial reinforcement modulated differential-growth-driven buckling, producing earlier folding and a greater cortical curvature under otherwise matched model conditions. Collectively, this study introduces FDrad as a noninvasive in utero MRI measure sensitive to radial glial fibers. By integrating spatial, temporal, histological, and computational evidence, our findings suggested a model in which developmental disassembly of the radial scaffold may modulate the mechanical response of the fetal cortex to differential growth, thereby contributing to cortical folding.

neuroscience↗

bioRxiv2026

High-resolution analysis of T cell subsets, clonality, and trajectories in psoriasis

Psoriasis is sustained by type 17 immunity, yet how transcriptionally defined T-cell states are clonally organized across lesions, clinically uninvolved skin, and the circulation remains incompletely understood. We performed paired single-cell RNA and T-cell receptor (TCR) sequencing of T cells isolated from two spatially separated lesions, non-lesional skin, and peripheral blood from 23 participants with psoriasis, together with healthy skin and blood comparators. We resolved 19 cutaneous T-cell populations and found that lesions were enriched for IL-17-associated CD4+ and CD8+ states and activated regulatory T-cell states. CD8+ Tc17 cells showed prominent clonal expansion, and expanded clonotypes contributed more prominently to skin than to blood. Clonotype sharing was greatest between paired lesions, while clonotypes detected in cutaneous IL-17-associated cells mapped to multiple circulating phenotypes, indicating that blood and skin capture complementary features of the disease-associated repertoire. At the sample level, T-cell composition separated 57 lesional samples into two recurrent compositional states that were largely concordant across paired body sites. HLA-C*06:02 status was associated with differences in pretreatment lesional CD8+ T-cell composition, clonotype overlap, and clonal-size distributions. Exploratory longitudinal analyses in eight treated participants showed heterogeneous remodeling of T-cell composition and clonotype detection after therapy. Together, these findings define tissue-restricted and tissue-shared features of the psoriatic T-cell repertoire and identify clonal architecture across skin sites and blood as an organizing feature of lesion heterogeneity.

immunology↗

bioRxiv2026

Characterizing features of Kv channel activation currents by a minimal-state kinetic model

Voltage-gated Potassium channels (Kv channels) comprise twelve subfamilies found in the human genome. They demonstrate diversified activation behaviors, represented by the varied shapes of activation currents, which are usually modeled by individual kinetic schemes of many parameters that make channel comparisons difficult. Here, we present a minimal-state kinetic model, aiming to compare different Kv channel activation currents by a unified model system. By omitting the short-lived transient states and neglecting the detailed transition pathways, this model employs only minimal significant states necessary to approximate the activation currents. Few model-parameters are used that capture the varied current-features, leading to a convenient comparison among Kv channels. In addition, this model incorporates a gating factor, which accurately represents the channel opening event upon applying a voltage pulse. A special feature of the model is its adaptability via simple modifications, that any channel-dependent kinetic scheme can be easily incorporated into this model framework, helping develop exact channel mechanisms.

biophysics↗

bioRxiv2026

NeoOmni Atlas: an integrated database for pan-cancer neoantigen derived from proteogenomics analysis

Tumor neoantigens derived from diverse molecular aberrations are important targets for personalized cancer immunotherapy, but existing resources incompletely integrate mass-spectrometry-supported canonical and non-canonical antigen evidence across cancer types. NeoOmni Atlas is an interactive pan-cancer T-cell epitope resource, built via proteogenomic reanalysis of 7,561 immunopeptidomics datasets comprising 511 million raw spectra from 2,341 samples across 26 cancer types. The analysis yielded 872,414 eluted canonical peptides and 198,961 non-canonical peptides spanning 18 molecular alteration classes, along with 759,386 unique ligands presented by 322 human leukocyte antigen (HLA) alleles. Relative to existing repositories, NeoOmni Atlas covers a broader range of cancer types, includes 60 additional HLA alleles, and catalogs 369,781 novel ligands. A computational tumor-specific filtering framework identified 316,126 tumor-associated epitopes and 61,231 tumor-specific epitopes. Tumor-specific epitopes showed stronger predicted binding affinity than tumor-associated epitopes for HLA class I A and B alleles, and 65 conserved tumor-specific epitopes recurrent across more than 10 tumor types represent potential shared antigen candidates. NeoOmni Atlas also prioritizes candidate tumor-associated antigens including PMEL (gp100:209-217) and CSPG4, and supports browsing, searching, and downloading by cancer type, human leukocyte antigen allele, peptide sequence, and source event. NeoOmni Atlas is freely accessible at http://modinfor.com/NeoOmni-Atlas/.

bioinformatics↗

bioRxiv2026

Structural Basis of γδ T-Cell Receptor Crosslinking and Activation by a Spontaneously Dimerized Fab

The gamma delta T-cell receptor ({gamma}{delta} TCR) mediates {gamma}{delta} T-cell responses that are crucial for immune defense, tissue surveillance, and homeostasis. While recent studies suggest that {gamma}{delta} TCRs engage ligands multivalently, how multivalent engagement activates the {gamma}{delta} TCR remains elusive. Here, we present the structures of the V{gamma}9V{delta}2 (clone G115) TCR in both the inactive and the agonist-crosslinked active states. In the {gamma}{delta} TCR lipoprotein complex, cholesterol and phospholipids form a "barrier" that isolates CD3{zeta}{zeta} from the other subunits and likely prevents autoactivation. As an agonist, the Fab fragment of the UCHT1 antibody dimerizes upon binding the V{gamma}9V{delta}2 TCR, thereby crosslinking and activating the receptor. Cryo-EM analysis of Fab-crosslinked V{gamma}9V{delta}2 TCR identifies three Fab dimer interfaces, one between the two light chains and the other two between light and heavy chains. These Fab-Fab interfaces, together with the Fab-CD3{epsilon} interface, mediate the assembly of the V{gamma}9V{delta}2 TCR and UCHT1 Fab into 2:2 tetramers. Upon activation, the V{gamma}9V{delta}2 TCR becomes conformationally plastic and loses enriched lipids, including cholesterol and phosphatidylethanolamine. Our findings reveal a dimerization-driven activation mechanism, inform the design of rigid TCR-crosslinking agonists, and suggest multivalency-induced clustering as a general paradigm for {gamma}{delta} TCR activation.

immunology↗

bioRxiv2026

FLASH X-rays preserve neutrophil chromatin to boost antitumor immunity

Ultrahigh dose-rate FLASH radiotherapy spares normal tissue while preserving antitumor activity, positioning it as a promising technology in radiation oncology, but its immunomodulatory mechanisms remain elusive. Here, using a bilateral subcutaneous tumor model in mice, we show that 8-Gy FLASH X-rays, versus an equal dose of conventional dose-rate (CONV) X-rays, elicit a robust abscopal antitumor effect with anti-PD-1 therapy. Single-cell transcriptome and T cell receptor (TCR) profiling reveal that FLASH X-rays plus anti-PD-1 enhance antitumor immune infiltration and TCR clonal expansion in both irradiated and abscopal tumor lesions. Mechanistically, the ultrashort temporal continuity of FLASH dose delivery conserves chromatin compaction in neutrophils during exposure and inhibits neutrophil extracellular trap (NET) formation, thereby dismantling NET-mediated CD8+ T-cell exclusion within primary tumors. Conversely, CONV or split-dose FLASH X-rays induce marked chromatin modifications prior to dose completion, leading to chromatin hyper-relaxation which promotes NETosis and consequently abrogates systemic antitumor immunity. Notably, this detrimental effect can be reversed by pharmacologically suppressing PARylation-mediated chromatin modification and decondensation in neutrophils. These findings identify radiation-induced aberrant chromatin relaxation in neutrophils as a critical determinant of radioimmunotherapy outcomes, providing a rationale for redefining the FLASH effect and advancing its clinical translation.

cancer biology↗

bioRxiv2026

scPRIME-seq uncovers synchronized multimodal molecular collapse facilitated by pre-neoplastic epigenetic burden in prostate cancer

Tumorigenesis involves alterations across the genome, epigenome and transcriptome, yet how these layers interact to drive malignant transformation remains unclear, largely due to the lack of scalable multimodal single-cell approaches. Here, we developed scPRIME-seq, a high-throughput platform for simultaneous single-cell profiling of transcriptome, genome and DNA methylome, and applied it to 436,908 cells from 29 prostate cancers and 15 benign tissues. This multimodal atlas resolved dynamic changes across 30 cell types and a unified tumorigenic trajectory. Integrated analysis revealed a cell-state transition tipping point, where the onset of aneuploidy is temporally coupled with global methylomic alterations and transcriptomic rewiring. Early focal epigenetic alterations, including TMEM106A promoter hypermethylation and the emergence of hypomethylated domains, were present in founder aneuploid clones and benign tissues, indicating a pre-neoplastic origin of epigenetic burden. These pre-neoplastic alterations coincide with transcriptomic changes that affect epithelial interactions with stromal and immune compartments, promoting a putative tumor-permissive microenvironment. scPRIME-seq provides a high-throughput multimodal framework for identifying conserved, cell-intrinsic molecular programs underlying tumorigenesis.

cancer biology↗

bioRxiv2026

Metatranscriptomic surveillance reveals overlooked liver-associated parasite diversity and broad host ranges in small mammals from southern China

Parasite communities in the internal organs of small mammals remain poorly characterized because metatranscriptomic pathogen discovery has largely focused on viruses and bacteria. We individually sequenced liver transcriptomes from 351 small mammals collected across 14 cities in Guangdong Province, China, and combined sequence-based detection with phylogenetic, abundance, transcriptional, and morphological analyses. Parasites were detected in 148 animals (42.2%). Four liver-associated taxa were identified, including three putatively novel or highly divergent lineages. Trichinellidae sp1 dominated the community, occurring in 36.2% of animals (127/351), five host species spanning Rodentia and Eulipotyphla, and all surveyed cities. Hydatigera taeniaeformis occurred in 3.7% (13/351), and its identification was supported by hepatic cysts and morphologically recovered strobilocerci. Eucoccidiorida sp1 and Trypanosoma sp1 were detected sporadically. Mapping to available reference genomes revealed transcripts from multiple genes and functional categories, supporting genuine biological signals rather than isolated marker-gene matches. Amsterdam virus covaried with Trichinellidae sp1 (r = 0.59), whereas Wenzhou tapeworm virus 1 covaried with H. taeniaeformis (r = 0.47). These findings reveal an unexpectedly prevalent, phylogenetically diverse, and broadly distributed liver-associated parasite community and establish individual-organ metatranscriptomics as a useful framework for parasite discovery and surveillance.

microbiology↗

bioRxiv2026

Cytosolic MagLOV Magnetofluorescence in Mammalian Cell Lines and Primary Neurons

Magnetic fields can influence the outcome of photochemical reactions through the radical pair mechanism, but whether this sensitivity extends to standard experimental conditions in mammalian cells has remained unclear. Here, we quantify the cytosolic magnetofluorescence of MagLOV, a genetically encoded, flavin-binding fluorescent protein, in mammalian cells, validated against extensive artifact controls. Excitation intensity and magnetic field strength differentially tune response kinetics and amplitude, respectively, with amplitude saturating above approximately 8 mT. Magnetic field-effect amplitude is further modulated by cellular culture state. This response generalizes across HEK293T, HeLa, U2OS, and A549 cells and primary mouse cortical neurons, with plateau amplitudes ranging from 1.4% to 2.7%. Together, these results establish that genetically encoded spin-dependent photochemistry can be quantitatively interrogated under standard mammalian live-cell imaging conditions, and generalizes across mammalian cell types.

biophysics↗

bioRxiv2026

Diffusion MR Microscopy of the Human Hippocampus at 50 μm Resolution at 14.1 T for 3D Virtual Histology

Bridging the gap between macroscopic neuroimaging and microscopic histology remains a challenge in neuroscience. Here, we present a technical feasibility study of diffusion MR microscopy (dMRM) in the ex vivo human hippocampus using a 14.1 T ultrahigh-field MRI system. Mid-hippocampal blocks from control and Alzheimers disease (AD) patients were acquired at 50 x 50 x 100 {micro}m3, representing, to our knowledge, the highest resolution reported for human brain diffusion MRI. At a spatial scale approaching cellular dimensions, dMRM maps and tractography showed close correspondence with immunohistological markers of axons and dendrites. The acquired data delineated six hippocampal laminae, distinguished the inner and outer molecular layers, and preserved short, lamina-specific trajectories that became attenuated or blurred at 100 {micro}m resolution. Tractography further depicted the major components of the hippocampal tri-synaptic circuit--the perforant path, mossy fibers, and Schaffer collaterals in 3D. In the AD specimen, dMRM revealed reduced laminar contrast, local discontinuities, and altered radial and tangential fibers that were paralleled by pathological staining. With the 3D nondestructive characterization of human brain microstructure and circuitry, ex vivo dMRM showed its potential toward the goal of 3D virtual histology.

neuroscience↗

bioRxiv2026

Multi-kingdom microbial diversity and interaction landscapes in mosquitoes revealed by 5,163 individual meta-transcriptomes

Mosquitoes are pathogen vectors embedded within diverse microbial ecosystems. However, the nature and interactions among their multi-kingdom microbiome remain poorly understood. We conducted a nationwide single-mosquito meta-transcriptomic survey of 5,163 mosquitoes representing 100 species across China, integrating viral discovery with marker-gene profiling of bacteria, archaea, fungi, and other eukaryotic microbes. From this, we identified 1,606 microbial species-level taxa, including extensive novel diversity, and revealed pronounced host species-specific organization of mosquito-associated communities. We detected 34 pathogens or potential pathogens of human or animal relevance, whose prevalence, abundance, host range, and geographic distribution defined distinct epidemiological patterns. Network analysis uncovered pervasive cross-kingdom microbial associations, including candidate antiviral relationships involving Wolbachia and other microbial taxa. Our study establishes a detailed view of the full-spectrum microbiome and provides a resource and conceptual framework for studying vector competence, pathogen emergence, and microbiome-informed mosquito-borne disease control.

microbiology↗

bioRxiv2026

A patient-centric therapeutic paradigm uncouples prostate cancer suppression from systemic metabolic collapse

The clinical benefits of cancer therapies are often compromised by the tolerable adverse effects that impair systemic organismal health and may evolve into latent life threats. Here, we identified profound abiraterone-induced but androgen-independent metabolic perturbations in prostate cancer patients and developed Lifehug-9892 to balance tumor therapy with systemic metabolic homeostasis. By integrating population cohorts with high-resolution metabolomics, we demonstrate that abiraterone induces profound systemic lipidomic dysregulation, characterized by the massive, pathological accumulation of desmosterol. Abiraterone inhibits but stabilizes DHCR24, leading to a metabolic trap in patients showing elevated levels of both desmosterol and cholesterol. Desmosterol accumulation is highly lipotoxic, potently triggering endothelial cell senescence and necrosis, macrophage foam cell formation, murine atherosclerosis, and hepatic senescence. To mechanistically uncouple and therapeutically rescue this systemic metabolic collapse, Lifehug-9892 was rationally designed to selectively retain on-target CYP17A1 inhibition while completely sparing DHCR24 function. Lifehug-9892 maintains potent tumor-suppressive activity while fully preserving the desmosterol-cholesterol metabolic axis and preventing systemic cardiovascular and hepatic damage. Our study uncovers a critical mechanistic link between drug-induced metabolic dysregulation and organismal health in cancer patients, providing a biochemical framework for developing patient-centric targeted therapies that preserve host homeostasis.

cancer biology↗

bioRxiv2026

Contrasting selective pressures shape human pepsinogen A gene copy-number variation across Eurasia

Diet has repeatedly shaped human genomes, yet adaptation of protein digestion remains poorly understood. Using 1,348 haplotype-resolved assemblies, we reconstructed the structural evolution of the human pepsinogen A (PGA) locus and found a west-to-east increase in copy-number across Eurasia that tracked regional reliance on plant-derived protein. Modern and ancient genomes further revealed a recent selective sweep in the East but signatures of balancing selection in the West. We traced this divergence primarily to expansion of PGA34A, the most proteolytically active paralog in vitro, and showed that recurrent nonallelic homologous recombination continually generated structural diversity in this locus. Independent PGA expansions were also enriched in plant-dominant mammals. These findings link paralog-specific dosage variation in protein digestion to dietary adaptation across human populations and diverse mammalian lineages.

genomics↗

bioRxiv2026

Dll4 and Jag1a signalling act sequentially and cooperatively to drive hematopoietic stem cell fate specification

Hematopoietic stem and progenitor cells (HSPCs) arise from a specialized subset of arterial endothelial cells, the hemogenic endothelium (HE), during embryonic development and sustain blood production throughout life. Notch signalling is a key regulator of this process: its ligand Jag1 promotes HSPC formation, whereas Dll4 promotes arterial identity. However, how the activities of these ligands are temporally coordinated during HSPC emergence remains unresolved. Here we demonstrate that Dll4 is required prior to circulation onset, acting by dampening MAPK signalling to drive the transition from pre-HE to HE fate and enabling HE differentiation towards HSPCs. Subsequently, after circulation starts, Jag1a acts to maintain gene expression in HE and support transition to HSPC fate. Jag1a activity depends on blood flow-induced shear stress and rescues HSPC loss caused by impaired flow. Thus, rather than playing opposing roles, Dll4 and Jag1a act sequentially and coordinately to drive the endothelial-to-hematopoietic transition and promote HSPC emergence.

developmental biology↗

bioRxiv2026

WHaloForce enables chemigenetic imaging of molecular tension in living cells and animals

Piconewton forces borne by individual proteins within complex assemblies underlie cell adhesion, migration, and tissue morphogenesis, yet remain difficult to image in living systems. Here, we introduce WHaloForce, a chemigenetic HaloTag-based tension sensor that converts force-dependent relief of tryptophan-mediated dye quenching into a fluorescence lifetime change. Optical tweezers revealed a switch-like unquenching transition near 5 pN, and the sensor responded reversibly to force changes in cells. WHaloForce enabled quantitative tension imaging of diverse force-bearing proteins (vinculin, E-cadherin, -catenin, and laminin) in mammalian cells, mouse tissue, and C. elegans. Bright synthetic dyes made tension measurements possible at endogenous expression levels. In C. elegans, vinculin and laminin showed opposite tension patterns between tissues, revealing distinct force-transmission routes through adhesions and the extracellular matrix. During ovulation, laminin tension accumulated over repeated stretch-relaxation cycles, scaling with cumulative loading history. WHaloForce thus offers a modular platform for imaging spatiotemporal tension patterns in living systems.

cell biology↗

bioRxiv2026

PanSVmerger: a flexible pipeline for merging multiallelic structural variants in pangenome graphs

SummaryPangenome graphs capture extensive genetic diversity but introduce analytical challenges due to the redundant representation of structural variations (SVs). While existing tools effectively address cross-sample redundancy or cross-locus redundancy, none specifically target the intra-locus allelic redundancy inherent to pangenome graphs. Here, we present PanSVmerger, an open-source tool designed to consolidate redundant multiallelic SVs within individual loci using three complementary clustering strategies: adaptive k-mer-based Jaccard distance, global alignment distance via VSEARCH, and length distribution. Validation on HPRC pangenome data demonstrates that PanSVmerger effectively reduces multiallelic complexity (e.g., AC [≥] 3 loci from 62.4% to 4.7% using Strategy A) with a modest trade-off: Recall decreased from 97.13% to 93.58%, while precision improved from 94.95% to 96.56%, yielding an overall F1-score of 95.05%. These results demonstrate that PanSVmerger effectively consolidates redundant allele representations with only a minimal loss of sensitivity, making it well-suited for downstream applications that require clean, non-redundant variants. Availability and implementationPanSVmerger is implemented in Python 3.8+ and freely available under the MIT license at GitHub: https://github.com/tingting100/PanSVmerger. The software requires vcflib, bcftools, and optionally VSEARCH. Comprehensive documentation and tutorials are provided.

bioinformatics↗

bioRxiv2026

Ab initio side-chain sampling with PUD+ enables high-fidelity protein dynamics across AI-driven and classical simulations

The fidelity of molecular dynamics (MD) simulations fundamentally depends on the quality and coverage of the ab initio data used to parameterize the underlying force field, yet the role of side-chain conformational space remains insufficiently explored. In this study, we systematically investigate how comprehensive ab initio sampling of dipeptide conformations--specifically targeting side-chain degrees of freedom--impacts force field accuracy and MD simulation predictive power. We present the Protein Unit Dataset Plus (PUD+), a 40-million-conformation quantum mechanical dataset featuring unprecedented coverage of both backbone and side-chain conformational space. Machine learning force fields trained on PUD+ and integrated into AI2BMD simulations demonstrate superior energy and force prediction accuracy, capturing high-fidelity protein folding dynamics and the conformational flexibility of long-side-chain systems. Furthermore, leveraging PUD+ to reparameterize the CMAP term of the classical ff19SB force field markedly improves the description of intrinsically disordered protein (IDP) dynamics and IDP-ligand binding. Collectively, these results demonstrate that ab initio sampling of dipeptide side-chain conformations enables high-fidelity modeling of protein dynamics across both AI-driven and classical simulation paradigms.

biophysics↗

bioRxiv2026

Hidden genetic diversity in 320 nearly-complete East Asian genome assemblies

East Asian populations, representing over 20% of the global population, remain critically underrepresented in human genomic studies, limiting our understanding of population-stratified genetic variation and its implications for health and disease. Here we present the first phase of the Asian Pan-Genome project (APG), comprising 320 nearly complete, fully phased haploid genome assemblies from 160 East Asian individuals. These assemblies achieve unprecedented quality, with an average contig N50 of 144.3 megabase pairs and an average quality value of 64.5. Leveraging these superior assemblies, we reveal previously uncharacterized diversity in human repeatome, including population-stratified patterns in centromere satellites and rDNA arrays. Compared to existing global human genome assemblies, the newly generated genomes supplement 152 million base pairs of novel sequences, 355 gene gains, 18,300 structural variation loci and 26 large euchromatic inversions missing from current human pangenomes. We perform population stratification analyses of structural variations, and further resolve the structural haplotypes of complex genomic regions such as Major Histocompatibility Complex and Survival Motor Neuron loci across global pangenomes, exemplifying tandem-duplicate and inversion-rich complex locus architectures in the human genome, respectively. This resource provides a critical foundation for human genetic studies, especially for East Asian populations, promoting more accurate variant discovery, reducing bias, and ultimately advancing the equity and efficacy of genomic medicine.

genomics↗