Biology subjects

Tao, K.

Publications and source records attributed to Tao, K..

At least 19 recordsLinked to original sources

bioRxiv2026

Marrow-mimicry MEW scaffolds recapitulate erythroblastic islands for high-density cRBC biomanufacturing

Biomanufactured cell therapies are delivering a step-change in modern medicine, but their high costs have prevented widespread adoption. Cultured red blood cells (cRBCs) are one type of cell therapy in clinical trials for off-the-shelf blood transfusion but remain limited by the exorbitant costs of manufacturing trillions of RBCs required for a blood transfusion. These costs could be mitigated if culture platforms could grow cells at higher density, like those found in the bone marrow, requiring less media and lower concentrations of expensive growth factors per cell. We engineered melt electrowritten (MEW) polycaprolactone (PCL) scaffolds in geometries which imitate marrow trabeculae structures and were then plasma-treated to enable peripheral blood mononuclear cells (PB MNC) attachment. PB MNC monocytes first adhered to the scaffold and rapidly differentiated into CD68+ macrophage-like cells. These macrophage-loaded scaffolds adhered CD71+ erythroblasts, which then grew from 10 to 25% between days 4 and 8 and produced CD235a+ erythroid cells by day 20, under erythrogenic culture conditions. MEW PCL scaffolds in trabecular-like geometries had greater surface area, adhered more macrophages, and generated more erythroblasts than traditional MEW crosshatch geometries. The MEW scaffolds continuously released less-adherent cells to the supernatant, providing a 74% increase in supernatant cell numbers versus liquid suspension controls with identical cell seeding numbers and media volumes. High-cell-density scaffolds exhibited increased metabolism and endogenous production of self-supportive cytokines, which may offer cost-saving opportunities through future media optimisation. This study reports marrow trabeculae-mimetic MEW PCL designs capable of selectively adhering PB MN cells to develop macrophage-coated scaffolds, which provided physical and paracrine support for cRBC production. This high-cell-density culture platform may be useful for future cell therapy biomanufacturing protocols.

bioengineering↗

bioRxiv2026

DQHTFI: Dynamic-Query Hypergraph Transformer for Fine-Grained Drug-Target Interaction and Affinity Prediction

Drug-target interaction prediction and binding affinity prediction are two key tasks in drug discovery and drug repurposing. Although deep learning methods have made significant progress, existing models typically rely on global representations of drugs and proteins, making it difficult to adequately model fine-grained interactions between their local units. Fixed multimodal fusion strategies also struggle to dynamically adjust the contributions of different modalities for different drug-target combinations. To address these issues, we propose DQHTFI, a fine-grained interaction prediction framework for drug-target interaction classification and binding affinity regression. DQHTFI employs BRICS fragments and Pfam functional domains as the basic interaction units and jointly learns semantic and structural representations. We design a dynamic-query hypergraph Transformer framework in which hyperedges are constructed among the multimodal features of fragment-domain pairs. Dynamic queries are generated from the cross-conditioned features of fragment-domain pairs to adaptively adjust the contribution of each modality, thereby modeling higher-order interactions between local units. Our proposed model achieves competitive results on multiple benchmark datasets.

bioinformatics↗

bioRxiv2026

The common symbiosis pathway controls plant root microbiomes in a host-specific manner

Crop nutrition depends on plant-microbe interactions, yet it remains unclear whether conserved genetic pathways impose universal rules on root microbiome assembly across plant hosts. Here, we show that the Common Symbiosis Signalling Pathway (CSSP), a conserved genetic module controlling endosymbiosis with arbuscular mycorrhizal fungi and nitrogen-fixing bacteria, regulates root microbiome assembly in a host-specific manner across contrasting fertilisation regimes. Using Lotus japonicus and Hordeum vulgare, we demonstrate that mutations in orthologous CSSP genes remodel root bacterial communities in both species, but with distinct taxonomic outcomes. In Lotus, CSSP disruption reduces rhizobial colonisation and promotes niche replacement by commensal taxa, whereas in Hordeum, the same mutations broadly restructure bacterial lineages without converging on Lotus-like responses. Root exudate profiling reveals host-specific metabolic differences, particularly in phenylpropanoid (flavonoids and coumarins) and gibberellin pathways, linking CSSP activity to chemically distinct rhizosphere environments that correlate with divergent microbiome assembly patterns across hosts. Moreover, root bacterial community composition accurately predicts plant nutritional status, highlighting tight coupling between host physiology and microbiome composition. Together, our results show that conserved symbiosis signalling regulates root microbiome assembly, while host-specific metabolic environments determine taxonomic outcomes. This extends CSSP function beyond canonical endosymbioses and positions symbiosis signalling as a general determinant of plant-microbiome interactions with implications for crop nutrition. Significance StatementRoot microbiomes influence plant nutrition, yet how conserved host genetic pathways controlling interactions with intracellular symbionts shape root-associated microbiome assembly across divergent plant species remains unresolved. The Common Symbiosis Signalling Pathway (CSSP), conserved across most land plants, regulates root microbiome composition in both a legume and a cereal, but with distinct taxonomic outcomes. These effects correlate with CSSP-dependent differences in root exudate chemistry and host metabolic profiles. Together, our results show that conserved symbiosis signalling operates within host-specific metabolic contexts, providing a framework for understanding why disruption of the same genetic pathway can lead to divergent microbiome configurations across plant species.

plant biology↗

bioRxiv2026

Cell fusion reprograms tumor cells and promotes RUNX1-mediated invasion and dissemination in colorectal cancer

Metastasis remains the primary cause of cancer-related morbidity and mortality, despite significant advances in targeted therapies. Although metastatic dissemination requires tumor cells to escape the primary lesion and colonize distant organs, the mechanisms by which primary tumor cells gain metastatic competence remain poorly understood. Increasing evidence demonstrates that fusion of tumor (i.e., neoplastic) and immune (e.g., macrophages) cells generate a distinct population of tumor-immune hybrid cells with enhanced functional ability to migrate and disseminate into peripheral blood. Herein, our study investigates tumor-macrophage hybrid cells, an underexplored population of disseminated tumor cells, and their inherent heterogeneity and acquisition of molecular mechanisms underlying their dissemination as metastatic effectors in colorectal cancer (CRC). Through hybrid cell phenotyping utilizing integrative single-cell RNA sequencing (scRNA-seq), cyclic immunofluorescence (cyCIF) and functional assays with an in vitro model of CRC hybrid cells, we identify Runt-related transcription factor 1 (Runx1) as a central regulator of hybrid cell motility and invasion. Runx1 depletion in hybrid cells suppressed functional protease expression, chemotactic activity and extracellular matrix (ECM) invasion. Furthermore, pharmacologic inhibition of RUNX1 in an in vivo model reduced hybrid tumor growth and dissemination into peripheral blood, key attributes of metastatic spread of disease. In patients with CRC, RUNX1+ hybrid cells were identified in both primary tumor and peripheral blood, where circulating hybrid cells (CHCs) exhibited enriched migratory and epithelial-to-mesenchymal transition (EMT) phenotypes. Taken together, these findings reveal a mechanistic role for RUNX1 in driving invasive behavior of tumor-immune hybrids and highlight disseminated CHCs as an under-recognized contributor to metastatic spread and a promising noninvasive biomarker for tumor progression.

cancer biology↗

bioRxiv2026

A Conserved Metabolic Oxidative Axis Underlies Immune Cell Cryo-vulnerability

Immunotherapy has emerged as a transformative approach for treating cancer and other diseases, yet its widespread deployment requires effective cryopreservation strategies to enable scalable global distribution. However, many immune cell types remain acutely vulnerable to freeze-thaw stress, and the underlying mechanisms of this cryo-vulnerability are not well defined. In this study, we combined metabolic flux analysis, ROS quantification, lipidomics, and preclinical xenograft models to investigate how metabolic state influences cryopreservation outcomes. We found that immune cell activation induces a metabolic shift characterized by elevated glucose utilization and excessive ROS production, leading to profound post-thaw loss of viability and function, as demonstrated by a [~]25% survival rate in natural killer (NK) cells. Targeted pretreatments--including inhibitors of glucose metabolism, antioxidants, and suppression of lipid peroxidation--restored post-thaw recovery to nearly 90% while preserving effector activity and antitumor efficacy. Similar protective effects were observed across {beta} T cells, {gamma}{delta} T cells, and macrophages, defining a conserved metabolic-oxidative pathway of cryo-vulnerability and offering applicable strategies to enhance immune cell preservation.

immunology↗

bioRxiv2025

Deep learning reveals a microprotein atlas in maize and uncovers novel regulators of seed amino acid metabolism

Microproteins represent a vast and functionally important class of genes that remain largely unexplored in plant genomes. Here, we developed DeepMp, a deep learning framework that integrated multi-omics evidence and built the most comprehensive plant microprotein atlas to date, identifying 18,338 high-confidence candidates in maize. The majority of these appear to have originated de novo from regions previously annotated as noncoding, and they show hallmarks of rapid, lineage-specific evolution and pronounced tissue specificity. These novel microproteins were found integrated into core regulatory networks, particularly in organ development and nutrient storage. Focusing on the maize kernel, population-scale analyses linked microprotein expression to natural variation in amino acid content. We functionally validated three grain-filling-specific candidates originating from noncoding regions by CRISPR-Cas9 knockouts, which confirmed their roles as precise modulators of arginine, aspartate, and methionine levels, without pleiotropic effects on kernel morphology. Our study provides a foundational resource and analytical framework, establishes microproteins as a new and functionally important coding layer in maize, and uncovers a previously untapped source of targets for crop improvement.

genomics↗

bioRxiv2025

Engineering NIR probes to enhance affinity and clinical workflow compatibility for prostate cancer imaging

Positive surgical margins following radical prostatectomy increase the risk of biochemical recurrence and subsequent disease progression. Fluorescence guided surgery (FGS) using targeted contrast agents has shown clinical benefits for several cancer types. However, current prostate cancer targeted imaging probes exhibit long pharmacokinetic (PK) profiles, necessitating extended waiting periods or repeated hospital visits, limiting their integration into standard clinical workflow. To overcome this critical clinical compatibility challenge, we developed an innovative tri-compartment, chemistry-driven probe design strategy. Specifically, we developed a congeneric library of near infrared (NIR) water soluble fluorescent probes incorporating: (1) a glutamic acid-urea-lysine (EuK) ligand targeting prostate specific membrane antigen (PSMA); (2) a NIR heptamethine cyanine fluorophore optimized for enhanced PSMA binding via secondary binding sites interactions; and (3) distinct PK modulators residing outside the PSMA binding pocket to promote rapid off-target tissue clearance. While molecular docking scores, photophysical properties and live-cell staining results showed similar overall performance, probes bearing PK modulators produced stronger tumor-specific fluorescence in vivo than the control lacking a PK modulator. This effort enabled identification of a lead probe with robust tumor targeting and accelerated off-target clearance, providing optimal tumor-specific signal and contrast in a timeframe, fully compatible with robotic-assisted radical prostatectomy (RARP) timelines.

pharmacology and toxicology↗

bioRxiv2024

DDX41 dissolves G-quadruplexes to maintain erythroid genome integrity and prevent cGAS-mediated cell death

Deleterious germline DDX41 variants constitute the most common inherited predisposition disorder linked to myeloid neoplasms (MNs). The role of DDX41 in hematopoiesis and how its germline and somatic mutations contribute to MNs remain unclear. Here we show that DDX41 is essential for erythropoiesis but dispensable for the development of other hematopoietic lineages. Using stage-specific Cre models for erythropoiesis, we reveal that Ddx41 knockout in early erythropoiesis is embryonically lethal, while knockout in late-stage terminal erythropoiesis allows mice to survive with normal blood counts. DDX41 deficiency induces a significant upregulation of G-quadruplexes (G4), noncanonical DNA structures that tend to accumulate in the early stages of erythroid precursors. We show that DDX41 co-localizes with G4 on the erythroid genome. DDX41 directly binds to and dissolves G4, which is significantly compromised in MN-associated DDX41 mutants. Accumulation of G4 by DDX41 deficiency induces erythroid genome instability, defects in ribosomal biogenesis, and upregulation of p53. However, p53 deficiency does not rescue the embryonic death of Ddx41 hematopoietic-specific knockout mice. In parallel, genome instability also activates the cGas-Sting pathway, which is detrimental to survival since cGas-deficient and hematopoietic-specific Ddx41 knockout mice are viable without detectable hematologic phenotypes, although these mice continue to show erythroid ribosomal defects and upregulation of p53. These findings are further supported by data from a DDX41 mutated MN patient and human iPSC-derived bone marrow organoids. Our study establishes DDX41 as a G4 dissolver, essential for erythroid genome stability and suppressing the cGAS-STING pathway.

cancer biology↗

bioRxiv2024

Sexual representation of social memory in the ventral CA1 neurons

Recognizing familiar individuals is crucial for adaptive social interactions among animals. However, the multidimensional nature of social memory encompassing sexual information remains unelucidated. We found that neurons in the ventral CA1 region (vCA1) of the mouse hippocampus encoded the identities and social properties, specifically sex and strain, of familiar conspecifics by using both rate and theta-based temporal coding. Optogenetic reactivation of social memories of females, but not males, induced place preference. Ablation of the upstream hippocampal dorsal CA2 region (dCA2) or the medial amygdala (MeA) disrupted the representation of sex and the sexual dichotomy of social memory valence. Selective reactivation of overlapping neural populations of distinct female social memories representing the female sex was sufficient to induce preference. Thus, vCA1 neurons employ dual coding schemes to represent the identities and social properties of familiar conspecifics as a cohesive memory. One-Sentence SummarySocial memory in the mouse ventral hippocampus maps the identities and social properties of familiar conspecifics.

neuroscience↗

bioRxiv2024

Conditional knockout of Shank3 in the ventral CA1 by quantitative in vivo genome-editing impairs social memory

Individuals with autism spectrum disorder (ASD) have a higher prevalence of social memory impairment. A series of our previous studies revealed that hippocampal ventral CA1 (vCA1) neurons possess social memory engram and that the neurophysiological representation of social memory in the vCA1 neurons is disrupted in ASD-associated Shank3 knockout mice. However, whether the dysfunction of Shank3 in vCA1 causes the social memory impairment observed in ASD remains unclear. In this study, we found that vCA1-specific Shank3 conditional knockout (cKO) by the adeno-associated virus (AAV)- or specialized extracellular vesicle (EV)-mediated in vivo gene editing was sufficient to recapitulate the social memory impairment in male mice. Furthermore, the utilization of EV-mediated Shank3-cKO allowed us to quantitatively examine the role of Shank3 in social memory. Our results suggested that there is a certain threshold for the proportion of Shank3-cKO neurons required for social memory disruption. Thus, our study provides insight into the population coding of social memory in vCA1, as well as the pathological mechanisms underlying social memory impairment in ASD.

neuroscience↗

bioRxiv2023

Nitrogen source and Nod factor signaling map out the assemblies of Lotus japonicus root bacterial communities

Symbiosis with soil-dwelling bacteria that fix atmospheric nitrogen allows legume plants to grow in nitrogen-depleted soil. Symbiosis impacts the assembly of root microbiota, but it is not known how this process takes place and whether it is independent of nitrogen nutrition. We use plant and bacterial mutants to address the role of Nod factor signaling on Lotus japonicus root microbiota assembly. We found that Nod factors are produced by symbionts to activate Nod factor signaling in the host, and this modulates the assembly of a symbiotic root microbiota. Lotus plants grown in symbiosis-permissive or suppressive soils delineated three nitrogen-dependent nutritional states: starved, symbiotic, or inorganic. We found that root and rhizosphere microbiomes associated with these states differ in composition and connectivity, demonstrating that symbiosis and inorganic nitrogen impact the legume root microbiota differently. Finally, we demonstrated that selected bacterial genera delineating state-dependent microbiomes have a high level of accurate prediction.

plant biology↗

bioRxiv2022

Multiplexed and millimeter-scale superresolution imaging of cells and tissue sections via prism-illumination and microfluidics-enhanced DNA-PAINT

Fluorescence nanoscopy has become increasingly powerful for biomedical research, but it has historically afforded a small field-of-view (FOV) around 50 {micro}m x 50 {micro}m at once and more recently up to ~200 {micro}m x 200 {micro}m. Efforts to further increase the FOV in fluorescence nanoscopy have thus far relied on the use of fabricated waveguide substrates, adding cost and sample constraints on the applications. Here we report PRism-Illumination and Microfluidics-Enhanced DNA-PAINT (PRIME-PAINT) for multiplexed fluorescence nanoscopy across millimeter-scale FOVs. Built upon the well-established prism-type total internal reflection microscopy, PRIME-PAINT achieves robust single-molecule localization with up to ~520 {micro}m x 520 {micro}m single FOVs and 25-40 nm lateral resolutions. Through stitching, nanoscopic imaging over mm2 sample areas can be completed in as little as 40 minutes per target. An on-stage microfluidics chamber facilitates probe exchange for multiplexing and enhances image quality particularly for formalin-fixed paraffin-embedded (FFPE) tissue sections. We demonstrate the utility of PRIME-PAINT by analyzing ~106 caveolae structures in ~1,000 cells and imaging entire pancreatic cancer lesions from patient tissue biopsies. By imaging from nanometers to millimeters with multiplexity and broad sample compatibility, PRIME-PAINT will be useful for building multiscale, Google-Earth-like views of biological systems.

biophysics↗

bioRxiv2021

Coronavirus Resistance Database (CoV-RDB): SARS-CoV-2 susceptibility to monoclonal antibodies, convalescent plasma, and plasma from vaccinated persons

As novel SARS-CoV-2 variants with different patterns of spike mutations have emerged, the susceptibility of these variants to neutralization by antibodies has been rapidly assessed. However, neutralization data are generated using different approaches and are scattered across different publications making it difficult for these data to be located and synthesized. The Stanford Coronavirus Resistance Database (CoV-RDB; https://covdb.stanford.edu) is designed to house comprehensively curated published data on the neutralizing susceptibility of SARS-CoV-2 variants and spike mutations to monoclonal antibodies (mAbs), convalescent plasma (CP), and vaccinee plasma (VP). As of October 2021, CoV-RDB contains 186 publications including 64 (34%) containing 7,328 neutralizing mAb susceptibility results, 96 (52%) containing 11,390 neutralizing CP susceptibility results, and 125 (68%) containing 20,872 neutralizing VP results. The database also records which spike mutations are selected during in vitro passage of SARS-CoV-2 in the presence of mAbs and which emerge in persons receiving mAbs as treatment. The CoV-RDB interface interactively displays neutralizing susceptibility data at different levels of granularity by filtering and/or aggregating query results according to one or more experimental conditions. The CoV-RDB website provides a companion sequence analysis program that outputs information about mutations present in a submitted sequence and that also assists users in determining the appropriate mutation-detection thresholds for identifying non-consensus amino acids. The most recent data underlying the CoV-RDB can be downloaded in its entirety from a Github repository in a documented machine-readable format.

bioinformatics↗

bioRxiv2021

Disrupted social memory ensembles in the ventral hippocampus underlie social amnesia in autism-associated Shank3 mutant mice

The ability to remember conspecifics is critical for adaptive cognitive functioning and social communication, and impairments of this ability are hallmarks of autism spectrum disorders (ASDs). Although hippocampal ventral CA1 (vCA1) neurons are known to store social memories, how their activities are coordinated remains unclear. Here we show that vCA1 social memory neurons, characterized by enhanced activity in response to memorized individuals, were preferentially reactivated during sharp-wave ripples (SPW-Rs). Spike sequences of these social replays reflected the temporal orders of neuronal activities within theta cycles during social experiences. In ASD model Shank3 knockout mice, the proportion of social memory neurons was reduced, and neuronal ensemble spike sequences during SPW-Rs were disrupted, which correlated with impaired discriminatory social behavior. These results suggest that SPW-R-mediated sequential reactivation of neuronal ensembles is a canonical mechanism for coordinating hippocampus-dependent social memories and its disruption underlies the pathophysiology of social memory defects associated with ASD.

neuroscience↗

bioRxiv2021

Host preference and invasiveness of commensals in the Lotus and Arabidopsis root microbiota

Healthy plants are colonized by microorganisms from the surrounding environment, which form stable communities and provide beneficial services to the host. Culture-independent profiling of the bacterial root microbiota shows that different plant species are colonized by distinct bacterial communities, even if they share the same habitat. It is, however, not known to what extent the host actively selects these communities and whether commensal bacteria are adapted to a specific plant species. Here, we report a sequence-indexed culture collection from roots and nodules of the model legume Lotus japonicus that contains representatives from the majority of species found in culture-independent profiles. Using taxonomically paired synthetic communities from L. japonicus and the crucifer Arabidopsis thaliana in a multi-species gnotobiotic system, we detect clear signatures of host preference among commensal bacteria in a community context, but not in mono-associations. Sequential inoculation of either host reveals strong priority effects during the assembly of the root microbiota, where established communities are resilient to invasion by late-comers. However, we found that host preference by commensal bacteria confers a competitive advantage in their native host. We reveal that host preference is prevalent in commensal bacteria from diverse taxonomic groups and that this trait is directly linked to their invasiveness into standing root-associated communities.

plant biology↗

bioRxiv2021

Single-cell and single-variant resolution analysis of clonal evolution in human liver cancer

Genetic heterogeneity of tumor is closely related to clonal evolution, phenotypic diversity and treatment resistance. Such heterogeneity has been characterized in liver cancer at single-cell sub-chromosomal scale, and a more precise single-variant resolution analysis is lacking. Here we employed a strategy to analyze both the single-cell genomic mutations and transcriptomic changes in 5 patients with liver cancer. Target sequencing was done for a total of 480 single cells in a patient-specific manner. DNA copy number status of point mutations was obtained from single-cell mutational profiling. The clonal structures of liver cancers were then uncovered at single-variant resolution, and mutation combinations in single cells enabled reconstruction of their evolutionary history. A common origin but independent evolutionary fate was revealed for primary liver tumor and intrahepatic metastatic portal vein tumor thrombus. The mutational signature suggested early evolutionary process may be related to specific etiology like aristolochic acids. By parallel single-cell RNA-Seq, the transcriptomic phenotype was found to be related with genetic heterogeneity in liver cancer. We reconstructed the single-cell and single-variant resolution clonal evolutionary history of liver cancer, and dissection of both genetic and phenotypic heterogeneity provides knowledge for mechanistic understanding of liver cancer initiation and progression.

genomics↗

bioRxiv2020

Identification of Cross-Reactive CD8+ T Cell Receptors with High Functional Avidity to a SARS-CoV-2 Immunodominant Epitope and Its Natural Mutant Variants

Despite the growing knowledge of T cell responses and their epitopes in COVID-19 patients, there is a lack of detailed characterizations for T cell-antigen interactions and T cell functions. Using a peptide library predicted with HLA class I-restriction, specific CD8+ T cell responses were identified in over 75% of COVID-19 convalescent patients. Among the 15 SARS-CoV-2 epitopes identified from the S and N proteins, N361-369 (KTFPPTEPK) was the most dominant epitope. Importantly, we discovered 2 N361-369-specific T cell receptors (TCRs) with high functional avidity, and they exhibited complementary cross-reactivity to reported N361-369 mutant variants. In dendritic cells (DCs) and the lung organoid model, we found that the N361-369 epitope could be processed and endogenously presented to elicit the activation and cytotoxicity of CD8+ T cells ex vivo. Our study evidenced potential mechanisms of cellular immunity to SARS-CoV-2, illuminating natural ways of viral clearance with high relevancy in the vaccine development.

immunology↗

bioRxiv2020

Identity and provenance of neighbors, genotype-specific traits and abiotic stress affect intraspecific interactions in the annual legume Medicago truncatula

O_LIAccounting for intraspecific variation may improve our understanding of species coexistence. However, our knowledge of what factors maintain intraspecific variation is limited. We predicted that 1) a plant grows larger when with non-kin (i.e. different genotypes) than kin (i.e. same genotype) neighbors, 2) abiotic stress alters the outcome of kin vs. non-kin interactions, 3) genetic identity of plants affects composition of soil microbiome. C_LIO_LIWe set up mini-communities of Medicago truncatula, where focal genotypes were grown together with two kin or two non-kin neighbors from different origins. We analyzed how origin, identity of interacting genotypes and abiotic stress affected growth and fruit production. We also analyzed the composition of soil microbial communities. C_LIO_LIFocal plants grew larger in non-kin than in kin mini-communities. This pattern was stronger in low level of abiotic stress and when interacting genotypes were from similar origins. However, genotypic variation in growth and response to competition had a stronger effect on growth than mini-community type. Plant genotype identity did not affect soil microbiome. C_LIO_LIWe find that intraspecific variation is affected by genotype-specific traits and abiotic stress. Geographic, rather than genetic, distance among interacting genotypes affects the outcome of intraspecific interactions. C_LI

plant biology↗