Biology subjects

Xue, H.

Publications and source records attributed to Xue, H..

At least 19 recordsLinked to original sources

bioRxiv2026

Population-scale dietary signatures of the oral microbiome

Diet is an environmental factor that influences oral microbial communities. How specific foods, nutrients and dietary patterns relate to microbial diversity, species composition and functional potential remains incompletely characterised. Here, we combined detailed dietary records with buccal metagenomic profiles from 5,824 Human Phenotype Project participants. Using these data, we examined diet-oral microbiome associations with prediction models and covariate-adjusted analyses. Plant-based and guideline-based dietary patterns showed similar associations across oral microbial species. However, species within the same genus could show opposite associations with a dietary pattern. For example, a whole-food plant-based diet score was positively associated with Streptococcus sanguinis but negatively with S. gordonii and S. oralis. Some diet-oral microbiome associations were replicated at the genus level in an independent US National Health and Nutrition Examination Survey cohort of 4,667 participants. We map dietary associations with oral microbial diversity, species composition and functional potential, revealing shared microbial signatures across dietary patterns.

microbiology↗

bioRxiv2026

Efficient recovery of transgene-free edited tobacco using the transgene self-elimination system via de novo regeneration

Elimination of integrated editing constructs remains a major challenge for generating transgene-free progeny in plant genome editing based on Agrobacterium-mediated regeneration. Here, we adapted the Transgene Killer CRISPR (TKC) concept to tobacco and established the transgene self-elimination system, in which CRISPR/Cas9 is coupled with developmentally regulated BARNASE cassettes. Three pU3TR-derived vectors carrying DLL-, OsRP3- or PHAS-driven Barnase regenerated normally after leaf-disc transformation. The DLL construct pEB138 showed the highest T editing frequency, with 56 of 69 independent T plants (81.16%) carrying mutations at one or both NtDFR target loci. Under a stringent lineage-level screen in which up to 48 T progeny were tested per T line, 36 of 43 pEB138 lineages (83.72%) yielded uniformly marker-negative progeny for the three assayed T-DNA markers, compared with 0 of 7 lineages transformed with the parental pU3TR vector. The platform also supported recovery of dfr mutants with altered flower pigmentation and NtA622-edited lines with reduced nicotine accumulation. Moreover, introduction of DLL-iBarnase into the independent pDC45 editing backbone did not impair shoot regeneration, and representative NtBBL progeny showed markedly reduced nicotine content together with loss of the selectable cassette. These results demonstrate that BARNASE-assisted transgene elimination can be integrated with Agrobacterium-mediated de novo regeneration in a dicot, enabling one-step recovery of transgene-free edited tobacco progeny.

molecular biology↗

bioRxiv2026

An intrinsically disordered proline-rich domain acts in synergy with AGP-type glycosylation to control the protein fate of FLA4

The functional roles of glycans attached to the proline (Pro) rich region of arabinogalactan proteins are largely elusive. We have tested the possibility of type II arabinogalactans acting as protein fate determinants for the FASCICLIN LIKE ARABINOGALACTAN PROTEIN 4 (FLA4). Pro-to-Ala substitutions in the carboxy-terminal region caused in planta protein destabilization in an ECHIDNA-dependent trans-Golgi compartment and plasma membrane shedding in an aspartate protease-dependent manner. The introduction of diverse glycomodules to the FLA4 carboxy-terminus counteracted the stability loss, with AGP type glycosylation motifs more efficient than N-glycosylation signals and extensin structures. The resistance of FLA4 stability and localization to genetic interference with O-glycosylation suggested that additional protein properties, such as intrinsic disorder and secondary structure were crucial for FLA4 stability. Consistently, disorder-maintaining site directed mutants maintained FLA4 stability in a glycosylation-independent manner. Our data support a role for proline-rich regions in determining protein fate by generating intrinsically disordered domains in the peptide chain and providing acceptor sites for O-glycosylation.

plant biology↗

bioRxiv2026

Detecting domain-level organization in genome-wide association study summary statistics using frequency-impact-reliability profiles

Genome-wide association studies (GWAS) identify trait-associated variants but are typically interpreted through single-variant significance and locus-level peaks, treating summary statistics as collections of independent signals. Here we show that GWAS summary statistics exhibit previously unrecognized local genetic-statistical organization along genomic coordinates. We develop FIR-GWAS, a framework that integrates allele frequency, effect magnitude and statistical reliability to define frequency-impact-reliability (FIR) profiles and quantify their spatial continuity. Across EUR height GWAS, ancestry-specific datasets and eight additional human complex traits, we find consistent enrichment of same-profile adjacency and coordinate-contiguous FIR domains beyond chromosome-preserving null expectations. These patterns persist after removal of genome-wide significant variants and are reproducible across SNP- and window-based analyses. We further show that FIR-domain architecture separates genome-wide significant structured regions from isolated association peaks and identifies subthreshold domains with coherent statistical organization. FIR-domain structure is consistently associated with regulatory annotations and trait-related gene sets, and highlights biologically plausible subthreshold candidate regions. Across Arabidopsis and chicken GWAS, we observe that FIR-domain architecture is not restricted to human traits but recurs across independent association-summary landscapes. Decomposition analyses suggest that this spatial regularity arises from coordinated local continuity in allele frequency, effect size and statistical reliability. Together, these results reveal GWAS summary statistics as structured genetic-statistical landscapes rather than collections of independent signals, defining a domain-level layer of organization that complements conventional single-variant and locus-based interpretation.

genetics↗

bioRxiv2026

A Stress-Adaptive Lipid Kinase Axis Defines Metabolic Vulnerabilities in Neuroendocrine Prostate Cancer

Neuroendocrine prostate cancer (NEPC) persists in a profoundly hypoxic microenvironment, yet the mechanisms enabling tumor adaptation to this metabolically challenging niche remain undefined. Here, we identify the lipid kinase PIKfyve as overexpressed in NEPC, functioning as a central node in a stress-lipid kinase axis that drives adaptation to persistent endoplasmic reticulum (ER) stress. Mechanistically, NEPC requires PIKfyve-mediated lysosomal degradation and lipid recycling to maintain metabolic homeostasis under hypoxia. PIKfyve inhibition disrupts lysosomal function, leading to ER stress accumulation and activation of a compensatory, sterol regulatory element-binding protein (SREBP)-dependent de novo lipogenesis program essential for NEPC survival. This stress-lipid axis creates a synthetic vulnerability between PIKfyve and fatty acid synthase (FASN), where dual inhibition synergistically amplifies ER stress, triggers the terminal unfolded protein response, and induces tumor cell death. These findings reveal a metabolic adaptation in NEPC and provide preclinical evidence that co-targeting PIKfyve and FASN can overcome hypoxia-associated stress adaptation.

cancer biology↗

bioRxiv2026

Network-Level Characterization of Spontaneous Calcium Activity in an In-Vitro Alzheimer's Disease Model

The neurodegenerative disorder Alzheimers disease (AD) is widely known for biomarkers such as amyloid beta plaques and tauopathy, as well as functional differences in memory and cognitive ability. Despite this devastating functional impact, a large body of work only focuses on molecular biomarkers of AD. In this study, we investigate collective neural dynamics in vitro and assess how network-level properties differ between a well-established model of familial AD (FAD) and a newly developed in vitro accelerated model (acAD). The new model system reliably develops the key structural characteristics of AD in three weeks, but its calcium dynamics had not been characterized previously. Spontaneous network dynamics influences information processing as part of the internal network state. Here we measure this spontaneous activity of a network of hundreds of cells in each field of view. We find that the FAD model has a larger fraction of hyperactive cells, while the acAD model displays similar characteristics to healthy cells. Additionally, the FAD model has altered cooperation between cells, losing a proportion of highly correlated cellular activities, both for fast and slow coupling among cells. The acAD model is again consistent with healthy networks. Since the acAD model does not show the same spontaneous network dysfunction seen in FAD, it can enable measurements of changes in learning and memory associated with the plasticity, rather than the structure of the internal network state.

biophysics↗

bioRxiv2026

A graph-based pangenome reveals the genetic basis of climate-resilient and horticultural traits in pear

Climate change poses an increasing threat to the cultivation of deciduous fruit trees, placing greater demands on modern pear breeding. Using pear germplasm adapted to diverse environments, we assembled 11 chromosome-level genomes. In combination with 13 publicly accessible pear genomes, we analyzed presence-absence variations (PAVs) and constructed a graph-based pangenome for pear. By performing a PAV-eQTL analysis of the fruit of 123 pear accessions, we identified PAVs significantly associated with expression levels of genes that may be involved in regulating agronomic traits. Population analysis of 268 pear accessions revealed two stop-gained variants in DAM1 of independent origin, which may function in advancing the blooming date and reducing the chilling requirement. We detected complex PAVs at the NOR1 locus, including two copy-number variations and one deletion. These PAVs contributed to the rapid diversification of the NOR1 locus and the fruit development period through regulating ARF5 and other ripening-related genes. We revealed the selection history of the NOR1 locus and developed novel pear individuals that accumulated alleles for low chilling requirement, early blooming date, and short fruit development period. The results provide valuable resources for pear genomics research and offer a guideline for breeding modern pears with climate resilience.

plant biology↗

bioRxiv2026

Sex stratified analyses enable new genetic insights into brain imaging phenotypes

Sex differences are commonly observed in neuroimaging phenotypes and in the risk of brain diseases, yet the underlying genetic mechanisms remain poorly understood. We investigated sex differences in the genetic architecture of 805 neuroimaging phenotypes in 22,950 males and 22,950 females matched for sample size and covariates, and systematically compared sex-stratified with sex-combined genetic analyses. We found eight variant-trait associations with significant sex differences, 235 fine-mapped sex-dominant causal associations, 457 sex-dominant colocalizations with sex hormones, and 96 sex-dominant colocalizations with schizophrenia. Compared with sex-combined analysis, sex-stratified analysis identified 47 new genetic associations, 170 new fine-mapped causal associations, 1,019 new colocalizations with sex hormones, and 191 new colocalizations with schizophrenia. Additionally, sex-stratified analysis improved global heritability and genetic-correlation estimates and enhanced polygenic prediction for certain phenotypes. This work highlights the need to routinely perform sex-stratified genetic association analyses to elucidate sex-specific and sex-shared genetic control of neuroimaging phenotypes and related disorders.

genetics↗

bioRxiv2026

Neurogenin-2 Reprograms Human Microglial Lineage Cells into Neurons In Vitro and in Chimeric Brains

Progressive neuronal loss is a hallmark of many neurological disorders, yet the adult human brain has a limited capacity for endogenous neuronal replacement. Direct neuronal reprogramming represents an alternative strategy for generating new neurons. Microglia, the brains resident immune cells, are uniquely positioned as candidate cellular substrates due to their abundance, self-renewal capacity, high motility, and rapid recruitment to sites of injury. Here, using live-cell imaging and electrophysiological recordings, we show that human pluripotent stem cell (hPSC)-derived primitive macrophage progenitors (PMPs) and their microglial derivatives exhibit neuronal reprogramming competence. Inducible expression of NEUROG2 in hPSC-derived PMPs drives acquisition of neuronal morphology, sequential expression of early and mature neuronal markers, organization of synaptic proteins, and functional excitability characterized by action potential firing. Single-nucleus RNA sequencing reveals a continuous, directionally ordered reprogramming trajectory marked by suppression of myeloid transcriptional programs, progression through intermediate remodeling states, and progressive activation of neuronal gene regulatory networks, consistent with a regulated lineage conversion rather than partial identity switching. Using a xenotransplantation-based human microglia chimeric brain model, we further demonstrate that inducible NEUROG2 expression reprograms donor-derived human microglia toward a neuronal identity in vivo. Together, these findings establish human microglial lineage cells as a previously unexplored substrate for neuronal reprogramming, providing a conceptual framework for microglia-based strategies aimed at neuronal replacement and neural repair.

neuroscience↗

bioRxiv2026

Histone H2BK120 ubiquitination modulates PRC1 activity and H2AK119ub deposition on nucleosomes

Polycomb group and Trithorax group complexes antagonistically regulate developmental gene expression, yet the mechanisms coordinating their interplay remain poorly understood. Here, we uncover a synergistic histone crosstalk in which H2BK120ub (histone H2B ubiquitination at lysine 120), a Trithorax-associated active mark, enhances Polycomb repressive complex 1 (PRC1) activity by directly binding specific PCGF subunits of PRC1 on the nucleosome surface, as shown in cryo-electron microscopy (cryo-EM) analysis. Beyond regulating enzymatic activity, H2BK120ub also modulates the competitive binding between the catalytic RNF2-BMI1 module and the RYBP subunit of noncanonical PRC1.4 complexes to nucleosomes, potentially restricting H2AK119ub (histone H2A ubiquitination at lysine 119) spreading to neighboring nucleosomes. In mouse embryonic stem cells, H2BK120ub directs the deposition of H2AK119ub within the gene bodies of a subset of developmental genes, which exhibit more rapid activation compared to canonical H3K4me3/H3K27me3 bivalent genes. These findings reveal a previously unrecognized mechanism that links active and repressive histone modifications, providing new insights into the intricate chromatin regulation of gene expression during development.

molecular biology↗

bioRxiv2025

FAM19A4 Enhances Neutrophil Respiratory Burst via p38 MAPK in Lethal Sepsis

Sepsis causes high mortality and resource strain, with neutrophil-derived reactive oxygen species (ROS) contributing to excessive inflammation. The secretory protein FAM19A4 modulates ROS release, but its role in sepsis was unclear. We measured elevated FAM19A4 levels in septic patients and cecal ligation and puncture (CLP) mice, correlating with increased mortality. Fam19a4-/- mice subjected to CLP showed significantly improved survival and attenuated multiorgan injury without impaired peritoneal bacterial clearance or altered circulating neutrophil counts. Deficiency reduced the cell counts of neutrophil (Ly6G+) and macrophage (F4/80+) in lungs and liver, diminished systemic ROS production tracked by bioluminescence, and decreased neutrophil extracellular trap (NET) formation in serum and lung tissue. In vitro, FAM19A4 enhanced neutrophil phagocytosis and ROS generation but did not affect lipopolysaccharide-induced chemotaxis. Mechanistically, bulk RNA sequencing, western blotting, and the p38 inhibitor SB203580 demonstrated that FAM19A4 drives neutrophil ROS release specifically through p38 MAPK signaling activation. These results indicate that FAM19A4 is upregulated during sepsis and exacerbates outcomes by enhancing neutrophil ROS production via p38 MAPK, representing a promising therapeutic target for this condition.

molecular biology↗

bioRxiv2025

Harry Potter meets Markov: Neural event representation in the reading network during narrative processing

People segment ongoing information into meaningful mental representations known as events. Recent studies have found a spatio-temporal hierarchy in the event structure during movie watching and story listening. How the human brain segments stories while reading remains unclear. We examined event segmentation while reading Harry Potter using publicly available 3T fMRI data. To identify neural events, we employed a Hidden Markov Model (HMM) within six regions of interest (ROI) in the reading network. The ROIs included the inferior frontal gyrus (IFG), middle frontal gyrus (MFG), angular gyrus (AG), inferior frontal gyrus orbital (IFGorb), anterior temporal lobe (ATL), and posterior temporal lobe (PTL). These regions are also associated with DMN. The results revealed multiple timescales of events, with the IFG and AG representing shorter events, while the IFGorb, ATL, PTL and MFG represent relatively longer events. Boundaries of longer events were partially aligned within short events, suggesting a nested hierarchical event structure. Further comparisons identified associations between neural events and annotations from humans and ChatGPT (automated and less subjective segmentation) in the inferior frontal, temporal and parietal areas. Notably, the AG (a core region of the DMN and memory processing) and the IFG (relevant for language processing) exhibited stronger alignment with both sets of annotations. The findings suggest an important role of AG and IFG in event segmentation in reading. They also confirm the connection between the reading network and the DMN in event segmentation. This connection seems to be linked to the hierarchical processing of context-dependent semantic information during reading.

neuroscience↗

bioRxiv2025

Transfer RNA modifications during rhizome development in Oryza longistaminata

The rhizome organ endows many clonal plants with the ability to reproduce under stressful climates. Such rhizome-mediated perenniality also underlies the recent success of perennial rice breeding. Despite the importance of this organ, its developmental regulation is poorly understood. Here, using Oryza longistaminata, an emerging model for rhizome biology, we explored the involvement of tRNA modification in rhizome development. Through comparative profiling of modified nucleotides in rhizome samples at different developmental stages and/or subjected to various treatments, we identified a number of key rhizome-related tRNA modifications and revealed that, akin to the observations in many non-plant organisms, tRNA modifications are associated with hormonal signalling to regulate rhizomes responses to environmental cues. Furthermore, genome-wide analysis of tRNA-modifying genes was performed to facilitate future functional studies. These results and analyses not only deepen our understanding of rhizome development but also underscore the regulatory roles of tRNA modification in plant organ development.

plant biology↗

bioRxiv2025

Supergene control of chiral development in mirror-image flowers

How genes determine the left-versus right-handed development of chiral structures is a fascinating question. The reciprocal placement of female and male organs on opposite sides of the midline in mirror-image flowers limits selfing and promotes efficient cross-pollination. Here we identify the molecular and developmental basis of floral handedness in butterfly lilies. Female and male organs deflect by a combination of genetically controlled chirality and gravitropism, orienting left and right with respect to an external rather than internal reference axis. Coordinated organ placement is controlled by a hemizygous supergene containing two causal loci, MIR156-R and YUCCA-R, responsible for opposite female and male organ orientation, respectively. This genomic architecture results in differential placement of the supergene alleles on the pollinators and maintenance of the reproductive polymorphism.

plant biology↗

bioRxiv2025

Hypobaric hypoxia drives citrate cycle reprogramming to suppress tumor progression

High altitude residents present lower tumor incidence and mortality than plain residents, suggesting that hypobaric hypoxia displays protective effect against tumor development. The results of our studies showed that hypobaric hypoxia exposure significantly suppressed tumor progression in subcutaneous bearing and lung metastasis tumor models. With single-cell transcriptome analysis, we identified HIF-1 pathway was significantly downregulated in tumor tissues with high altitude hypoxia, leading to decreased glycolysis and angiogenesis and improved antitumor immune response. Mechanistically, systemic hypoxia rewired citric acid cycle, with enhanced CS and IDH2 expression and reduced OGDH and SUCLG2 expression, to induce -ketoglutarate accumulation and succinate decline in tumor microenvironment, further mediating HIF-1 pathway inhibition. Moreover, hypobaric hypoxia treatment significantly improved the antitumor effects of adjuvant therapies (including chemotherapy, anti-angiogenic therapy and immunotherapy). Our findings reveal the role and mechanism of hypobaric hypoxia for tumor regression and yield new insights into tumor therapy.

cancer biology↗

bioRxiv2025

Functional recovery by transplantation of human iPSC-derived A2B5 positive neural progenitor cell after spinal cord injury in mice

Human induced pluripotent stem cells (hiPSCs) hold great potential for patient-specific therapies. Transplantation of hiPSC-derived neural progenitor cells (NPCs) is a promising reparative strategy for spinal cord injury (SCI), but clinical translation requires efficient differentiation into desired neural lineages and purification before transplantation. Here, differentiated hiPSCs--reprogrammed from human skin fibroblasts using Sendai virus-mediated expression of OCT4, SOX2, KLF4, and C-MYC--into neural rosettes expressing SOX1 and PAX6, followed by neuronal precursors ({beta}-tubulin III/NESTIN) and glial precursors (GFAP/NESTIN). Both neuronal and glial precursors expressed the A2B5 surface antigen. A2B5+ NPCs, purified by fluorescence-activated cell sorting (FACS), proliferated in vitro with mitogens and differentiated into mature neurons and astrocytes under lineage-specific conditions. NOD-SCID mice received a T9 contusion injury followed by transplantation of A2B5+ NPCs, human fibroblasts, or control medium at 8 days post-injury. At two months, grafted NPCs showed robust survival, progressive neuronal maturation ({beta}-tubulin III [->] doublecortin [->] NeuN), and astrocytic differentiation (GFAP), particularly in spared white matter. Transplantation significantly increased spared white matter volume and improved hindlimb locomotor recovery, with no teratoma formation observed. These results demonstrate that hiPSC-derived, FACS-purified A2B5+ NPCs can survive, differentiate into neurons and astrocytes, and enhance functional recovery after SCI. This approach offers a safe and effective candidate cell source for treating SCI and potentially other neurological disorders.

neuroscience↗

bioRxiv2025

Longitudinal single-cell analysis reveals RUNX1T1 as an early driver in treatment-induced neuroendocrine transdifferentiation

Treatment-induced neuroendocrine prostate cancer (t-NEPC) is a lethal form of advanced prostate cancer that can emerge from adenocarcinoma under androgen receptor pathway inhibition, but the tumor-cell states and regulators underlying this transition remain incompletely defined. Here, we analyzed longitudinal single-cell RNA sequencing data from the LTL331/331R patient-derived xenograft model across seven disease stages, comprising 32,269 tumor-cell transcriptomes from treatment-naive adenocarcinoma, post-castration regression, and relapsed NEPC. We identified an AR-low/NE-low intermediate state that emerged after castration and before overt relapse, as well as two transcriptionally distinct terminal NEPC states marked by ASCL1high/FOXA2low and ASCL1low/FOXA2high programs. RUNX1T1 was induced in the intermediate state and remained elevated across both terminal states. RUNX1T1 enhanced NE-associated features and cell viability during enzalutamide treatment in adenocarcinoma cells, whereas its knockdown in NCI-H660 cells reduced NE-associated transcriptional programs, proliferation, and survival and shifted the transcriptome toward an intermediate-like state. Chromatin interactome analysis and co-immunoprecipitation linked RUNX1T1 to G9A/LASP1-containing chromatin repressor complexes. These findings define a temporal framework for treatment-induced NEPC progression and identify RUNX1T1 as an early-induced and sustained regulator of NE lineage transition and maintenance of established NEPC.

cancer biology↗

bioRxiv2025

Macrophage Migration Inhibitory Factor Suppresses Natural Killer Cell Response and Promotes Hypoimmunogenic Stem Cell Engraftment Following Spinal Cord Injury

Human induced pluripotent stem cells (iPSCs) offer immense potential as a source for cell therapy in spinal cord injury (SCI) and other diseases. The development of hypoimmunogenic, universal cells that could be transplanted to any recipient without requiring a matching donor, could significantly enhance their therapeutic potential and accelerate clinical translation. To create off-the-shelf hypoimmunogenic cells, we used CRISPR-Cas9 to delete B2M (HLA class I) and CIITA (master regulator of HLA class II). Double-knockout (DKO) iPSC-derived neural progenitor cells (NPCs) evaded T cell-mediated immune rejection in vitro and after grafting into the injured spinal cord of athymic rats and humanized mice. However, loss of HLA class I heightened susceptibility to host natural killer (NK) cell attack, limiting graft survival. To counter this negative effect, we engineered DKO NPCs to overexpress macrophage migration inhibitory factor (MIF), an NK cell checkpoint ligand. MIF expression markedly reduced NK cell-mediated cytotoxicity and improved long-term engraftment and integration of NPCs in the animal models for spinal cord injury. These findings demonstrate that MIF overexpression, combined with concurrent B2M and CIITA deletion, generates hiPSC neural derivatives that escape both T- and NK-cell surveillance. This strategy provides a scalable route to universal donor cells for regenerative therapies in SCI and potentially other disorders.

cell biology↗