Biology subjects

Lai, Y.

Publications and source records attributed to Lai, Y..

At least 19 recordsLinked to original sources

bioRxiv2026

Glioblastoma Hijacks Astrocyte Ribosomes to Feul Malignancy through Translatome Reprogramming

Cancer cells demand elevated protein synthesis, yet whether they directly requisition ribosomes from microenvironmental host cells remains unknown. Here, utilizing in vivo and in vitro ribosome tracing, we show that glioblastoma (GBM) cells hijack ribosomes from surrounding astrocytes via tunneling nanotube-like structures. This transfer supports GBM malignancy in both murine and patient derived models. Single cell RNA sequencing along with whole cell and cell source traceable ribosome profiling reveal that transferred ribosomes are translationally active and selectively reprogram the tumor translatome, prioritizing cell-cycle genes and driving interferon-response-mediated immune evasion. Through a genome wide CRISPR screen, we identify INTS12 as a critical mediator of ribosome transfer. Genetic inactivation or AAV-mediated knockdown of INTS12 impairs ribosome uptake, curbs translation and proliferation, remodels the immunosuppressive landscape, and extends survival in orthotopic models. Our study uncovers a parasitic translation-support mechanism in GBM, establishing INTS12 as a therapeutic vulnerability to disrupt ribosome transfer.

cancer biology↗

bioRxiv2026

Evaluation of Densified Collagen Tubes as an Interposition Graft in Abdominal Aorta

A major challenge in vascular tissue engineering is the development of scalable fabrication methods capable of producing vascular grafts with suitable mechanical properties and hemocompatibility for both preclinical evaluation and future clinical translation. Using a recently developed method to generate acellular vascular grafts from densified collagen hydrogel, we present a proof-of-concept in vivo evaluation of the scalable collagen graft technology. Thick-walled, genipin-crosslinked grafts, representative of a fabrication approach applicable to clinically relevant vessel sizes, were implanted as interposition grafts in the rat abdominal aorta. These grafts supported rapid neointima formation and re-endothelialisation of the luminal surface but developed late thrombosis, highlighting the challenges of evaluating clinically scalable grafts in small-animal models. To enable assessment of the platform in millimetre-scale vessels, we developed a thin-walled (~100 {micro}m), non-crosslinked graft using a constrained densification approach and hyaluronic acid-mediated modulation of collagen fibril assembly to improve compliance matching and hemocompatibility, with the latter providing a matrix-level approach that may complement surface-bound antithrombotic coatings. These grafts remained patent for up to 17 weeks and exhibited neointima formation, re-endothelialisation, and early cellular infiltration into the graft wall. Together, these findings demonstrate in vivo functionality of densified collagen vascular grafts and establish a foundation for future evaluation in larger animal models.

bioengineering↗

bioRxiv2026

Spatiotemporal atlas resolves the mesenchymal-epithelial stem cell axis governing human hair follicle aging and pathology

How adult stem cell populations coordinate tissue regeneration across physiological and pathological states remains unclear. Hair follicles contain epithelial and mesenchymal stem cells that codetermine hair regeneration. Here, we integrate a multimodal spatiotemporal atlas with functional validation to define the mesenchymal-epithelial stem cell dynamics governing human hair follicle homeostasis, aging, and androgenetic alopecia. Aging is characterized by passive depletion of hDSC-derived regenerative cues, whereas AGA involves a shift of hDSC toward an inhibitory signaling hub that promotes HFSC dysfunction. We further pinpoint hDSC-secreted PTN as a key regenerative factor that promotes hair growth and counteracts androgen-induced growth suppression. This study provides a holistic framework of adult stem cell crosstalk across physiological and pathological states, offering a mechanistic roadmap to reinstate tissue regeneration.

cell biology↗

bioRxiv2026

Intramembrane protease SPPL2b deficiency linked to synaptic proteostasis remodeling with brain aging

Signal peptide peptidase-like 2b (SPPL2b) is a brain-enriched intramembrane protease implicated in synaptic function, immune signaling, and neuronal development, but its physiological role in brain and neuronal homeostasis remains poorly understood. We investigated the impact of constitutive Sppl2b deletion on the brain proteome and neuronal function using quantitative shotgun proteomics in cortex and hippocampus from wild-type and SPPL2b-deficient mice at 3 and 12 months, combined with western blot, immunofluorescence, dendritic spine analysis, and behavioral testing. SPPL2b deficiency was associated with alterations in biological processes linked to axonal transport and synaptic vesicle trafficking, including consistent upregulation of the kinesin motor protein KIF1A and vesicle-associated membrane protein 2 (VAMP2). SPPL2b deletion also attenuated age-associated proteomic changes in synaptic pathways and was accompanied by increased dendritic spine density, morphological remodeling of pyramidal neurons, increased locomotor activity, and reduced anxiety-like behavior. These findings reveal a previously unrecognized association between SPPL2b and synaptic proteome remodeling during aging and nominate SPPL2b-dependent pathways as candidates for further mechanistic and functional investigation in neurodegenerative disease.

neuroscience↗

bioRxiv2026

Effector-triggered stomatal immunity prevents leaf invasion by bacterial pathogens

The phytopathogen Pseudomonas syringae must enter the leaf interior through natural openings such as stomata to cause disease. Plants restrict pathogen entry into the leaf upon non-self recognition-driven closure of their stomata. P. syringae counters this stomatal immunity by deploying a range of toxins and effectors. Here, we show that stomatal immunity in Arabidopsis thaliana is reinforced upon recognition of the ubiquitous P. syringae type III effector AvrE1 by the resistance protein CAR1. CAR1 expression is enriched in guard cells, and its activation prolongs the effective duration of stomatal immunity. We also show that CAR1 prevents the invasion of leaf tissue by natural isolates of P. syringae, demonstrating that CAR1-mediated stomatal immunity against the conserved effector AvrE1 provides a broadly significant barrier to host accessibility by P. syringae.

plant biology↗

bioRxiv2026

SPCoral: diagonal integration of spatial multi-omics across diverse modalities and technologies

Spatial multi-omics is indispensable for decoding the comprehensive molecular landscape of biological systems. However, the integration of multi-omics remains largely unresolved due to inherent disparities in molecular features, spatial morphology, and resolution. Here we developed SPCoral for diagonal integration of spatial multiomics across adjacent slices. SPCoral extracts spatial covariation patterns via graph attention networks, followed by the use of optimal transport to identify high-confidence anchors in an unsupervised, feature-independent manner. SPCoral utilizes a crossmodality attention network to enable seamless cross-resolution feature integration alongside robust cross-omics prediction. Comprehensive benchmarking demonstrates SPCorals superior performance across different technologies, modalities and varied resolutions. The integrated multi-omics representation further improves spatial domain identification, effectively augments experimental data, enables cross-modal association analysis, and facilitates cell-cell communication. SPCoral exhibits good scalability with data size, reveals biological insights that are not attainable using a single modality. In summary, SPCoral offers a powerful framework for spatial multi-omics integration across various technologies and biological scenarios.

bioinformatics↗

bioRxiv2025

DRP1 induces neuroinflammation via transcriptional regulation of NF-ĸB

Neuroinflammation is a major pathogenic mechanism in neurodegenerative diseases. Understanding the regulation of neuroinflammation is critical to therapeutic development. We report here that dynamin related protein 1 (DRP1), well-recognized for its role in mitochondrial fission, is a transcription factor that regulates neuroinflammation. Using multiple inflammatory models, we provide evidence demonstrating that DRP1, when challenged with pro-inflammatory lipopolysaccharides, translocates from the cytosol to the nucleus, then binds to the promoter region of Rela (encoding NF-{kappa}B) to activate its gene products and other downstream inflammatory cytokines. Our data also demonstrate the significant role of the proinflammatory lipocalin 2 in the brain. In combination, this study highlights a previously unidentified function of DRP1 in mediating neuroinflammation via the NF-{kappa}B-lipocalin 2 axis. Through such mechanisms of DRP1, this study also provides potential therapeutic targets for neurodegenerative diseases and other conditions linked to inflammation.

neuroscience↗

bioRxiv2025

Merits and challenges of plasma proteomics on association replicability

Developments in proteomic platforms have enabled the generation of large-scale high-throughput plasma proteomics data [1-3]. With recent breakthroughs in AI modelling, these data have significantly enhanced our understanding of molecular mechanisms underlying human behaviors and diseases [4-6]. However, the replicability of associations between plasma proteomics and phenotypes remains underexplored. Here, we systematically assessed the replicability of associations with recent plasma proteomics data in the UK biobank. Over 75% of cognitive function and mental health traits demonstrated high overall (proteomics-wide) replicability when brain-related traits were considered as phenotypes. Although mean cortical thickness (CT) as phenotype exhibited clearly reduced replicability, total cortical surface area (CSA) and cortical volume (CV) showed high overall replicability across hemispheres and over twenty brain regions. In comparative multi-omics analyses based on the same cohort of participants, proteomics outperformed genomics across all brain-related traits, and exceeded metabolomics for over half of traits where metabolomics also exhibited high overall replicability. Furthermore, we developed a predictive framework to estimate the replicability for potential future proteomics panels based on the crucial influential factors including dilution level, proportion of samples below the limit of detection (LOD), and sample size. Moreover, we constructed an individual replicability index for proteins and identified eleven proteins with highly replicable associations across cognitive function and mental health traits, which was in line with the recent identifications of pleiotropic proteins in large-scale population studies. Collectively, our results revealed the challenges in the association replicability of plasma proteomics under reduced data quality (from "Explore" to "Expansion" assay panels), and we further explored how to sustain high replicability in potential future panels. Fundamentally, our findings affirm the merits of plasma proteomics: this molecular omics platform enables highly replicable associations for mapping biomedical signatures.

bioinformatics↗

bioRxiv2025

Metabolic modulation of intratumoral cholesterol with gut microbiota for the treatment of colorectal cancer

Excess cholesterol is positively correlated with colorectal cancer (CRC). Current therapeutic strategies for modulating cholesterol levels in CRC are limited and often come with complications. Here, we demonstrated that microbiome shunting of intestinal cholesterol to anticancer metabolites is a safe and applicable therapeutic approach for CRC. By screening major microbial metabolic products of cholesterol, we found that 4-cholesten-3-one (4-C-3) was selectively depleted in fecal samples and tumor tissues of patients with CRC. 4-C-3 exhibits strong antitumor effects on human CRC cell lines, patient-derived organoids, and patient-derived xenograft (PDX) models. Mechanistically, 4-C-3 suppresses CRC tumorigenesis by dually targeting the epidermal growth factor receptor (EGFR) and Kirsten rat sarcoma viral oncogene homologue (KRAS). 4-C-3 directly binds to EGFR, blocking its signal transduction by inhibiting the binding of EGFR ligands. Additionally, 4-C-3 inhibits oncogenic KRAS variants, such as KRASG12D, by suppressing nucleotide exchange activity and effector engagement. By targeting both EGFR and KRAS, 4-C-3 reduces primary resistance to anti-EGFR therapies caused by KRAS mutations in CRC. As a proof-of-concept study, we showed that delivery of 4-C-3 by Oscillibacter ruminantium, a 4-C-3- producing commensal bacterium that is reduced in CRC patients, or a nonpathogenic Escherichia coli strain engineered to specifically convert intestinal cholesterol into 4-C-3, removed intratumoral cholesterol and led to rapid tumor regression in multiple models of CRC. These results suggest that microbial therapies for restoring intestinal cholesterol homeostasis represent a new therapeutic avenue for CRC.

cancer biology↗

bioRxiv2025

Integration of the hammerhead ribozyme into structured RNAs to measure ligand-binding events for riboswitch candidates and aptamers

Some structured RNAs, such as riboswitches and aptamers, can bind their cognate ligands and have been used in biosensors and gene expression control elements. However, current methods for detecting ligand binding to structured RNAs are either severely limited or inconvenient. In this study, we design a multi-base pair bridge to integrate a hammerhead ribozyme into structured RNAs to detect ligand binding events. The experimental results demonstrate that the length of the bridge has a significant effect on the cleavage of the ribozyme; optimal cleavage can be achieved with three to six base pairs in the bridge. The dissociation constant (KD) values obtained through this method are in agreement with those determined by in-line probing techniques, and 1 pmol of allosteric ribozyme RNA is sufficient for measurement. We apply this method to evaluate the binding affinity of the riboswitch candidate Motif_9307. Our findings indicate that this motif has no binding affinity for S-adenosylmethionine or several other tested ligands, which is consistent with the results of the in-line probing experiments. Notably, our method reveals an increase in cleavage activity when yeast extract is added as a mixture of ligands, suggesting that the ligand of Motif_9307 is present in the extract. In conclusion, we develop an alternative approach for measuring ligand binding events associated with riboswitch candidates and aptamers.

molecular biology↗

bioRxiv2025

Microbiome functional gene pathways predict cognitive performance in older adults with Alzheimers disease

Disturbances in the gut microbiome is increasing correlated with neurodegenerative disorders, including Alzheimers Disease. The microbiome may in fact influence disease pathology in AD by triggering or potentiating systemic and neuroinflammation, thereby driving disease pathology along the "microbiota-gut-brain-axis". Currently, drivers of cognitive decline and symptomatic progression in AD remain unknown and understudied. Changes in gut microbiome composition may offer clues to potential systemic physiologic and neuropathologic changes that contribute to cognitive decline. Here, we recruited a cohort of 260 older adults (age 60+) living in the community and followed them over time, tracking objective measures of cognition, clinical information, and gut microbiomes. Subjects were classified as healthy controls or as having mild cognitive impairment based on cognitive performance. Those with a diagnosis of Alzheimers Diseases with confirmed using serum biomarkers. Using metagenomic sequencing, we found that relative species abundances correlated well with cognition status (MCI or AD). Furthermore, gene pathways analyses suggest certain microbial metabolic pathways to either be correlated with cognitive decline or maintaining cognitive function. Specifically, genes involved in the urea cycle or production of methionine and cysteine predicted worse cognitive performance. Our study suggests that gut microbiome composition may predict AD cognitive performance.

microbiology↗

bioRxiv2025

Hyperactivity of the Amygdala Mediates Depressive-Like Phenotypes and Decreased Serotonin Release

Clinical and preclinical studies have consistently demonstrated a correlation between hyperactivity of the amygdala and the onset of depression. However, the underlying mechanisms influencing serotonin levels a critical neurotransmitter implicated in depression and a primary target for selective serotonin reuptake inhibitors (SSRIs) remain inadequately understood. In this study, we employed a restrained inescapable shock (RIS) model to investigate these mechanisms in mice. The RIS paradigm elicited depressive-like phenotypes, increased c-Fos expression in the amygdala, diminished serotonin levels, and elevated corticosterone concentrations. Notably, chemogenetic inhibition of the amygdala mitigated depressive symptoms, reduced neuronal activity in this region, and restored serotonin levels. Anatomical analyses revealed a significant connectivity between the central amygdala (CeA) and the dorsal raphe nucleus (DRN). Fiber photometry recordings indicated that serotonergic neuronal activity in the DRN decreased in response to aversive stimuli, accompanied by amygdala activation following RIS, with no notable alterations in DRN GABAergic activity. These findings suggest that chronic stress may exacerbate amygdala hyperactivity, which subsequently inhibits serotonin release in the brain, potentially intensifying depressive states. Therefore, targeting amygdala hyperactivity may represent a novel therapeutic strategy for the management of stress-related depressive and anxiety disorders.

neuroscience↗

bioRxiv2025

Construction and characterization of coronavirus nonstructural protein 3-host protein interaction networks unravel an important role of cleavage and polyadenylation specificity factor 6 in regulation of viral RNA replication

Coronavirus nonstructural protein 3 (nsp3) plays a crucial role in viral replication and immune evasion. However, functional and proteomic characterization of this protein, especially the interaction networks between nsp3 from different coronaviruses and host cell factors, is hindered by its huge size, complex structural feature and the presence of multiple transmembrane domains. In this study, we report the application of a high-performance cytoplasmic expression system to efficiently and accurately express the full-length nsp3 from betacoronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and gammacoronavirus infectious bronchitis virus (IBV), to investigate their interactions with host proteins using proteomics approaches. Our study identified 1,150 host proteins that interact with IBV nsp3 and 920 with SARS-CoV-2 nsp3. Among them, 658 are shared by the two nsp3 proteins. Further validation and preliminary characterization of seven selected candidates, DDX5, DDX39, DHX9, elF4A3, SRRT and CPSF6, demonstrated the reproducibility and reliability of the proteomics data. More interestingly, an important regulatory role of the nsp3-CPSF6 interaction in the replication and transcription of IBV gRNA and sgRNA was unraveled. The construction of nsp3-host protein interaction networks from two distantly related coronaviruses would have provided a foundation for future studies of host cell factors in the regulation of coronavirus replication and pathogenesis.

microbiology↗

bioRxiv2025

Imbalanced mitochondrial dynamics in human and mouse PD brains

Mitochondrial dysfunction is a major pathogenic mechanism in Parkinsons disease (PD). Emerging studies have shown that dysregulation in mitochondrial dynamics (fission/fusion/movement) has a major negative impact on mitochondria - both morphologically and functionally. Partial genetic deletion and pharmacological inhibition of the mitochondrial fission dynamin-related protein 1 (Drp1) have been demonstrated to be beneficial in experimental models of PD. However, the expression of DRP1 (and other fission and fusion genes/proteins) has not been investigated in the brains of Parkinsons patients. Without these data, the question remains whether targeting DRP1 is a valid therapeutic target for PD. To address this gap of knowledge, first, we used post-mortem substantia nigra specimens of Parkinsons patients and controls. Significant increases in the levels of both DNM1L, which encodes DRP1, as well as the DRP1 protein were detected in Parkinsons patients. Immunostaining revealed increased DRP1 expression in dopamine (DA) neurons, astrocytes, and microglia. In addition to DRP1, the levels of other fission and fusion genes/proteins were also altered in Parkinsons patients. To complement these human studies and given the significant role of -synuclein in PD pathogenesis, we performed time-course studies (3-, 6- and 12-month) using transgenic mice overexpressing human wild-type SNCA under the mouseThy-1 promoter. As early as 6 months old, we detected an upregulation of Dnm1l and Drp1 in the nigral DA neurons of the SNCA mice as compared to their WT littermates. Furthermore, these mutant animals exhibited more Drp1 phosphorylation at serine 616, which promotes its translocation to mitochondria to induce fragmentation. Together, this study shows an upregulation of DRP1/Drp1 and alterations in other fission/fusion proteins in both human and mouse PD brains, leading to a pro-fission phenotype, providing additional evidence that blocking mitochondrial fission or promoting fusion is a potential therapeutic strategy for PD.

neuroscience↗

bioRxiv2025

Single-Cell Genomics Elucidates Molecular Variations and Regulatory Mechanisms in Circulating Immune Cells

The human peripheral blood displays diverse molecular characteristics across populations, understanding the drivers and underlying mechanisms of which remains challenging. Here, we introduce the Chinese Immune Multi-Omics Atlas (CIMA), elucidating sex-, age-, and genetic-related molecular variations by analyzing multi-omics data from 428 adults with over 10 million immune cells. CIMA generated an enhancer-driven gene regulatory network, identifying 237 high-quality regulons and revealing cell type-specific regulatory mechanisms. Additionally, 11,521 lead cis-expression quantitative trait loci (eQTLs) and 46,339 chromatin accessibility QTLs (caQTLs) were identified at cell type level. CIMA also uncovered pleiotropic associations among immune-related disease risk loci, eQTLs, and caQTLs in a cell type-specific manner. Lastly, a novel cell language model, CIMA-CLM, was developed to predict chromatin accessibility and noncoding variant effects using chromatin sequences and gene expressions. This work represents a population-scale multi-omics resource of human immune cells, providing a valuable reference for future investigation of immune-related diseases.

immunology↗

bioRxiv2025

Roles of spoVF operon subunits A and B in regulating cell morphology and biofilm formation in the biocontrol agent Bacillus subtilis

Enhanced expression of spoVF operon (sporulation initiation factor; dipicolinic acid (DPA) synthase) in Bacillus subtilis vegetative cells has been reported to increase host attachment and biocontrol ability. However, how the spoVF operon regulates these essential biocontrol factors remains unknown. In this study, it was found that the knockout of the spoVFA or spoVFB subunits, individually ({Delta}A and{Delta} B), or together ({Delta}A{Delta}B), decreased DPA biosynthesis, host attachment, nutrient competition ability, and biocontrol efficacy in B. subtilis. Moreover, the cell shape of the knockout strains changed from short rod to spherical. qRT-PCR analysis indicated that the spoVF operon regulates TCA cycle expression and biofilm formation by balancing the amounts of various transcriptional factors, such as spo0A, SinR, and AbrB, and the cofactor NADPH. The regulatory mechanism of the spoVF operon in B. subtilis biofilm-related genes was proposed for the first time. IMPORTANCEBacillus subtilis SpoVF operon contains the spoVFA or spoVFB subunits, which are responsible for the dipicolinic acid synthase activity. Dipicolinic acid is an important component of B. subtilis spores. In this study, the roles of spoVFA or spoVFB subunits in the biocontrol ability B. subtilis were examined, indicating that the spoVFA subunit plays a key role in B. subtilis biofilm formation, cell morphology, growth, and nutrient competition ability. Additionally, the regulatory network connecting the spoVF operon with biofilm formation-related genes of B. subtilis was proposed. The results obtained in this study help to understand key genes involved in the biocontrol ability of B. subtilis.

microbiology↗

bioRxiv2024

Mapping Grip Force to Muscular Activity Towards Understanding Upper Limb Musculoskeletal Intent using a Novel Grip Strength Model

This work aims to evaluate a grip strength model, developed using a piecewise linear function based on the Woods and Bigland-Ritchie EMG-force model, which correlates the relationship between measured grip force and muscular activity. The grip strength model is compared against the results derived from an upper limb musculoskeletal model. Experimental results demonstrate the models efficacy in estimating surface electromyography (sEMG) readings from force measurements, with a mean root mean square error (RMSE) of 0.2035 and a standard deviation of 0.1207 for muscle activation (dimension-less). Moreover, incorporating sEMG readings associated with grip force does not significantly affect the optimization of muscle activation in the upper arm, as evidenced by kinematic data analysis from dynamic tasks. This validation underscores the models potential to enhance musculoskeletal model-based motion analysis pipelines without distorting results. Consequently, this research emphasizes the prospect of integrating external models into existing human motion analysis frameworks, presenting promising implications for physical Human-Robot Interactions (pHRI).

physiology↗

bioRxiv2024

In vivo genome editing of human hematopoietic stem cells for treatment of blood disorders by mRNA delivery

Ex vivo autologous hematopoietic stem cells (HSCs) gene therapy provides promising new treatments for hematological disorders. However, current methods involve complex processes and chemotherapeutic conditioning, leading to limited accessibility for treatment and significant side effects. Here, we developed an antibody-free targeted lipid nanoparticles (LNPs) for mRNA delivery to HSCs in vivo, enabling efficient base editing of the HBG target in human HSCs to reactivate fetal hemoglobin in derived erythroid cells. Delivery of ABE8e/sgRNA mRNA with optimized structure LNPs achieves efficient in vivo base editing of HBG in transfusion-dependent {beta}-thalassemia (TDT) patients derived HSCs engrafted in immunodeficient NCG-X mice, showing restored globin chain balance in erythroid cells. Our research indicated that utilizing LNPs for delivery of genome editor achieves efficient editing of endogenous genes of human HSCs. Notably, this non-viral delivery system eliminates the need for harvesting or mobilizing HSCs, providing a potent and one-time treatment potential for blood disorders like sickle cell disease (SCD) and TDT. HighlightsO_LIAntibody-free targeted LNPs system achieves efficient mRNA delivery and base editing in human bone marrow cells including HSCs via one-time intravenous injection. C_LIO_LIDelivery of ABE8e/sgRNA mRNA with optimized LNPs achieves efficient in vivo base editing of HBG in TDT patients derived HSCs engrafted in immunodeficient NCG-X mice, showing restored globin chain balance in erythroid cells. C_LIO_LILNPs efficiently deliver gene editing system to the BM for in vivo editing of human HSCs, providing preclinical evidence for the next generation non-viral gene therapy for blood disorders. C_LI

bioengineering↗