Biology subjects

Sun, J.

Publications and source records attributed to Sun, J..

At least 73 records · Page 4Linked to original sources

bioRxiv2026

Construction of a GnRH mRNA Immunocastration Vaccine and Evaluation of Its Immunogenicity and Safety in Mice and Cats

Immunocastration has emerged as an alternative to surgical and chemical castration for managing reproductive function in animals, yet the development of safe and effective vaccines remains challenging. This study aimed to develop a gonadotropin-releasing hormone (GnRH)-based messenger RNA (mRNA) vaccine and systematically evaluate its immunogenicity, reproductive suppression efficacy, long-term durability, and biosafety in mice and cats. GnRH epitopes were fused to three carrier proteins, Fc, Foldon, and lumazine synthase nanoparticles (pLS) via a flexible linker. After identifying pLS as the optimal scaffold, three mRNA vaccine candidates (GnRH-3, GnRH-4, and GnRH-5) were generated with one, five, or ten tandem GnRH repeats, encapsulated in lipid nanoparticles (LNPs), and assessed in rodent and feline models. Immunogenicity was determined by enzyme-linked immunosorbent assay, gonadal histopathology, hormone measurements, transcriptomic analysis, and mating trials. Among the fusion partners, the pLS-based vaccine (GnRH-3) induced the strongest antibody responses and most pronounced reproductive suppression. Further optimization showed that GnRH-4, containing five tandem GnRH repeats, elicited the highest antibody titers, induced severe gonadal atrophy, and reduced litter size by 93.8% in mice. Transcriptomic analysis revealed that differentially expressed genes in males were enriched in spermatogenesis and motility pathways, whereas those in females were associated with RNA splicing and immune responses. In cats, the optimal regimen was a twoLdose schedule with 50Lg per dose and a 21Lday interval, which induced robust antibody responses lasting at least 12 Lmonths and sustained reproductive suppression. HighLdose (500Lg) administration showed no clinical toxicity or histopathological abnormalities, confirming favorable biosafety. This study successfully developed a pLSLbased GnRH mRNA vaccine (GnRH-4) with five tandem GnRH epitopes that demonstrates strong immunogenicity, longLlasting contraceptive effects, and excellent safety in both rodent and feline models, supporting its potential for clinical application in immunocastration.

immunology↗

bioRxiv2026

Identifying genetic regulations on immune cell type proportions and their impacts on autoimmune diseases

Genetic regulation of immune cell composition plays a crucial role in the etiology of complex diseases, yet remains poorly understood. We propose a unified analytical framework that integrates genome-wide association studies (GWAS) of cell type proportions with cell-type-wide association studies (cWAS) to systematically characterize both the genetic regulation of immune cell composition and its downstream effects on disease risk. Using single-cell RNA sequencing data from the OneK1K cohort, we conducted a GWAS of immune cell-type proportions with a depth-weighted quasi-binomial model designed for bounded, overdispersed traits. We identified 47 genome-wide significant loci influencing eight fine-labeled immune cell subtypes. Leveraging these identified genetic effects, we further imputed genetically regulated proportions (GRPs) using polygenic risk score (PRS)-based imputation and assessed their associations with complex diseases through cWAS. We identified five significant cell type-disease associations, including two with type 1 diabetes, two with Crohns disease, and one with ulcerative colitis. Together, our results demonstrate that cell type proportions observed in scRNA-seq can reveal regulatory loci and offer insights into how genetic variations regulate immune cell type proportions to affect disease risk. Although we focused on immune single-cell data, our framework is applicable to other tissues or cellular compositions as scRNA-seq datasets expand. Author SummaryGenome-wide association studies (GWASs) have uncovered many disease-associated signals, yet most lie in noncoding regions and are difficult to interpret. Mapping GWAS signals to the relevant cell types is therefore important for better understanding the biological mechanisms that drive disease. A major challenge is that observed gene expression and measured cell-type proportions can be influenced by environmental factors and disease status. In contrast, genotypes are less affected by these factors, making them more reliable for interpreting factors of diseases. Moreover, the cell-type proportions are bounded and often skewed, so standard GWAS models that rely on Gaussian assumptions may lose power. To address this, we developed a quasi-binomial approach that better matches the data and improves discovery while controlling false positives. In real data, our method identified more genetic loci associated with cell-type proportions than a traditional linear model. To further investigate how genetic variation regulates immune cell composition to influence disease risk, we integrated our results with disease GWAS summary statistics to identify immune cell types that may contribute to disease susceptibility. Together, our results link disease-associated GWAS signals to specific immune cell types and provide insights into the cellular mechanisms that may underlie these diseases.

genetics↗

bioRxiv2026

Unleashed condensation by recurrent mutations of an epigenetic regulator promotes cancer

The pathological mechanisms and significance for the prevalent hotspot mutations in disordered protein regions are poorly understood. ASXL1 is an obligate co-factor for BAP1 in H2AK119 deubiquitination. ASXL1 mutations are very frequent in myeloid malignancies, and are mostly C-terminal truncating mutations concentrated in a specific disordered region of ASXL1. ASXL1 truncations are gain-of-function mutations that promote myeloid malignancies, but the underlying mechanisms remain poorly understood. Here we show that the frequently truncated mutants of ASXL1 possess an intrinsic property of forming phase-separated biomolecular condensates, and this property is normally suppressed by the frequently deleted regions. A disease-mutant of the endogenous ASXL1 in leukemia cells forms dynamic nuclear co-condensates with other endogenous factors important for gene activation. The ASXL1 disease-mutants can greatly enhance H2A deubiquitination activity of BAP1 in cells and in vitro reconstituted system, enhance myeloid leukemia cell growth, and promote leukemogenesis in a mouse transplant model by turning on myeloid leukemogenic transcriptional programs. However, substitution of residues important for condensation disrupted or impaired all these abilities, suggesting that the condensation property is crucially important for the ASXL1 mutants in promoting cancer. Moreover, we discover that the conserved negative charges in the highly disordered and frequently deleted region on ASXL1 suppress the condensation of the wild type ASXL1. Charge-neutralizing mutations in this region restores condensation of the full-length ASXL1, and are sufficient to turn ASXL1 into a leukemogenic protein. Biochemical, biophysical, and simulation analyses suggest the intramolecular interactions normally mask the N-terminal region in engaging intermolecular interactions required for phase separation, and disease truncations escape from the regulatory interactions and unleash the phase separation property to form nuclear hubs to promote expression of tumorigenic gene programs. Finally, by showing a striking correlation of the mutation frequencies with the condensation properties and leukemogenesis activity for a series of human patient mutations, we suggest that dysregulation of condensation is a central mechanism for ASXL1 mutations in promoting myeloid malignancies. This suggests that dysregulation of condensation may be a key mechanism for some of the prevalent hotspot disease mutations in the disordered proteomes.

biochemistry↗

bioRxiv2026

PlantMDCS: A code-free, modular toolkit for rapid deployment of plant multi-omics databases

With the rapid accumulation of diverse omics datasets, achieving efficient management and integrative analysis of plant multi-omics data remains a major challenge. Conventional solutions rely on constructing web-based databases, which often demand substantial programming expertise and long-term financial support. To address these limitations, we developed the Plant Multi-omics Database Construction System (PlantMDCS)-a locally deployable, user-friendly, and collaborative platform that unifies database construction and downstream multi-omics analysis within a graphical environment. PlantMDCS adopts a decoupled front-end/back-end architecture. The back end serves as the core engine for data management and computation, and is responsible for the storage, preprocessing, integration, and hierarchical association of multi-omics data. Once initialized, the front end supports the complete research workflow, including data import, querying, integrative analysis and visualization. All operations can be performed without programming, while local resource usage is dominated by disk storage required for user-provided datasets rather than sustained computational overhead. Benchmarking across plant species ranging from Arabidopsis to hexaploid wheat demonstrated that database construction can be completed within minutes, independent of genome size or data complexity. PlantMDCS is designed for local deployment to ensure data security, while allowing multi-user collaboration within local networks and supporting controlled remote access for teams distributed across different regions. Overall, PlantMDCS offers a secure and sustainable framework that integrates data management and analysis within a unified system. This design shifts multi-omics research away from fragmented file-based processing toward persistent, database-driven exploration, thereby enhancing analytical efficiency and reproducibility.

bioinformatics↗

bioRxiv2026

An immune-poised state of human bronchial epithelial cells mediates RSV resistance in adults

Respiratory syncytial virus (RSV) impairs STAT3 activation in infected ciliated cells in infants, but not adults, causing apoptosis to facilitate virus spread. How age regulates the STAT3 response to RSV in human bronchial epithelial cells (BEpiCs) is unknown. Here, we identify an age-associated immune-poised physiological state in human bronchial basal stem cells (BSCs) and progeny BEpiCs, rendering robust RIG-I to guard against the inactivation of RIG-I-STAT3 signaling by RSV nonstructural protein 2. In contrast, infant BEpiCs are vulnerable to such inactivation by RSV due to lower RIG-I levels. We show that acute respiratory viral infection in specific pathogen-free mice, rather than physical age, triggered sustained epigenetic and transcriptomic remodeling in BEpiCs that resembled age-associated changes in human BEpiCs. In addition, cytokine pretreatment of human neonatal BSCs induced an adult-like immune-poised state that was maintained in progeny BEpiCs to protect against RSV. Therefore, respiratory infection and inflammation during a lifetime imparts the effect of age to BSCs, which fortifies RIG-I in progeny cells to mediate RSV resistance.

microbiology↗

bioRxiv2026

Multiomics reveals epigenetic control of fibroblast activity after myocardial infarction and a key role for RUNX transcription factors

BackgroundAfter myocardial infarction (MI), cardiac fibroblasts proliferate and undergo a sequential differentiation process. They first transition into cardiac myofibroblasts, a transient and highly contractile state, and ultimately into matrifibrocytes, a more stable state that partially resembles chondrocytes. These dynamic transitions are essential for infarct healing and scar formation. While insufficient fibroblast activation can compromise infarct integrity, excessive activation promotes pathological fibrosis that impairs cardiac function. Despite its clinical importance, the transcriptional and epigenetic regulation of these transitions remain poorly understood. Elucidating underlying mechanisms is critical for developing strategies to fine-tune fibroblast activity during cardiac repair. MethodsWe performed bulk RNAseq, ATACseq, CUT&Tag, CUT&RUN, EMseq, and Hi-C on cardiac fibroblasts from uninjured and post-MI mouse hearts. In parallel, we conducted single-nucleus multiomic (snRNAseq and snATACseq) profiling across multiple time points after MI. Subsequent integrated analysis explored epigenetic mechanisms regulating cardiac fibroblast gene expression and activity. Using an improved computational strategy, we constructed gene regulatory networks to identify key transcription factors and biological processes regulated by these transcription factors. To assess the role of Runx1 specifically, we used tamoxifen-inducible, fibroblast-specific Runx1 knockout mice to evaluate transcriptional, epigenetic, and functional outcomes with the same genomic tools and additional complementary assays. ResultsCardiac fibroblasts undergo extensive chromatin remodeling after MI, which is highly correlated with changes in transcriptomic profiles. In contrast, the role of DNA methylation is relatively minor. Gene regulatory network analysis identified Runx1 as a central regulator of cardiac fibroblast proliferation and matrifibrocyte differentiation. In vitro and in vivo validation confirmed Runx1 as a key modulator of transcriptional and epigenetic changes in cardiac fibroblasts. Runx1 KO reduced cardiac fibroblast proliferation, disrupted the myofibroblast-to-matrifibrocyte transition, and affected macrophage cytokine expression through altered cardiac fibroblast-macrophage communication. Fibroblast-specific Runx1 knockout mice showed improved post-MI survival and reduced cardiac dilatation, especially in males. Simultaneous Runx2 deletion further enhanced the effects of Runx1 knockout. ConclusionsCardiac fibroblast activation and differentiation after MI are regulated by dynamic epigenetic changes. Runx1 plays a pivotal role in modulating cardiac fibroblast activities, and its deletion improves cardiac repair by mitigating maladaptive fibroblast responses. By illuminating the centrality of Runx1 in post-MI repair, this study identifies an actionable pathway for therapeutically steering fibroblast responses.

genomics↗

bioRxiv2026

Dopamine Accumulation Dynamics Control Time Perception

Accurate timing is fundamental to perception and behavior, and the dopaminergic system plays a key role. According to the dopamine clock hypothesis, elevated dopamine accelerates the interval clock, while reduced levels slow it. However, optogenetic activation of substantia nigra pars compacta (SNc) dopaminergic neurons paradoxically disrupts this model, suggesting greater complexity. To resolve this paradox, we monitored ventral tegmental area (VTA) dopamine activity in mice performing a time perception task. We observed a ramping-to-threshold pattern, where slower ramping corresponded to longer durations. Optogenetic activation accelerated time estimation, whereas inhibition prolonged it. Systemic dopamine elevation had no effect, but reuptake inhibition accelerated timing. Strikingly, prolonged high dopamine levels slowed time estimation, correlating with slower accumulation due to increased reuptake. Our findings challenge the dopamine clock hypothesis, demonstrating that time perception depends not on absolute dopamine levels but on their temporal accumulation dynamics. This revised framework reconciles previous contradictions and highlights the role of dopamine accumulation rates in temporal cognition.

neuroscience↗

bioRxiv2026

Genomic and pan-genomic insight into longan domestication and improvement

Longan (Dimocarpus longan) is a tropical tree in Sapindaceae family with economic importance known for its nutritous fruits. Genetic improvement of longan requires knowledge of reliable molecular markers and functional genes associated with key traits. However, it is largely impeded by lacking a complete genome and pangenome reference encompassing the broad genetic diversity in diverse longan germplasms. Here, we present a telomere-to-telomere (T2T) gap-free genome of longan cultivar Shixia and a graph-based pangenome constructed using newly assembled chromosome-level genomes of 101 accessions. We completely assemble the longan centromere regions primarily composed of Gypsy-CRM retrotransposons. The pan-genome analysis reveals 58,978 non-redundant structural variants (SVs) that exhibit signs of genomic selective sweep during longan domestication and breeding. Additionally, haplotype-resolved genome analysis suggests allele-specific gene expression associated with SV-driven changes in 3D genome architecture. Importantly, the graph-based pan-genome empowers population-scale SV genotyping and genomewide association with various longan traits. SV-GWAS revealed 12 QTLs significantly linked with longan maturity period. Among them, a 758bp insertion is located downstream of the DlDAZ gene encoding a C2H2 zinc-finger transcription factor, and DIDAZ-transgenic tomatoes showed delayed maturity. Together, our T2T genome and pan-genome provide valuable resources to facilitate longan genetic research and precise improvement.

genomics↗

bioRxiv2025

Primordial cardiomyocytes orchestrate myocardial morphogenesis and vascularization but are dispensable for regeneration

The vertebrate heart is composed of heterogeneous cardiomyocyte (CM) populations, however, the roles of distinct CM subpopulations in heart development and repair remain poorly defined. Here, using single-cell RNA sequencing analysis of adult zebrafish heart, we identified a unique CM subpopulation marked by the expression of phlda2, which is associated with anaerobic metabolism and different from mature CMs which are enriched for oxidative phosphorylation genes. We demonstrated that phlda2+ cells constituted a primordial CM compartment localized between compact and trabecular muscles. Genetic ablation of phlda2+ CMs during development severely disrupted heart morphogenesis, leading to defective myocardial trabeculation and compaction, and impaired coronary vascularization. Surprisingly, despite their essential roles in development, the depletion of phlda2+ CMs didnt impair myocardial restoration and revascularization following ventricular resection. We found that this was probably due to the limited regenerative capacity of the primordial CMs themselves, as they failed to regenerate after either surgical amputation or genetic ablation. Our findings identify primordial CMs as an organizer for heart morphogenesis but not essential for regeneration, revealing a fundamental difference between developmental and regenerative programs in the vertebrate heart.

developmental biology↗

bioRxiv2025

A cell membrane-hybridized nanocarrier-based RNA delivery system for ocular neovascular diseases

Ocular neovascularization is a common pathological feature of various blinding eye diseases. Current anti vascular endothelial growth factor (VEGF) therapies face challenges such as low response rates, frequent injections, and multiple complications. RNA-based therapeutics offer advantages including strong targeting capability and reversible modulation, but encounter obstacles like low delivery efficiency, susceptibility to degradation, and lack of targeting specificity. This study developed an endothelial cell membrane-hybridized lipid nanoparticle that achieve specific targeting of neovascular endothelial cells through "homing effects". The carrier exhibits excellent biocompatibility, high small interfering RNA (siRNA) delivery efficiency, and lysosomal escape capability, effectively penetrating the vitreous barrier. In a laser-induced choroidal neovascularization mouse model, it significantly enhanced drug accumulation at the lesion site, providing a safe and effective delivery strategy for RNA therapy of ocular neovascular diseases.

bioengineering↗

bioRxiv2025

Temporal single-cell profiling uncovers age-associated delays in immune resolution to respiratory viral infection

Aging is a major risk factor for increased morbidity and mortality following acute respiratory virus infections. To elucidate the immune determinants underlying viral pathogenesis and delayed lung repair in the aged lung, a comprehensive time-course study was conducted. Single-cell RNA sequencing (scRNAseq) and high-dimensional flow cytometry were utilized to compare lungs from young and aged mice infected with influenza A virus (IAV). Aged hosts displayed diminished alveolar macrophage (AM) and dendritic cell (DC) but elevated monocyte-derived macrophage (MoM) and interstitial macrophage (IM) presence following infection. Additionally, enhanced accumulation of adaptive immune cells, including CD4+ tissue-resident helper (TRH) cells, CD8+ tissue-resident memory (TRM) cells, and a B cell subset resembling age-associated B cells, was observed in the memory phase. Pathway analysis revealed that elevated type I and II interferon (IFN/{gamma}) signaling, especially in MoM/IM subsets, distinguished the aged hosts from the young. Inhibition of IFN/{gamma} signaling after viral clearance improved long-term respiratory outcomes and reduced both IM and TRH populations in aged mice. These findings highlight the pivotal role of IFN/{gamma} signaling, likely within MoM/IM subsets, in driving the exuberant persistence of adaptive immune cells and chronic immunopathology in the aged lung following acute viral infection.

immunology↗

bioRxiv2025

Structural Basis of Asymmetric Class C GPCR activation and distinct Gq coupling induced by force stimulation

Mechanosensation is essential for diverse physiological processes. While many G protein-coupled receptors (GPCRs) are known to be mechanosensitive, the underlying mechanism remains largely unknown. Here, we reveal that mechanical force induces Gq activation of mGlu2, a balance modulator residing in kinocilia, but not other 7 mGlu members. Force activates mGlu2 through a conserved N-terminal force transduction motif (FTM) via a unique cis mechanism. We engineered a potent FTM-derived peptide agonist that recapitulates force-induced activation and resolved cryo-EM structures of apo-mGlu2, FTM-mGlu2, LFTM-{Psi}EK-mGlu2 and LFTM-{Psi}EK-mGlu2-Gq. The structures reveal that an atypical FTM binding to a previously uncharacterized pocket induces asymmetric 7TM domain rearrangement, enabling Gq coupling via an ICL1-TM3/6/7 interface, fundamentally distinct from the glutamate-induced Gi coupling mode of mGlu2. Compared with Gi-coupled mGlu2, the 5 helix of Gq rotated by 180{degrees}, penetrating deeper (8 [A]) into a hydrophobic pocket. Disruption of the M7947.32-F7806.57-F7766.53 hydrophobic triad core and a conformational propagation path predominantly comprising TM6-7 residues are identified as key elements mediating force induced mGlu2 activation. Further In vivo rescue experiments support that mGlu2s mechanosensitivity is dependent on FTM and is required for vestibular function. This work establishes a paradigm for class C GPCR mechanotransduction, revealing unprecedented structural mechanisms underlying force-induced Gq coupling and offering a chemical toolset to modulate mechanical signaling of GPCR.

cell biology↗

bioRxiv2025

A Mechanosensitive GPCR at vestibular kinocilium is required for normal balance

Intracellular calcium increase and neurotransmitter release in vestibular hair cells (VHCs) play central roles in equilibrioception, which is one of the basic senses essential for daily life activities and movement in mammals. Independent of mechano-electrical transduction (MET), whether Gq protein-coupled receptor (GqPCR) signaling participate in the regulation of intracellular calcium dynamics and induce neuronal transmitter release in hair cells remains unknown. We screened mechanosensitive GqPCRs in VHCs and found that a Class C GPCR, metabotropic glutamate receptor 2 (mGlu2), is expressed in kinocilia and is essential for normal balance. Notably, the dispensable role of mGlu2 in normal hearing is consistent with absent of mature kinocilia in cochlea hair cells. Different from the conventional mGlu2-Gi signaling, the sensing of mechanical signals by mGlu2 activates the Gq-PLCD4 pathway, increases intracellular calcium concentration and promotes neurotransmitter release in VHCs. Hair cell-specific deficiency of either Grm2 or Gnaq, or knockdown of Plcd4 expression, but not deficiency of another GqPCR Gpr68, causes significant balance deficits. Reintroduction of mGlu2 into the VHCs of Pou4f3-CreER+/- Grm2fl/fl mice restore vestibular functions. Our study reveals a previously uncharacterized role of GPCR signaling in equilibrioception and provides important insight into kinocilia signaling in VHCs, which are absent in mature cochlear hair cells.

cell biology↗

bioRxiv2025

Rapamycin Differentially Impacts Germline Stem Cell Quiescence Across Diverse Genetic Backgrounds of Drosophila Melanogaster

In response to ionizing radiation, stem cells enter a state of temporary quiescence, safeguarding the stem cell pool for tissue regeneration. Quiescence requires the inhibition of mTORC1, a kinase complex that promotes growth and suppresses autophagy, and cell cycle re-entry requires the reactivation of mTORC1. The pharmacological inhibition of mTORC1 in quiescent stem cells by rapamycin prevents cell cycle re-entry and subsequent tissue regeneration. It is well established that pharmacological responses can vary across genetic backgrounds, however, the extent to which genetic variation can impact the quiescence response to rapamycin is unclear. Here, we tested the sensitivity of stem cell quiescence to rapamycin in different genetic backgrounds within the Drosophila Genetic Reference Panel. These analyses revealed substantial variation across different genetic backgrounds, indicating that genetic variation can modulate drug-induced effects on stem cell dynamics. Our analyses suggest that mitophagy, rather than DNA damage response, is associated with the persistence of quiescence and delayed tissue regeneration by rapamycin. This work underscores the critical role of genetic background in determining drug efficacy, highlighting important implications for the therapeutic application of rapamycin.

developmental biology↗

bioRxiv2025

Robust brain complexity measurement using T2* informed multivariate sample entropy from multi-echo BOLD fMRI

Sample entropy is a useful tool to analyze resting-state fMRI data and evaluate the complexity of neural activity. However, sample entropy computed from conventional BOLD signals is not highly resistant to artifacts. In contrast, T2* may be more sensitive to certain neural-related changes, and directly incorporating T2* information enables the detection of features that are often lost in BOLD-only sample entropy due to noise influences. To further improve the robustness and reliability of complexity estimation, we introduce a multivariate sample entropy approach that incorporates T2* signals derived from multi-echo BOLD signal. We applied this method to compare a cohort of 23 elder adults and 12 younger adults, and observed significant group differences in several brain regions. Notably, the proposed method yielded more pronounced group differences than conventional sample entropy computed without T2* information. Moreover, in regions with reduced neural activity due to ischemia, as well as in ventricular areas, our approach demonstrated superior performance. These results indicate that the proposed method enhances the ability to characterize the complexity of neural activity.

biophysics↗

bioRxiv2025

Representation, Alignment, and Generation: A Comprehensive Survey of Foundation Models for Non-Invasive Brain Decoding

The ability to decode human thoughts, intentions, and perceptions directly from non-invasive brain recordings holds transformative potential for healthcare, communication, and human-computer interaction. However, translating the safety and scalability of methods like Functional Magnetic Resonance Imaging (fMRI), Electroencephalography (EEG), and Magnetoencephalography (MEG) into real-world utility has traditionally been hindered by low signal-to-noise ratios, limited spatial-temporal resolution, and the difficulty to collect large-scale high-quality data from an individual user. Recently, the emergence of Foundation Models (FMs)--large-scale, pre-trained architectures--has expanded the feasible operating region of non-invasive brain decoding under controlled protocols, primarily through representation learning, neuro-semantic alignment, and strong generative priors. However, evidence for robust cross-subject and real-world deployment remains uneven, as many results are still demonstrated on limited cohorts or highly controlled settings. This survey provides a comprehensive overview of how FMs are redefining the boundaries of non-invasive brain decoding. We propose a unified methodological framework that synthesizes recent advancements into a coherent process: extracting robust, transferable representations from noisy neural signals; aligning these signals with the rich semantic spaces of pre-trained vision and language models; and leveraging powerful conditional generative priors to reconstruct high-fidelity outputs. We systematically review state-of-the-art applications across three key domains: visual reconstruction, language and speech decoding, and auditory processing. Furthermore, we critically examine the persisting challenges of computational efficiency, cross-subject generalization, and privacy governance. By mapping the current landscape and identifying key gaps, this work outlines a strategic research agenda aimed at transitioning FM-driven neurotechnology from laboratory proofs-of-concept to reliable, real-world applications.

neuroscience↗

bioRxiv2025

scMOBA: A conversational single-cell Multi-Omics Brain Agent across species

Single-cell and spatial multi-omics are revolutionizing our understanding of the complexity in the developmental, aging, and diseased brain, but integrating this knowledge across modalities and species remains challenging. To bridge this gap, we propose scMOBA, a conversational single-cell Multi-Omics Brain Agent established by a large language model, a gene encoder, and a cross-attention projector. The scMOBA was pre-trained on 130 million single-cell and spatial multi-omics data spanning the entire brain across diverse species, development, aging and diseases. The pre-training utilized a novel multi-omics Feature-Question-Answer (FQA) paradigm, enabling the model to generate biological answers from feature inputs and textual queries. This unique scheme facilitates superior zero-shot inference capabilities without requiring additional fine-tuning. We demonstrate that scMOBA achieves state-of-the-art performance in fine-grained cell type classification across different species and modalities, as well as in batch correction and multi-omics data integration. Furthermore, scMOBA significantly boosts the accuracy of kinds of critical downstream tasks, including cell-type specific aging clock construction and disease status prediction. Overall, scMOBA serves as a powerful scientific discovery engine for multi-omics brain research, advancing the precision prediction and early intervention of neurological aging and diseases.

bioinformatics↗

bioRxiv2025

Disrupted tRNA modification leads to intestinal mitochondrial dysfunction and microbial dysbiosis

Background and aimsTransfer RNA (tRNA) modifications determine translation fidelity and efficiency. It occurs through the action of specific enzymes that modify the nucleotides within the tRNA molecule. Our previous study demonstrated tRNA modopathies and altered queuine-related metabolites in inflammatory bowel diseases. Queuine tRNA-ribosyltransferase catalytic subunit 1 (QTRT1) and QTRT 2 co-localize in mitochondria and form a heterodimeric TGT participating in tRNA Queuosine (tRNA-Q) modification. Human body acquires Queuine/Vitamin Q from intestinal microbiota or from diet. However, the roles of tRNA-Q modifications in the maintenance of intestinal mitochondrial homeostasis and microbiome are still unclear. MethodsWe used publicly available human IBD datasets, QTRT1 knockout (KO) mice, QTRT1 intestinal epithelial conditional KO (QTRT1{Delta}IEC) mice, cultured cell lines with QTRT1-specific siRNA, and organoids from patients with IBD to investigate the mechanism of tRNA-Q modifications in intestinal mitochondrial homeostasis and therapeutic potential in anti-inflammation. ResultsIn single cell RNA sequencing datasets of human IBD, we identified significant reduced intestinal epithelial QTRT1 expression in the patients with Crohns Disease. Using publicly available datasets, we identified significantly changes of Vitamin Q-associated bacteria in human IBD, compared to the healthy control. Qtrt1-/- mice had significant reduction of Q-associated bacteria, e.g., Bacteroides. Alcian Blue and Mucin-2 staining revealed mucosal barrier damage and disrupted homeostasis, with reduced colonic cell proliferation. Intestinal tight junction integrity was impaired in QTRT1-KO mice, as evidenced by reduced ZO-1 and increased Claudin-10 expression. QTRT1{Delta}IEC mice also showed dysbiosis and disrupted TJs. ATP synthesis was significantly decreased in the colon of QTRT1-KO mice, accompanied by severe mitochondrial dysfunction: reduced mitochondrial quality, Cytochrome-C release, and mitochondrial DNA (mtDNA) leakage. Mitochondrial dysfunction contributed to colonic cell death, as shown by elevated expressions of Cleaved Caspase-3 and Cleaved Caspase-1, increased BAX/Bcl-2 ratio, and positive TUNEL signals. Elevated CDC42, CD14, and CD4 levels in QTRT1-KO colon suggested mucosal immune activation and tissue repair responses. QTRT1-deficient CaCO2-BBE cells showed mitochondrial dysfunction. Cytochrome-C and mito-DNA release leading to cell death characterized by elevated expressions of Cleaved Caspase-3 and Caspase-1, increased BAX/Bcl-2 ratio, and higher apoptosis rate. Organoids isolated from patients with IBD showed reduced levels of QTRT1 and dysfunctional mitochondria. Restoring mitochondrial function leads to enhanced QTRT1. ConclusionsThese findings underscore the critical role of QTRT1/Q-tRNA modification in maintaining intestinal and microbial homeostasis. Mechanistically, QTRT1 loss impacts mitochondrial integrity and mucosal homeostasis. Our study highlights the novel roles of tRNA-Q modification in maintaining mucosal barriers and innate immunity in intestinal health. What is already known about this subject?O_LIEukaryotes acquire queuine (q), also known as Vitamin Q, as a micronutrient factor from intestinal microbiota or from diet. C_LIO_LIVitamin Q is needed for queuosine (Q) modification of tRNAs for the protein translation rate and fidelity. C_LIO_LIQueuine tRNA-ribosyltransferase catalytic subunit 1 (QTRT1) is reduced in human IBD. C_LIO_LIHowever, health consequences of disturbed availability of queuine and altered Q-tRNA modification in digestive diseases remain to be investigated. C_LI What are the new findings?O_LIQTRT1 deficiency leads to altered microbiome and reduced Vitamin Q-associated bacteria in human IBD and a QTRT1 KO animal model. C_LIO_LIQTRT1 protects the host against losing intestinal integrity during inflammation. C_LIO_LIQTRT1 localizes in mitochondria and plays novel functions by maintaining intestinal mitochondrial function. QTRT1 loss impacts tRNA modification in the intestine, linking to mitochondrial integrity and mucosal homeostasis. C_LIO_LIHuman IBD showed reduced levels of QTRT1 and dysfunctional mitochondria. Restoring mitochondrial function leads to enhanced QTRT1. C_LI How might it impact on clinical practice in the foreseeable future?Targeting tRNA-Q modification in enhancing mitochondrial function will be a novel method to maintain intestinal health.

cell biology↗