Biology subjects

Luo, Y.

Publications and source records attributed to Luo, Y..

At least 109 records · Page 6Linked to original sources

bioRxiv2025

DrugPT: A Flexible Framework for Integrating Gene and Chemical Representations in Perturbation Modeling

Accurately modeling the transcriptional response of cells to drug perturbations is critical for drug discovery and precision medicine. Here, we propose DrugPT, a novel Transformer-based framework for predicting gene expression changes upon drug treatment. DrugPT consists of three modular components: (1) a gene representation module that encodes pre-treatment expression profiles using GPT-derived embeddings; (2) a drug representation module that captures chemical structure information using a pre-trained GPT2 model; and (3) a Transformer-based prediction module that integrates gene and drug embeddings to predict perturbed gene expression profiles. Unlike previous approaches, DrugPT formulates the prediction task as a sequence modeling problem, leveraging pre-trained language models for both gene and drug modalities. We demonstrate the architecture of DrugPT and highlight its generalizable design for encoding heterogeneous biological and chemical information. This work introduces a unified modeling framework, laying the foundation for future developments in multimodal perturbation prediction tasks.

bioinformatics↗

bioRxiv2025

Prediction of bacterial protein-compound interactions with only positive samples

Prediction of Compound-Protein Interactions (CPI) in bacteria is crucial to advance various pharmaceutical and chemical engineering fields, including bio-catalysis, drug discovery, and industrial processing. However, current CPI models cannot be applied for bacterial CPI prediction due to the lack of curated negative interaction samples. This paper introduces a novel Positive-Unlabeled (PU) learning framework, named BIN-PU, to address this limitation. BIN-PU generates pseudo positive and negative labels from known positive interaction data, enabling effective training of deep learning models for CPI prediction. We also propose a weighted positive loss function that weights to truly positive samples. We have validated BIN-PU with multiple CPI backbone models, comparing the performance with the existing PU model using bacterial cytochrome P450 (CYP) data. Extensive experiments demonstrate the superiority of BIN-PU over the benchmark model in predicting CPIs with only truly positive samples. Furthermore, we have validated BIN-PU on additional bacterial proteins obtained from literature review, human CYP datasets, and uncurated data for its reproducibility. We have also validated the CPI prediction for the uncurated CYP data with biological and biophysical experiments. BIN-PU represents a significant advancement in CPI prediction for bacterial proteins, opening new possibilities for improving predictive models in related biological interaction tasks.

bioinformatics↗

bioRxiv2025

mRNA 3'UTRs chaperone intrinsically disordered regions to control protein activity

Nearly 3,000 human mRNA 3'UTRs have hundreds of highly conserved nucleotides, but their biological roles are unclear. These mRNAs mostly encode proteins with long intrinsically disordered regions (IDRs), including MYC, UTX, and JMJD3. We show that these proteins are only fully active when translated from mRNA templates that include their 3'UTRs, raising the possibility of functional interactions between 3'UTRs and IDRs. Rather than affecting protein abundance or localization, we find that the KDM6B 3'UTR in the mRNA template changes the folding of the encoded IDR-containing JMJD3 protein. It promotes IDR-IDR interactions and suppresses folding between domains, suggesting that RNA acts as IDR chaperone that prevents interference of hydrophobic clusters in the IDR with folding of the structured domain. mRNA-based IDR chaperones are enriched in meshlike cytoplasmic condensates, suggesting localized chaperone activity. As hydrophobic clusters in IDRs are widespread, our data suggest that 3'UTR-dependent protein folding could be a widely used mechanism for activity regulation of transcriptional regulators.

molecular biology↗

bioRxiv2025

Biomechanical simplification of the motor control of whisking

1.Animal nervous systems must coordinate the sequence and timing of numerous muscles - a challenging control problem. The challenge is particularly acute for highly mobile sensing structures with many degrees of freedom, such as eyes, pinnae, hands, forepaws, and whiskers, because these low-mass, distal sensors require complex muscle coordination. This work examines how the geometry of the rat whisker array simplifies coordination required for "whisking" behavior 1-3. During whisking, 33 intrinsic ("sling") muscles are the primary drivers 4-12 of the rapid, rhythmic protractions of the large mystacial vibrissae (whiskers), which vary more than sixfold in length and threefold in base diameter 13-16. Although whisking is a rhythmic, centrally-patterned behavior 17-24, rodents can change the position, shape, and size of the whisker array, indicating considerable voluntary control 25-34. To begin quantifying how the arrays biomechanics contribute to whisking movements, we used three-dimensional anatomical reconstructions of follicle and sling muscle geometry to simulate the movement resulting from a "uniform motor command," defined as equal firing rates across all sling muscle motor neurons. This simulation provides a baseline profile of protraction under anatomically realistic but uniformly driven conditions. It does not isolate neural from biomechanical contributions but helps identify deviations that suggest active control. Simulations reveal that all follicles rotate through approximately equal angles, regardless of size. The angular fanning of the whiskers at their bases increases monotonically throughout protraction, while maximum distance between whisker tips occurs at approximately 90% of resting muscle length, after which whisker tips converge and sensing resolution increases monotonically.

neuroscience↗

bioRxiv2025

Human myelocyte and metamyelocyte-stage neutrophils suppress tumor immunity and promote cancer progression

Tumor-infiltrating neutrophils (TINs) are highly heterogeneous and mostly immunosuppressive in the tumor immune microenvironment (TIME). Current biomarkers of TINs and treatment strategies targeting TINs have not yielded optimal responses in patients across cancer types. Here, we separated human and mouse neutrophils into three developmental stages, including promyelocyte (PM), myelocyte & metamyelocyte (MC & MM), and banded & segmented (BD & SC) neutrophils. Based on this separation, we observed the predominance of human but not mouse MC & MM-stage neutrophils in bone marrow (BM), which exhibit potent immunosuppressive and tumor-promoting properties. MCs & MMs also occupy the majority of TINs among patients with 17 cancer types. Moreover, through the creation of a NCG-Gfi1-/- human immune system (HIS) mouse model, which supports efficient reconstitution of human TIN, we found a significant increase of BM MCs & MMs in tumor-bearing mice. By comparing the scRNA-seq analysis results of human neutrophils from both BM and tumors, we found CD63 and Galectin-3 distinguish MC & MM from neutrophil populations in cancer patients. Furthermore, we proposed a strategy with Flt3L to specifically induce the trans-differentiation of MCs & MMs into monocytic cells, and trigger tumor control in NCG-Gfi1-/- HIS mice. Thus, our findings establish an essential role of human MC & MM-stage neutrophils in promoting cancer progression, and suggest their potential as targets for developing potential biomarkers and immunotherapies for cancer.

immunology↗

bioRxiv2025

Spleen-derived Small Extracellular Vesicles Protect against Myocardial Infarction via Mediating Spleen-heart Crosstalk

Background and AimsAcute myocardial infarction (AMI) triggers systemic responses that influence cardiac injury and repair, but protective mediators within the cardiosplenic axis remain incompletely understood. This study aimed to investigate whether spleen-derived small extracellular vesicles (sEVs) exert cardioprotection after AMI, identify critical cargo, and evaluate their clinical relevance. MethodsThe effects of splenectomy, spleen-derived sEVs and pharmacological inhibition of sEVs biogenesis on cardiac injury were evaluated in mice with AMI. Parabiosis, donor splenectomy, and fluorescent labelling traced the origin and myocardial recruitment of circulating sEVs. 4D-proteomics profiled sEVs cargo with a focus on pyruvate carrier-1 (MPC1). ResultsSplenectomy worsened survival, ventricular function, infarct size, and fibrosis in mice with AMI. AMI upregulated splenic extracellular-vesicle pathways, with sEVs release peaking at day 3 (M3D-sEVs). Labelled splenic sEVs preferentially accumulated in ischemic myocardium, confirmed by parabiosis experiments. M3D-sEVs improved survival and cardiac function and reduced infarct size, fibrosis, apoptosis, inflammation, and hypertrophy. In addition, anti-apoptotic effects were reproduced in vitro. Inhibition of sEVs biogenesis decreased circulating sEVs, aggravated injury, and was rescued by M3D-sEVs. M3D-sEVs were enriched in MPC1, and MPC1 neutralization or pharmacological blockade abrogated sEVs-mediated restoration of respiration, ATP generation, and reduction of reactive oxygen species. Plasma sEVs-associated MPC1 was highest in patients with AMI, intermediate in coronary heart disease, and lowest in controls. ConclusionsThe spleen responds adaptively to AMI by releasing MPC1lenriched sEVs that travel to injured myocardium, preserve mitochondrial energetics, and reduce damage, supporting cargolspecific sEVs augmentation and sEVslMPC1 as a potential therapeutic target and biomarker in ischemic heart disease. Structured graphical abstractAcute myocardial infarction activates a spleen-heart axis in which the spleen releases mitochondrial pyruvate carrier 1 (MPC1) enriched small extracellular vesicles that home to the infarcted myocardium, preserve mitochondrial oxidative phosphorylation, reduce ROS, and limit infarct size, apoptosis, fibrosis, and hypertrophy. Circulating sEVs-associated MPC1 might serve as a potential biomarker for estimating risk of ischemic heart disease. Translational perspectiveO_LIOur findings reveal a novel heart-spleen communication axis mediated by splenic small extracellular vesicles (sEVs) following AMI. These vesicular messengers predominantly deliver mitochondrial pyruvate carrier 1 (MPC1), enhancing cardiac mitochondrial energy metabolism in the injured myocardium, ultimately improving post-AMI functional recovery in experimental models. C_LIO_LIA higher plasma sEVs-associated MPC1 level was observed in AMI patients when compared with non-AMI patients. These findings support the clinical relevance of the spleen-heart axis, introduce sEVs-associated MPC1 as a potential circulating biomarker for early myocardial injury and therapeutic target. C_LI

molecular biology↗

bioRxiv2025

Adaptive suppression of threat-history stimuli

Previous studies have found evidence of adaptive suppression mechanisms for physically salient stimuli. However, it remains unclear whether a similar mechanism exists for threat-history stimuli. This study used a threat conditioning task to generate stimuli with and without a history of threat. In the subsequent visual search task, the spatial probability of distractors was manipulated to examine the influence of threat-history stimuli on distractor suppression. The results showed that distractors appearing at high-probability locations were effectively suppressed, and suppression was stronger for threat-history distractors than for no-threat-history distractors. These findings suggest that threat-history distractors are more effectively suppressed when they appear at a predictable location through an adaptive attentional suppression mechanism. Data availabilityAll data supporting the findings are openly available via the Science Data Bank (https://www.scidb.cn/anonymous/VlpqNm55).

neuroscience↗

bioRxiv2025

Biocompatible Multi-functional Polymeric Material for Mineralized Tissue Adhesion

This study developed a biocompatible multifunctional thiol-ene resin system for adhesion to dentin mineralized tissue. Adhesive resins maintain the strength and longevity of dental composite restorations through chemophysical bonding to exposed dentin surfaces after cavity preparations. Dental pulp cells are exposed to residual monomers transported through dentinal tubules. Monomers of conventional adhesive systems may result in inhomogeneous polymer networks and the release of residual monomers that cause cytotoxicity. In this study, we develop a one-step multi-functional polymeric resin system by incorporating trimethylolpropane triacrylate (TMPTA) and bis[2-(methacryloyloxy)ethyl] phosphate (BMEP) to enhance both mechanical properties and adhesion to dentin. Molecular dynamics simulations identified an optimal triacylate:trithiol ratio of 2.5:1, which was consistent with rheological and mechanical tests that yielded a storage modulus of ~30 MPa with or without BMEP. Shear bond tests demonstrated that the addition of BMEP significantly improved dentin adhesion, achieving a shear bond strength of 10.8 MPa, comparable to the commercial primer Clearfil SE Bond. Nanoindentation modulus mapping characterized the hybrid layer and mechanical gradient of the adhesive resin system. Further, the triacrylate-BMEP resin showed biocompatibility with fibroblasts in vitro. These findings suggest the triacrylate-trithiol crosslinking and chemophysical bonding of BMEP provide enhanced bond strength and biocompatibility for dental applications.

bioengineering↗

bioRxiv2025

F-53B damages cell viability leading to impaired root development in Arabidopsis

The emerging contaminant chlorinated polyfluoroalkyl ether sulfonate (Cl-PFAES/F-53B) has been detected in many plant species, however, the impact of F-53B on the development in plants and the underpinning mechanisms remain largely unelucidated. In this study, we demonstrate by molecular biology, cytogenetics, and fluorescence microscopy mythologies that F-53B impairs cell viability leading to disrupted root development in Arabidopsis (Arabidopsis thaliana). We show that F-53B suppresses root length and the inhibitory effect is pronunanced at increasing concentrations. F-53B disrupts cell wall and microtubule-mediated cell plate formation and configuration in meristem cells, revealing its toxicity to cell division and cytoskeleton organization. F-53B induces cell death predominantly at the meristematic zone, however, gene exression and genetic studies indicate that F-53B does not trigger DNA double-strand breaks, implying a divergent effect on DNA stability across species. Moreover, we show that F-53B damages nuclei stability and viability, and induces Autophagy-Related 8 protein foci formation implying that it triggers autophagy-mediated cell responses. Taken together, this study provides cellular and molecular insights into the toxicity of F-53B to plant cells, which highlights its damage to agriculture and ecology security that deserve imperative environmental management actions. Environmental ImplicationF-53B has been detected in many plant species, which raises increasing concerns on its toxicity to plants and thus agriculture and ecology safety. However, the toxicity of F-53B to development in plants and the underpinning mechanisms remain largely unelucidated. Here, we demonstrate that F-53B damages nuclei stability and viability leading to cell death and impaired root development in the model plant species Arabidopsis thaliana. Our study provides cytogenetic and molecular insights into the F-53B toxicity to plant cells, which highlights imperative environmental management actions and can be referenced for developing F-53B control and management policies. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=143 SRC="FIGDIR/small/653422v1_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@159b211org.highwire.dtl.DTLVardef@1b99a95org.highwire.dtl.DTLVardef@53b964org.highwire.dtl.DTLVardef@b089be_HPS_FORMAT_FIGEXP M_FIG C_FIG One-sentence summaryF-53B triggers DNA double-strand break-free cell unviability leading to impaired meristematic cell division and root development in plants. HIGHLIGHTSO_LIF-53B impairs root development in Arabidopsis. C_LIO_LIF-53B prohibits mitotic cell division at root tips. C_LIO_LIF-53B damages cell viability predominantly at the meristematic zone in seedlings. C_LIO_LIF-53B does not induce DNA double-strand breaks in Arabidopsis seedlings. C_LIO_LIF-53B damages nuclei viability and stability in seedlings. C_LI

developmental biology↗

bioRxiv2025

NUSAP1 regulates mitotic processes via KIF2C interaction and AURKA phosphorylation in primary microcephaly

Primary microcephaly (PM) is a neurodevelopmental disorder characterized by a significantly smaller head than normal. Despite the identification of several genes associated with PM subtypes, the etiology remains unclear in a significant proportion of patients. Here, we reported two de novo nonsense mutations in the NUSAP1 gene identified in two independent PM families: c.1209 C>G (p.Tyr403*) and c.1213C>T (p.Gln405*). Nusap1-edited mouse models, designed to mimic Human NUSAP1 mutations, replicated the microcephaly phenotype, characterized by a small brain and thinner cerebral cortex. We demonstrated that Nusap1 was specifically expressed in neural stem/progenitor cells (NSPCs), and the number of NSPCs was significantly reduced in Nusap1-edited mice. In vitro experiments revealed that NUSAP1 mutations disrupted mitotic metaphase chromosome alignment, increased polyploidy, induced cell cycle arrest, and promoted apoptosis. Co-IP confirmed direct interactions between NUSAP1 and KIF2C, and showed that truncating mutations impaired their binding. Furthermore, NUSAP1 rescued the cell cycle arrest and increased apoptosis caused by KIF2C overexpression in NUSAP1 KO HEK293T cells, whereas the mutant truncated protein failed to exert such a rescue effect. We also uncovered an interaction between NUSAP1 and Aurora kinase A (AURKA). Intriguingly, subsequent experiments revealed that AURKA-mediated phosphorylation of NUSAP1 modulates its binding affinity to KIF2C. In conclusion, our findings established NUSAP1 as a novel pathogenic gene for PM. We proposed a model in which AURKA-mediated phosphorylation of NUSAP1 regulates its interaction with KIF2C, balancing spindle microtubule stability and depolymerization to ensure proper sister chromatid segregation. Disruptions in this pathway impair NSPCs mitosis, thereby affecting neocortical development.

genetics↗

bioRxiv2025

MAX2-dependent signaling regulates the transition from 2D to 3D growth by suppressing cytokinin accumulation in Physcomitrium patens

Plants undergo distinct developmental phases throughout their life cycle. Proper regulation of the timing of phase transition in response to internal and external cues is crucial to optimize proliferation and reproduction. In Physcomitrium patens (P. patens), a moss, the transition from growth of filamentous tissue growth called protonema to gametophore bud formation represents a shift from two-dimensional (2D) to three-demensional (3D) growrh, ultimately leading to reproductive development. MORE AXILLARY GROWTH2 (MAX2), an F-box protein, targets repressor proteins in the KARRIKIN INSENSITIVE2 (KAI2)-dependent signaling pathway for degradation via the 26S proteasome-dependent pathway. KAI2 perceives an unidentified ligand known as KAI2 ligand (KL) as well as karrikins. The four SMAX1-LIKE (SMXL) family proteins work as suppressors in the MAX2-dependent signaling in P. patens. Gametophore bud formation was accelerated when MAX2-dependent signaling was disrupted, while it was delayed in Ppsmxls, loss of function mutants of the PpSMXLs. These results indicate that MAX2-dependent signaling suppresses gametophore bud formation in P. patens, which has not been previously described. We demonstrate that cytokinin activity and contents are increased in Ppmax2 mutants, and cytokinin application rescued the delay in bud formation in Ppsmxl mutants, suggesting that MAX2-dependent signaling suppresses cytokinin accumulation. The four SMXL genes redundantly act to promote gametophore bud formation; PpSMXLC and PpSMXLD, which contain the conserved degron sequence, act as the repressor of MAX2-dependent signaling, while PpSMXLA and PpSMXLB function independent of proteolysis-dependent signaling. Based on these findings, we propose that modulating cytokinin activity to control developmental phase transition may be a conserved role of MAX2-dependent signaling in bryophytes. Significance StatementPlant hormones, both individually and in combination, regulate almost all aspects of plant growth and development. Gametophore bud formation in Physcomitrium patens, a moss, marks the transition from two-dimensional (2D) filamentous growth to three-dimensional (3D) shoot growth. We demonstrate that gametophore bud formation is controlled by the sequential action of two plant hormones, KL, an unidentified hormone that is transduced through MAX2-dependent signaling, and cytokinin. Four SMXL genes, repressors in MAX2-dependent signaling, redundantly promote bud formation: two function within the signaling pathway, while the other two operate independently of it. Our findings uncover novel mechanisms that directly link MAX2-dependent signaling to developmental phase transition by regulating stem cell activity, achieved through the regulation of cytokinin accumulation in Physcomitrium patens.

plant biology↗

bioRxiv2025

The HORMA-domain protein ASY1 recruits the plant-specific cyclin SDS to promote DMC1-mediated meiotic recombination

The chromosome axis is a proteinaceous scaffold essential for crossover formation in meiosis. While the axis associated HORMA-domain protein ASY1 is known to be necessary for the localization of the recombinase DMC1 to the axis, the molecular mechanism linking ASY1 to DMC1 loading remains unclear. Here, we demonstrate that ASY1 directly recruits the plant-specific cyclin SDS to chromosomes, which ensures efficient DMC1 localization and interhomolog recombination. Live-cell imaging and immunodetection revealed that SDS localizes to chromosomes from leptotene to zygotene and dissociates from chromosomes after pachytene resembling DMC1 dynamics. Biochemical assays demonstrated a direct interaction between ASY1 and SDS. Further analyses revealed that ASY1s closure motif, a conformational regulatory element, is required for SDS recruitment despite being dispensable for ASY1s own chromosome association. Moreover, unlike in sds mutants, depletion of the DMC1 inhibitor FIGL1-FLIP complex failed to restore DMC1 foci in asy1 mutants, positioning ASY1 upstream of both positive (SDS) and negative (FIGL1-FLIP) regulators of DMC1. These findings establish ASY1 as a key coordinator of meiotic recombination, bridging chromosome axis architecture with recombinase dynamics to control crossover formation and genome stability.

plant biology↗

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

Endothelial AGO1 Drives Vascular Inflammation and Atherosclerosis via a Non-Canonical Nuclear Mechanism

BACKGROUNDEndothelial cell (EC) dysfunction is a cause and consequence of vascular inflammation and lipid dysregulation in atherosclerosis, yet the molecular drivers linking EC dysfunction to systemic metabolic derangements remain incompletely understood. Moreover, whether inhibiting an endogenous gene in ECs can impact liver function, lipid profile, and the vascular inflammation in the context of atherosclerosis has not been demonstrated. We previously identified Argonaute 1 (AGO1), a component of the RNA-induced silencing complex, as a regulator of EC function in angiogenesis and obesity. However, the role of endothelial AGO1 in vascular inflammation and liver function in the context of hyperlipidemia and atherosclerosis is unknown. METHODSEC-conditional AGO1 knockout (EC-AGO1-KO) and wildtype mice were subjected to pro-atherosclerotic models induced by AAV9-PCSK9 coupled with a Western diet or partial carotid ligation. Metabolic and vascular phenotype and gene expression were analyzed. In human liver sinusoidal and aortic ECs, AGO1 was knocked down using antisense oligonucleotides (ASO), followed by assessment of inflammatory responses (qPCR, RNA-seq, ELISA, and monocyte adhesion assays). To identify the molecular mechanisms linking AGO1 and EC inflammation, Cut&Tag sequencing, chromatin immunoprecipitation, immunofluorescence, proximal ligation assay, and co-immunoprecipitation were performed. The therapeutic effect of AGO1 inhibition was assessed using ASO-delivered via lipid nanoparticle (LNP) for systemic distribution and monocyte membrane-coated nanoparticles (MoNP) to target the inflamed endothelium. RESULTSEC-AGO1-KO mice exhibited improved plasma lipid profiles, reduced hepatic steatosis, inflammation, and fibrosis, and decreased aortic atherosclerotic burden. AGO1 knockdown in ECs attenuated inflammatory responses. Mechanistically, AGO1 interacted with NF-{kappa}B p65 and promoted p65 nuclear translocation and the transcriptional activation of pro-inflammatory genes, including ICAM1 and THBS1. AGO1-ASO delivered through LNP or MoNP achieved the anti-inflammatory, anti-hyperlipidemic, and anti-atherosclerotic effects, recapitulating the phenotypes observed with EC-AGO1-KO. CONCLUSIONSEndothelial AGO1 promotes vascular inflammation and liver dysfunction in the context of hyperlipidemia and atherosclerosis, in part through a non-canonical nuclear action of AGO1 as an NF-{kappa}B coactivator. Inhibition of endothelial AGO1 provides the dual benefits of ameliorating lipid dysregulation and suppressing vascular inflammation. These results highlight EC-AGO1 as a possible therapeutic target for atherosclerosis and cardiometabolic diseases.

pathology↗

bioRxiv2025

Gene Editing and Aging: A Bibliometric Analysis of Global Trends and Frontier Themes (2015-2024)

ObjectiveThe accumulation of DNA damage and mutations is a key contributor to aging. Recent studies have shown that disrupting the Beclin 1-BCL2 autophagy regulatory complex through gene editing can extend lifespan in mice. The precise application of gene editing technologies offers a promising strategy for aging. This study conducted a bibliometric analysis to map the knowledge landscape of gene editing and aging. MethodsWe retrieved publications related to genome editing and aging from the Web of Science Core Collection, covering the period from 2015 to 2024. The data were analyzed using VOSviewer and R package Bibliometrix. These tools enabled us to identify the most productive researchers, journals, institutions, countries and visualized current trends, emerging research hotspots. ResultsA total of 982 publications on genome editing and aging were identified. The United States (n=285) and China (n=214) form a dual-core structure leading global output. Harvard University (n=116) emerged as the most prolific institution. Scientific Reports was the top-publishing journal, with 23 articles in 2024. ZHANG Y (n=12, citations=102, H-index=6) was identified as the most productive author. KIM Es 2017 publication in Nature Communications (TC=494, TC/year=54.9, NTC=9.33) has had a significant and ongoing impact. The analysis indicates that future directions will include CRISPR optimization and AI-assisted genomic analysis. ConclusionThis study presents the first comprehensive bibliometric analysis and visualization of the knowledge structure in gene editing and aging research up to 2024. It offers researchers a detailed overview of current developments, trends, and emerging frontiers in this rapidly evolving domain.

scientific communication and education↗

bioRxiv2025

Discovery of a tRNA-regulatory transcription factor that suppresses breast cancer metastasis

Transfer RNAs (tRNAs), once viewed as static adaptors in translation, are now recognized as dynamic regulators of gene expression. While recent studies have illuminated roles for tRNA stability, the upstream mechanisms governing tRNA transcription remain poorly understood. To address this gap, we generated the EXpression atlas of tRNA (EXTRNA), a high-resolution tRNA expression dataset spanning 24 cell lines across 9 human tissues. EXTRNA revealed both tissue-type-specific expression programs ("tRNAomes") and unexpected intra-tissue heterogeneity across breast cancer samples. Integrating EXTRNA with computational network analysis and data from other publicly available datasets, we identified Zinc Finger ZZ-Type And EF-Hand Domain Containing 1 (ZZEF1) as the first sequence-specific transcription factor of a particular tRNA. ZZEF1 promoted tRNA-LysUUU transcription by partnering with the ATP-dependent chromatin remodeler Chromodomain Helicase DNA Binding Protein 6 (CHD6), enhancing chromatin accessibility at tRNA-Lys-TTT-3 loci. ZZEF1 deficiency reduced tRNA-LysUUU abundance, decreased the translational efficiency of AAR codon-enriched mRNAs--including the tumor suppressor Serine/Threonine Kinase 3 (STK3)--and promoted metastatic progression in breast cancer in vivo. Together, our findings establish a previously unrecognized mechanism for RNA polymerase III-mediated tRNA transcription and define a regulatory circuit linking chromatin remodeling, codon-specific translation, and tumor suppression. More broadly, this work introduces a framework for dissecting the regulatory logic of the tRNAome and highlights tRNA expression control as a promising avenue for therapeutic intervention.

genomics↗

bioRxiv2025

SIMIT-seq: a bead-free, scalable microfluidic platform for single cell mRNA sequencing with ultrahigh cell-indexing rate

SIMIT-seq is a bead-free, scalable microfluidic platform designed for high-efficiency single-cell mRNA sequencing. Conventional microfluidic-based single-cell RNA sequencing platforms rely heavily on barcoded beads and intricate co-encapsulation schemes, often constrained by double Poisson limitations and the complexities of bead synthesis. In contrast, SIMIT-seq eliminates the need for beads entirely by employing a deterministic, orthogonal barcoding strategy within a two-dimensional micro-well array. This platform achieves an impressive single-cell indexing rate of 96.6% without the need for complex microfluidic operations. Here, we describe the design and fabrication of the SIMIT-seq platform, outline its workflow for transcript capture and library preparation, and demonstrate its application in profiling K562 cells. Our results validate both the high fidelity of molecular barcode immobilization and the systems capability to support downstream single-cell mRNA sequencing. SIMIT-seq offers a cost-effective and scalable alternative for single-cell transcriptomics, providing a promising foundation for future single-cell omics applications.

bioinformatics↗

bioRxiv2025

Single-Cell Multimodal Profiling Highlights Persistent Aortic Smooth Muscle Cell Changes in Diabetic Mice Despite Glycemic Control

BackgroundType 2 diabetes (T2D) is associated with accelerated vascular complications like hypertension and atherosclerosis. "Phenotypic switching" of vascular smooth muscle cells (SMC), a major driver of these complications, is enhanced in diabetes. Despite adequate glycemic control, SMC dysfunction can persist due to "metabolic memory" of prior hyperglycemia. However, the mechanisms of hyperglycemic memory associated with persistent SMC dysfunction are unclear. Here, leveraging single-cell (sc) multi-omics, we examined the effect of glucose normalization on transcriptomic and epigenomic changes associated with SMC phenotypic transition in T2D mice. MethodsWe treated T2D db/db mice with the antidiabetic drug dapagliflozin (DAPA) (db/dbDAPA) or vehicle (db/db), and non-diabetic control db/+ mice with vehicle for 6 weeks. Dissected aortas were subjected to scRNA-seq, scATAC-seq, and spatial transcriptomics (Xenium) to determine single-cell changes in gene expression and chromatin accessibility. ResultsDAPA treatment conferred effective glycemic control in db/db mice, with significant reductions in blood glucose/hemoglobin A1c. scRNA and scATAC-seq analysis of aortas identified major cell populations, including SMC, fibroblasts, endothelial and immune cells. SMC were further clustered into 9 subtypes, including contractile and fibromyocyte-like cells. Cell composition analysis revealed decreases in contractile SMC and increases in vascular remodeling associated fibromyocyte-like SMC in db/db versus db/+ mice. Interestingly, DAPA did not reverse diabetes-induced decreases in contractile markers but reversed changes in several fibromyocyte markers in db/db mice. Pseudotime trajectory analysis revealed increased activities of fibromyocyte enriched transcription factors (TFs) during contractile to fibromyocyte transition. Furthermore, increased expression of TFs regulating fibromyocyte phenotype (e.g. Atf4, Bach1, Hand2, Fosl2) in db/db were partially reversed by DAPA, whereas reduced contractile TF (Mef2c) expression was unchanged. Spatial transcriptomics analysis further mapped aortic cell types within intact aortas and confirmed that DAPA reversed alterations in key fibromyocyte but not contractile genes in db/db mouse aortas. ConclusionsPersistent epigenetic changes may contribute to sustained vascular remodeling and dysfunction in T2D. T2D reduced contractile SMC gene expression and related chromatin accessibility and promoted phenotypic transition to fibromyocytes. These changes are only partially reversed by a widely used antidiabetic drug like DAPA, underscoring the need for more effective therapies that target hyperglycemic memory.

biochemistry↗