Biology subjects

Lv, X.

Publications and source records attributed to Lv, X..

At least 19 recordsLinked to original sources

bioRxiv2026

An accumbal cholinergic ISR-HCN2 axis sustains maladaptive cue motivation

Environmental cues associated with rewarding outcomes can exert persistent control over behavior long after the reward is absent, yet the cellular adaptations that stabilize such maladaptive motivation remain unclear. Here we identify nucleus accumbens cholinergic interneurons (CINs) as causal regulators of persistent cue-driven seeking. Self-administration of addictive drugs or high-fat reward, but not sucrose, selectively increased CIN pacemaker firing. Cocaine-paired cues evoked rapid acetylcholine release in the nucleus accumbens core, and bidirectional manipulation of CINs suppressed or enhanced cue-induced cocaine seeking. Mechanistically, cocaine experience engaged the integrated stress response (ISR) in CINs, increased HCN2 expression and Ih, and stabilized a hyperexcitable state. CIN-specific ISR suppression or HCN2 knockdown reduced cocaine seeking, whereas HCN2 overexpression enhanced it. Local HCN blockade and systemic treatment with the clinically approved HCN blocker ivabradine reduced cue-driven seeking across addictive-drug and high-fat-reward paradigms while sparing sucrose seeking. These findings identify an ISR-HCN2-dependent cholinergic mechanism that stabilizes maladaptive cue-driven motivation and nominate HCN-dependent excitability as a tractable target for therapeutic intervention.

neuroscience↗

bioRxiv2026

Extracellular vesicles drive cross-genus mycovirus transmission and suppress two fungal diseases

Mycoviruses are typically transmitted vertically through fungal reproduction or horizontally via hyphal anastomosis, but identical viruses in phylogenetically divergent fungi hint at unknown inter-species transmission mechanisms. Here, we identify fungal extracellular vesicles (EVs) as mediators of cross-genus mycovirus transmission. Using the hypovirulent Botrytis cinerea strain IBc-374 (harboring 16 mycoviruses) as a donor, we show that up to 13 mycoviruses are horizontally transmitted to Sclerotinia sclerotiorum during dual culture or plant co-inoculation, even though these two fungi belong to different genera and are generally considered incapable of hyphal anastomosis. Electron microscopy reveals abundant vesicle structures in IBc-374 hyphae, and nanoparticle tracking analysis showed that the strain secretes >11-fold more EVs than a virus-free strain. RT-PCR detects genomic RNAs of 7 mycoviruses in purified EVs, and the full-length viral genome in EVs was further validated with BcHV5 as example by fluorescence in situ hybridization and RT-PCR. Incubation of protoplast-derived germlings of S. sclerotiorum or B. cinerea with IBc-374 EVs leads to infection by 4-6 donor mycoviruses, demonstrating EV-mediated cross-genus transmission. Injection of mycovirus-carrying EVs into tobacco leaves followed by fungal inoculation also transmits two hypoviruses to both species. Application of IBc-374 hyphal fragment suspension significantly reduces lesion sizes caused by both pathogens on plants, and rescued two pathogens carrying multiple mycoviruses exhibit hypovirulence and impaired growth. Our findings reveal EVs as a cell-free vector that bypasses vegetative incompatibility, providing a mechanistic basis for cross-species viral spread and opening avenues for EV-based virus cocktails to control multiple fungal diseases. IN BRIEFWu et al. discover that fungal extracellular vesicles (EVs) can package and transmit multiple mycoviruses across genera from Botrytis cinerea to Sclerotinia sclerotiorum. EV-mediated delivery overcomes vegetative incompatibility barriers and reduces disease caused by both fungal pathogens, offering a cell-free strategy for mycovirus-based biological control.

microbiology↗

bioRxiv2026

Novel Muscle-Tropic AAV Capsids with Dramatically Enhanced Transduction and Safety Profiles in Non-Human Primates

Adeno-associated virus (AAV) gene therapy holds immense promise for treating muscular dystrophies, yet its efficacy and safety are constrained by the suboptimal tissue tropism of natural serotypes. Here, we employed the REACH platform, which combines rational design and directed evolution, to engineer muscle targeting vectors. Systemic administration in non-human primates (NHPs) revealed that lead candidate M1 mediates a >10-fold increase in skeletal muscle transduction compared to the AAV9 and 2-3 fold higher than MyoAAV, while concurrently achieving a remarkable 183-fold reduction in liver distribution. Furthermore, M1 exhibited significant de-targeting from key off-target tissues, including dorsal root ganglia (11 fold), lung (27 fold), spleen (2 fold), and kidney (2 fold). These findings demonstrate that the REACH platform can generate AAV capsids with simultaneously enhanced muscle tropism and favorable safety profiles, addressing a critical bottleneck in muscle-directed gene therapy.

bioengineering↗

bioRxiv2026

HMA proteins produce 2',3'-cNMP signaling molecules and activate CNL-mediated immunity in rice

Plants deploy a sensor repertoire, usually NLRs, to perceive pathogen effectors and activate executor NLR-triggered immunity. Here we reveal that rice HMA proteins function as sensors detecting the Magnaporthe oryzae MAX effector AvrPigm to trigger broad-spectrum blast resistance mediated by the CNL PigmR. AvrPigm is conserved with multiple copies in blast genomes and targets HMA proteins, facilitating HMA translocation into the cytoplasm. Cryo-EM structure of the HPP04HMA reveals a filament-like oligomer with ssDNA/RNA bound inside the filament, which display cyclic nucleotide synthase activity to generate 2',3'-cNMP in a CNL-dependent manner. We further discovered that the LRR domains of the executor CNLs perceive 2',3'-cNMP to mount immunity. Our study thus establishes an unrecognized immunity mode with a distinct repertoire of sensor receptors that produce signaling molecules that are perceived by the LRR domains of executor NLRs to mediate immunity, shedding new light on the sensor-executor conception and immune activation in plants. HighlightsO_LIHMA proteins and CNL receptors form a new sensor-executor mode in plant immunity C_LIO_LICryo-EM reveals the filament-like structure of HMA-ssRNA/ssDNA C_LIO_LIHMA proteins are cyclic nucleotide synthetases to generate 2',3'-cNMP C_LIO_LILRR domains of CNLs perceive 2',3'-cNMP to mediate immunity C_LI

plant biology↗

bioRxiv2026

Near completely reversing the γ- to β-globin switch by enhancer release, retargeting and reinforcing

The {gamma}- to {beta}-globin switch is intricately regulated during human ontogeny, and this process is manipulated for therapeutic approaches to treat {beta}-hemoglobinopathies by activating {gamma}-globin expression. Several genetic strategies to reactivate HbF have partially reversed the {gamma}- to {beta}-globin switch and ameliorated the clinical symptoms of {beta}-hemoglobinopathies. However, whether the {gamma}- to {beta}-globin switch can be completely reversed remains unknown. Completely reversing the {gamma}- to {beta}-globin switch requires a thorough redirection of the locus control region (LCR) from interacting with the {beta}-globin gene (HBB) to interacting with the {gamma}-globin gene (HBG). Here, we found that disrupting the KLF1-mediated HBB-LCR interaction by mutating the CACCC motif in HBB leads to the release of the LCR and its retargeting to other {beta}-like globin genes. Moreover, simultaneously disrupting the KLF1-mediated HBB-LCR interaction and the epigenetic repression of HBG by combined editing of the CACCC motif in HBB and the TGACCA motif in HBG reinforces the HBG-LCR interaction, resulting in almost exclusive {gamma}-globin expression while nearly absent {beta}-globin expression, achieving near complete reversal of the {gamma}- to {beta}-globin switch. This finding demonstrates the comprehensive regulation of the {gamma}- to {beta}-globin switch by gene competition and gene silencing mechanisms. This finding also suggests that silenced genes can be fully activated through the redirection of enhancer-promoter contacts and that the specificity of enhancer-promoter contact within chromosomal domains is achieved through the transcription factor clusters binding to enhancers and promoters. Combined editing of the CACCC&TGACCA motifs also offer a more optimal therapeutic strategy for {beta}-hemoglobinopathies.

molecular biology↗

bioRxiv2026

Hyperactivated YAP1 Drives an Invasive EMT Subtype of Cervical Squamous Cell Carcinoma

Cervical cancer (CVC) is classically understood as an HPV-driven disease in which high-risk HPV infects cervical basal epithelial cells, induces neoplastic transformation, and drives upward epithelial expansion, pathogenic events underlying the success of cytology- and HPV-based screening. With widespread HPV vaccination and screening, the WHO has launched the CVC elimination initiative and believes that CVC will be the first cancer that would be eliminated as a public health problem. However, statistics showed that CVC remains the most common gynecologic malignancy worldwide, and in the United States, where HPV testing and Pap smears have reached near-maximal implementation, the CVC mortality rate has plateaued for more than two decades. These epidemiologic trends suggest the existence of a subset of CVC that can escape current screening strategies. Here, we demonstrate that hyperactivation of YAP1 caused by disruption of Hippo-YAP signaling is sufficient to induce a subtype of HPV-independent invasive CVC that lacks surface lesions and therefore evades HPV- and cytology-based detection. Using single-cell RNA sequencing combined with high-resolution spatial transcriptomics, we define the cellular architecture, molecular pathways, and immune microenvironment underlying this invasive subtype. We show that YAP1-driven tumors adopt an EMT-high transcriptional state and selectively recruit immunosuppressive myeloid-derived suppressor cells that functionally interact with cancer cells to promote invasion and progression. Our findings suggest that targeting the disrupted Hippo signaling may offer a new strategy to prevent the subset of invasive CVC that current HPV- and Pap-based programs cannot detect, an essential step toward achieving global CVC elimination.

cancer biology↗

bioRxiv2025

Dose-dependent NFI regulation of progenitor lifespan and output underlying human neocortical malformation

Nuclear Factor I (NFI) misexpressions in humans are associated with severe brain malformations, yet the underlying mechanisms remain poorly understood. Here we show that NFIs regulate the broad lineage progression and lifespan of radial glial progenitors (RGPs), and consequently neocortical development in a dose-dependent manner. Human cerebral organoids carrying patient-mimicking NFI mutations exhibit expression level-dependent bidirectional impairments in RGP temporal development, coinciding with patient phenotypes. In mouse models, selective removal of NFIs leads to a dramatic protraction of RGP lineage progression and lifespan, excessive progeny output, and neocortical overgrowth and abnormal folding, whereas overexpression of NFIs accelerates RGP lineage progression, resulting in developmental stage-dependent precocious productions of diverse neural progenies. Moreover, NFIs exhibit a positive auto-regulation and progressive increase in expression, and regulate distinct temporal-specific targets underlying RGP lineage progression. These results suggest that NFIs act as evolutionarily conserved key global temporal regulators of RGP lineage progression and neocortical development. HIGHLIGHTSO_LINFIs affect human RGP temporal development coinciding with patient phenotypes. C_LIO_LINFI removal protracts RGP lineage progression and lifespan with excessive progeny output. C_LIO_LINFI overexpression accelerates RGP lineage progression with precocious progeny output. C_LIO_LINFIs regulate distinct temporal-specific targets underlying RGP lineage progression. C_LI

neuroscience↗

bioRxiv2025

Fast Loading and Transformation of Large-Volume Bioimaging Data Consistently Approaching the I/O Peak Speed

High-resolution large-volume biological imaging techniques are now widely used in biological research, but inefficiencies in data processing and visualization persist due to bottlenecks in loading/saving pipelines and limitations of conventional pyramid formats. To address these issues, we have decoupled data loading process into reading from disk and in-memory decompression, while data saving has been separated into in-memory compression and writing to disk. This approach allows us to dedicate more CPU cores to decompression and compression tasks, optimizing resource allocation and maximizing disk I/O throughput. As a result, both loading and saving processes operate near the disks peak data transfer capacity. Further, we integrated a video stream-inspired format into the pyramid structure, allowing direct access to regions of interest (ROIs) without loading extraneous data into RAM, reducing memory overhead. Compared to the latest methods, our approach improves pyramid data transformation efficiency by at least 6x and dramatically accelerates downstream tasks like visualization and deep learning inference. TeaserNovel bioimaging data processing pipeline achieves near-peak I/O throughput via decoupled architecture and video-formatting.

bioinformatics↗

bioRxiv2025

Rete Ovarii Epithelial Cells as an Unappreciated Cell of Origin for Pelvic and Ovarian High-Grade Serous Carcinoma

Over the past two decades, converging clinicopathologic, molecular, and evolutionary evidence has established that pelvic and ovarian high-grade serous carcinoma (HGSC) originates predominantly from tubal-type epithelia rather than the ovarian surface epithelium. Consequently, Fallopian tube secretory epithelial cells are widely recognized as the principal cell of origin for HGSC. However, the female reproductive tract contains additional tubular epithelial networks whose potential contributions to HGSC pathogenesis remain unexplored. Here, we identify the rete ovarii (RO), a complex network of intra- and extra-ovarian tubules located within the ovarian hilus and mesovarium, as an alternative candidate tissue of origin for HGSC. We demonstrate that genetic and genomic alterations in rete ovarii epithelial cells (ROECs) can drive their malignant transformation, giving rise to tumors that closely recapitulate the histologic and molecular characteristics of human HGSC. Spatially resolved single-cell transcriptomic analyses of tumors derived from Brca/Trp53/Pten-deficient ROECs (BTP-RO) reveal distinct invasive and immunosuppressive molecular programs. These findings establish ROECs as a previously unrecognized cell of origin for HGSC, expanding the landscape of potential precursor populations beyond the Fallopian tube. The RO-based HGSC model provides a powerful framework for developing origin-informed prevention strategies, early detection approaches, and targeted therapeutics.

cancer biology↗

bioRxiv2025

Cost-effective genomic prediction for fertility traits: A comparison of machine learning and conventional models using low-coverage sequencing in Holstein heifers

Fertility is one of the major factors affecting the efficiency of dairy herd, and genomic selection (GS) on milk yield, while ignoring fertility, has resulted in a decline in heifer fertility. Consider the cost of breeding, it is important to enhance the accuracy of GS with cost-effective way for fertility traits. This study investigates the genomic prediction (GP) of fertility traits in Holstein heifers using both machine learning (ML) and conventional methods, based on data from SNP arrays and low-coverage sequencing data. In this study, we collected 45,320 Holstein heifers with phenotype and pedigree records, from which we generated genomic data for 3,683 Holstein heifers using lcGWS. We first estimated the heritability for age at first service (AFS), gestation length (GLh) and age at first calving (AFC). We then compared the prediction performance of ML methods, kernel ridge regression (KRR), support vector regression, and random forest regression, with GBLUP, ssGBLUP and BayesR3 regarding GP accuracy and unbiasedness. Inputs for ML includes genomic relationship matrices (GRM), principal components, and SNPs. The results revealed that the heritability for the three fertility traits ranged from 0.09 to 0.48. Prediction accuracy from imputed low-coverage sequencing data was comparable to that from standard SNP chips. When both pedigree and genotypic data were used for GS, ssGBLUP yielded the highest prediction accuracy for AFS and GLh. Crucially, using only genomic data, KRR_GRM improved GP accuracy by up to 28.57% compared to GBLUP and by up to 9.46% compared to BayesR3. Our results highlight the effectiveness of low-coverage sequencing data in breeding applications and the MLs potential to enhance GP accuracy for fertility traits, offering practical insights for dairy breeding programs. ImplicationsTo improve the accuracy of GS with cost-effective way for fertility traits, this study confirms that low-coverage sequencing offers both accuracy and cost-effectiveness for fertility in Holstein heifers. The research provides a decision-making framework for breeding workers: the ssGBLUP model is optimal when combining pedigree data, while machine learning methods are superior with only genomic data. This study offers a practical tool for achieving efficient and economical genetic improvement in dairy cattle.

genomics↗

bioRxiv2025

Genomic Regions and Variant Analysis Reveal Candidate Genes Associated with Age at First Service in Chinese Holstein Heifers

Understanding the genetic basis and identifying quantitative trait loci (QTL) for age at first service (AFS) is essential for improving reproductive efficiency and reducing economic costs in heifers rearing. We conducted a genome-wide association study (GWAS) for AFS using the genomic estimated breeding values (GEBVs) of 3,686 Chinese Holstein heifers, genotyped with 7,964,217 single nucleotide polymorphisms (SNPs) after quality control. Significant SNPs and candidate genes were identified and investigated through colocalization analysis of GWAS, expression QTL (eQTL), and splicing QTL (sQTL), and expression analysis in blood RNA sequencing (RNA-seq). The heritability estimate for AFS was moderate at 0.276 {+/-}0.025. Three QTL regions associated with AFS were identified: Region 1 on BTA6 (43688837-45007127 bp, 1.3 Mb with three 200kb windows), explaining 0.47% of genetic variance; Region 2 on BTA6 (62770788-62967316 bp) explaining 0.27% of the genetic variance; and Region 3 on BTA18 (6299721-6498934 bp) explaining 0.17% of the genetic variance. Combining GWAS and colocalization analysis, we identified ANAPC4, RBPJ, SEPSECS, SLC34A2, ZCCHC4, CCDC149, GNPDA2, GUF1, DHX15, SOD3, GUF1 and GNPDA2 as candidate genes. These genes are enriched in signaling pathways such as progesterone-mediated oocyte maturation, parathyroid hormone synthesis, secretion and action, and selenocompound metabolism. ANAPC4, DHX15, GUF1, SEPSECS, and SOD3 were also differently expressed genes (DEGs) in blood RNA-seq. Integrating the GWAS, colocalization, differential expression analysis, and existing literature, ANAPC4 and rs136363104 were highlighted as the putative causal gene and variant for puberty, respectively. In conclusion, our study identified three candidate regions and 12 candidate genes, confirming ANAPC4 as a putative causal gene influencing AFS. This research enhances the understanding of the genetic basis of AFS in Chinese Holstein heifers. The identified key genomic regions, candidate genes, and variants have the potential to improve reproductive efficiency and reduce economic costs in heifer rearing. Interpretative summaryThe economic burden of heifer-raising and reproductive inefficiency in dairy cattle is evident. The most important strategy for optimizing heifer-raising is selecting heifers with earlier puberty (sexual maturity) to shorten age at first service (AFS). In this study, we have identified key genomic regions and candidate genes on AFS in Chinese Holstein heifers by genome-wide association study, and validated them by colocalization and RNA-seq analysis. The findings have the potential to enhance the understanding of the genetic basis of reproductive traits, leading to more targeted breeding strategies for improved reproductive efficiency.

genetics↗

bioRxiv2025

A Universal RT-qPCR Method for DNA Aptamer Quantification

Aptamers are widely used in various applications; however, their quantification methods remain underdeveloped. In this study, we established a universal RT-qPCR-based method for DNA aptamer quantification. By incorporating reverse transcription, primers and probes could be added to aptamers, enabling their detection via qPCR (Figure 1). We developed a software tool for primer and probe design and optimized the reverse transcription process. Two aptamers, CD9-aptamer and CD63-aptamer, were selected as model systems representing two distinct aptamer types: the CD9-aptamer contains an intrinsic primer-binding site within its sequence, whereas the CD63-aptamer does not. Using this method, the limit of detection (LOD) for CD9-aptamer reached 10-14 M, while the LOD for CD63-aptamer was 10-12 M. Compared to existing quantification methods, this approach significantly improves accuracy and cost-effectiveness. Additionally, the method supports SYBR Green, TaqMan, and one-step RT-qPCR assays, broadening its applicability and enhancing precision for various aptamer-based applications. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=106 SRC="FIGDIR/small/662296v1_fig1.gif" ALT="Figure 1"> View larger version (19K): org.highwire.dtl.DTLVardef@44ec4corg.highwire.dtl.DTLVardef@f59184org.highwire.dtl.DTLVardef@2480fdorg.highwire.dtl.DTLVardef@906845_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOFigure 1.C_FLOATNO Schematic illustration of RT-qPCR-Based Aptamer Quantification. C_FIG

molecular biology↗

bioRxiv2025

Genomic Evidence for Males of Exceptional Reproductive Output (ERO) in Apes and Humans

It is widely suspected that a small percentage of males have exceptional reproductive output (ERO) but progeny numbers of males are rarely measurable, even in humans. If we define the variance ratio of reproductive-output in males and females as = VM/VF, the ERO hypothesis would predict >>1. Since autosomal, X, and Y chromosomes are found in males 1/2, 1/3, and 100% of the time, their DNA diversities can inform about . For example, autosomal and Y-linked diversities are governed, respectively, by (VM+VF)/2 and VM. When comparing the chromosomal diversities, appears to be near 20 for chimpanzees and orangutans, and 1-10 for gorillas. The exception is bonobos with < 1. In humans, the extensive genomic data are coupled to a theory, developed herein, that can filter out selection influences on Y-linked diversities. Hence, the estimation of is rigorous, yielding values near or above 20, depending on the population. When >10, the presence of ERO males is very likely. These analyses can be applied more generally to species with XY sex determination.

evolutionary biology↗

bioRxiv2025

An atlas of cell type specific regulatory effects in cattle

Understanding the genetic and molecular architecture of complex traits and artificial selection is crucial for advancing sustainable precision breeding in cattle and other livestock. Yet, how genetic variation affects cellular gene expression remains elusive in cattle. Here, by integrating 8,866 bulk RNA-seq samples and 999,192 single cells of 81 cell types in 22 bovine tissues, we presented a comprehensive atlas of regulatory variants at the cell type resolution in cattle. By colocalizing with bulk-tissue expression quantitative trait loci (beQTL), we detected 57,043 novel cell-type stratified eQTL and cell-type/state interaction eQTL in 18,153 genes, which also exhibited a stronger tissue/cell-type specificity than beQTL. By examining genome-wide associations (GWAS) of 44 complex traits, these cell-resolved eQTL were colocalized with 505 (24%) additional GWAS loci compared to beQTL. Through integrating this resource with selection signatures between dairy and beef cattle, we provided tissue/cell-specific regulatory insights into cattle breeding. Overall, the current atlas of cell-type-specific regulatory variants will serve as an invaluable resource for cattle genomics and selective breeding.

genetics↗

bioRxiv2025

Super-giga and tiny orchid genomes illuminate evolution of Orchidaceae

Orchidaceae (orchids) is commonly known as one of the largest families of seed plants, and grow in an extensive range of habitats worldwide. In the present study, we generated chromosome-level reference genomes for two orchids using a combination of PacBio, Illumina, and Hi-C sequencing, Cypripedium singchii has the largest genome and chromosomes among the sequenced species so far, with a genome size of 43.19 Gb (1C) with ten chromosomes, and Apostasia fujianica has the smallest known genome and chromosomes in Orchidaceae, with a genome size of 340.90 Mb (1C) with 35 chromosomes. We predicted a total of 32,412 and 21,724 protein-coding genes for C. singchii and A. fujianica, respectively. The overall BUSCO score was 85.01% for C. singchii and 91.80% in A. fujianica. Based on protein-coding sequences from 55 conserved single-copy families across 21 plant species, we constructed a high-confidence phylogenetic tree and estimated the divergence times. The high-quality genomes of super-giga and tiny orchids offer key insight for future evolutionary researches.

genomics↗

bioRxiv2025

GenVS TBDB: An Open AI-Generated andVirtual Screened Small-Molecule Database for Tuberculosis Drug Discovery

Tuberculosis (TB) remains a leading global health threat, with over 10 million new cases and 1.25 million deaths reported in 2023. Current TB therapies rely on a limited drug repertoire and prolonged treatment courses that have changed little in four decades. Here, we present GenVS-TBDB, a target-aware AI-generated and virtual-screened small-molecule database, which expands the chemical space against Mycobacterium tuberculosis (M.tb) essential proteins. We first identified 460 probable small-molecule binding pockets across 377 essential M.tb proteins by integrating multiple sources. Then, by leveraging the target-aware molecule generative model, over 1.2 million novel small molecules tailored to these pockets were produced. The key physicochemical properties were computed for all compounds to ensure medicinal chemistry tractability. These compounds were also evaluated using molecular docking and anti-TB specific graph neural network model, yielding binding propensity ranking and whole-cell activity prioritization for each target. To substantiate the integrated AI-driven workflow for anti-TB discovery, 30 compounds were obtained, including 22 AI-designed molecules synthesized de novo and 8 commercially available analogs. In validation, 2 synthesized compounds demonstrated significant thermal stabilization of FtsZ, confirming target engagement. 6 compounds exhibited cellular inhibition below 50 {micro}M, the most potent at 12 {micro}M. Furthermore, GDI-11785 showed binding to the cell wall biosynthesis pathway with 35 {micro}M cellular activity, establishing a promising starting point for tuberculosis drug discovery. Our findings contribute a significant library of bioactive molecules which may hasten the preliminary phase of tuberculosis drug discovery. The GenVS-TBDB small library is publicly accessible and can be downloaded freely at https://datascience.ghddi.org/database/view.

pharmacology and toxicology↗

bioRxiv2024

Delineation of Single-cell Altas Provides New Insights for Development of Coronary Artery Lesions in Kawasaki Disease: Bad and Good Signaling Molecules

BackgroundKawasaki Disease (KD) is a vasculitis syndrome featured with a high and persistent fever and mainly affects children under 5 years of age. It is the leading cause of acquired heart disease in the form of coronary artery lesions (CALs) for children in developed countries. Most KD can be relieved with the high-dosage Intravenous immunoglobulin (IVIG) therapy, but a small proportion develop CALs after IVIG treatment. MethodsWe performed the single-cell RNA sequencing for the peripheral blood mononuclear cells (PBMCs) from three KD non-CAL patients whose samples were acquired before and after IVIG treatment and three KD CAL patients whose samples were acquired only after IVIG treatment. Cell-to-cell communication patterns were also analyzed in KD CAL and non-CAL patients ResultsOverall cell expression feature analyses show immunoglobulin and adaptive immunity related genes are upregulated in KD CAL patients while B cell activation related genes are downregulated in them. Pseudo-time analyses demonstrate that both KD non-CAL patients before treatment and KD CAL patients after treatment have a dysregulated B cell developmental trajectory while the former has a mixed T and B lineage and the latter has a mixed monocyte and B lineage. The early elevated expression of SPI1 could partly explain the dysregulated B cell development in KD CAL patients. Cell communication analyses propose a disorder cell communication pattern in KD non-CAL patients before treatment and some persistent bad cell-to-cell signals in KD CAL patients after treatment. There are four signaling molecules, APP, CCL, and MCH-II, whose expression is significantly increased in the CD14 and CD16 monocytes of KD CAL patients, where the expression of RESISTIN is significantly increased in those KD non-CAL patients. ConclusionsOur results suggest that APP, CCL, and MCH-II might be the bad signals for indicating the possible development of CAL while RESISTIN is a good one for protecting from CAL.

immunology↗

bioRxiv2024

Mechanism of N-Myc Downstream Regulated Gene-1 regulating Integrin expression to inhibit gastric cancer metastasis

BackgroundN-myc downstream regulated gene-1 (NDRG1), the first member of the NDRG family, is widely distributed in various tissues and organs. In gastric cancer, the hypo-expression of NDRG1 has been positively associated with malignant biological behavior and poor prognosis. In-depth investigation of the potential regulatory mechanism of NDRG1 on gastric cancer is crucial for understanding the pathogenesis of this disease, identifying new therapeutic targets, and developing personalized treatment strategies. This study aims to explore the significance of NDRG1 in regulating the expression of integrins during the progression of gastric cancer. MethodsThe expression of NDRG1 in gastric cancer was analyzed using R software v4.0.3, Boxplot, and the Kaplan-Meier Plotter. Stable cell lines with NDRG1 knockdown and overexpression were subjected to wound healing assays, transwell migration assays, CCK8 assays, and colony formation assays, in order to determine the effects of NDRG1 on the migration and proliferation of gastric cancer cells. Western blotting was employed to examine the impact of NDRG1 on the expression of integrin-related proteins. Immunostaining was used to comprehensively analyze the in vitro experimental results. ResultsThe mRNA and protein levels of NDRG1 were downregulated substantially in gastric cancer, which was inversely correlated with the malignancy of pathological behavior and poor prognosis in gastric cancer. Knockdown of the NDRG1 gene significantly enhanced the proliferation and migration capabilities of gastric cancer cells, whereas overexpression of NDRG1 reduced their metastatic potential and inhibited both migration and proliferation. NDRG1 was found to regulate the expression of fibronectin 1, which in turn influenced the expression of a series of integrins, including v, 5, {beta}1, and {beta}3. This regulatory mechanism may play a crucial role in the early distant metastasis observed in gastric cancer. ConclusionsThis study demonstrated that NDRG1 could regulate the expression levels of integrins through specific signaling pathways, thereby interfering the adhesive and migratory capacities of gastric cancer cells. NDRG1 could serve as a valuable biomarker for the diagnosis and prognosis of gastric cancer, offering new potential targets for its treatment.

cancer biology↗