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Methotrexate (MTX) is a widely used chemotherapy drug, but its neurotoxicity can lead to cognitive impairments, particularly through effects on hippocampal function. Nevertheless, the underlying molecular mechanisms are not fully understood. Deciphering MTX-induced cognitive impairment-linked molecular mechanisms in cells of the hippocampus could uncover novel therapeutic targets. In this study, we established a mouse model of cognitive impairment induced by the chemotherapy drug MTX. We applied single-nucleus RNA sequencing (snRNA-seq) to analyze the transcriptomic alterations in hippocampal cells of mice following MTX treatment, with a focus on neuron-specific gene expression changes. MTX chemotherapy led to a decrease in excitatory neurons but an increase in inhibitory neurons, altering the excitatory-inhibitory balance of neural networks and thus mediate cognitive dysfunction. Furthermore, MTX significantly disrupted the transcriptional regulatory network and potential trajectory of GABAergic neurons. It enhanced the Nrg1-Erbb4 pathway while attenuating the Nrxn3-Lrrtm4 pathway, destabilizing trans-synaptic signaling and causing abnormalities in excitatory and inhibitory synaptic functions. These disruptions may ultimately lead to neural network imbalance and cognitive dysfunction. This study highlights the specific effects of MTX chemotherapy on hippocampal cellular function and provides valuable insights into the molecular mechanisms underlying cognitive deficits and potential therapeutic targets. Show less

Prostate cancer (PCa) is a leading cause of male cancer-related death globally. While the gut microbiota is linked to PCa, its genetic association remains unclear. We screened genetic instruments related to the gut microbiota and paired them with PCa genome-wide association study data to conduct Mendelian randomization (MR) analysis. Positive MR findings were then subjected to colocalization analysis. Subsequently, we utilized the Gene Expression Omnibus (GEO) dataset to perform differential expression analysis, aiming to identify differentially expressed associated genes (DEAGs). We determined the importance scores of these DEAGs through four machine learning models and constructed a nomogram based on these findings, and then validated it in another group of the GEO dataset. MR analysis found 16 gut bacteria causally linked to PCa (7 risk, 9 protective), with 144 related genes. PLCL1, VSNL1, ROR2, NRXN3, and TEAD1 were identified as feature genes for constructing a nomogram that provides a quantitative prediction of the risk of PCa onset. This study indicates that there are causal links between the gut microbiota and PCa. Feature genes may affect the occurrence of PCa by inhibiting the epithelial-mesenchymal transition, proliferation, migration, and invasion of cells. Show less

Intrahepatic cholangiocarcinoma (ICC) remains one of the most lethal malignancies with an increasing incidence worldwide. Gemcitabine has been considered the standard first-line chemotherapeutic agent for ICC but the therapeutic response is unsatisfactory due to the development of chemoresistance. Caspase-3-mediated pyroptosis has been reported to play significant roles in chemotherapeutic response but the relevant therapeutic strategy remains unstated due to the unclear molecular mechanisms under pyroptosis in ICC. This study was designed to comprehensively explore the crucial role and underlying mechanisms of NRXN3 in pyroptosis and chemosensitivity of ICC. We performed genome-scale CRISPR-Cas9 screen integrated with transcriptomic analysis to identify key regulators of pyroptosis and gemcitabine sensitivity in ICC. In vitro and in vivo experiments were employed to investigate the effects of NRXN3 on gemcitabine-induced pyroptosis. RNA-seq and IP-MS were conducted to explore the mechanisms of NRXN3-regulated pyroptosis and chemosensitivity. NRXN3 was identified to be a critical contributor to pyroptosis and chemosensitivity in ICC. Low NRXN3 expression correlates with poor prognosis and worse therapeutic response. Mechanistically, NRXN3 competitively blocks caspase-3 binding to the RSK1 serine/threonine-protein kinase, thereby inhibiting RSK1-dependent phosphorylation of caspase-3 at T152. Inhibition of caspase-3 phosphorylation impairs its interaction with the ubiquitin ligase component FBXO1 and enhances its stability, thus facilitating caspase-3/GSDME-dependent pyroptotic cell death and chemosensitivity. Furthermore, administration of an RSK1 inhibitor or caspase-3 activator boosts the efficacy of gemcitabine in murine models of ICC. NRXN3 plays a crucial role in maintaining chemotherapy-induced pyroptosis in ICC. Targeting the NRXN3/RSK1/FBXO1/caspase-3 axis emerges as a promising strategy for ICC treatment, with the potential to improve chemosensitivity and survival. Show less

Asymptomatic Alzheimer's Disease (AsymAD) is a preclinical stage of Alzheimer's Disease (AD) identified by amyloid plaques and neurofibrillary tangles in cognitively normal individuals and offers essential understanding for early diagnosis and treatment of AD. To uncover molecular insights into AsymAD, RNA sequencing (RNA-seq) datasets from two different consortia, ROSMAP (Religious Orders Study and Memory and Aging Project) and MSBB (Mount Sinai Brain Bank), were investigated. The individuals in the datasets were grouped into AD and AsymAD based on clinical and neuropathological criteria. Differentially expressed genes (DEGs), differentially expressed transcripts (DETs), and differentially used transcripts (DUTs) were identified between AD and AsymAD samples. The results were interpreted through functional enrichment analysis and compared with the predefined lists of AD-related and learning-memory-cognition-related genes, and genes from an independent mouse dataset. The genes from the list of DEGs, DETs and DUTs were mapped onto a human protein-protein interaction network, revealing subnetworks associated with AsymAD. This led to the discovery of biomarker candidate genes: NRXN3, DGKB, ADAMTS2, GNG4, ENPP5, PCOLCE, COL25A1, COL26A1, MRPL1, and MRPL30. This study introduces an innovative approach by including DETs and DUTs in the analyses, beyond the standard focus on DEGs, pointing out comprehensive insights into the molecular mechanisms of AsymAD. In addition, combining the results of the subnetwork analysis from DEGs, DETs, and DUTs provided a new perspective to AsymAD and resulted in the discovery of further important genes, which can pave the way for early detection and intervention of AD. Show less

Oral leukoplakia and proliferative verrucous leukoplakia represent oral potentially malignant disorders. Oral leukoplakia typically presents as solitary lesions, while proliferative verrucous leukoplakia manifests as multifocal lesions with higher malignant potential. This study aimed to investigate the genetic heterogeneity between these disorders through differential gene expression, genetic variants, and microRNA profiling to identify potential biomarkers for diagnosis and prognosis. Biopsies and peripheral blood samples were obtained from 20 patients. Subsequently, RNA extraction, RNA-Seq libraries preparation, and bioinformatic analyses were conducted to ascertain differential gene expression, genetic variants, and microRNA expression. In mRNA analysis, overexpressed genes in proliferative verrucous leukoplakia are primarily associated with inflammation and immune regulation, while underexpressed genes relate to skin barrier maintenance. Pathway analysis reveals underexpressed genes related to impaired keratinization in proliferative verrucous leukoplakia and with keratin envelope formation in oral leukoplakia, while overexpressed genes are linked to synaptic processes and protein-protein interactions. Somatic mutation drivers in proliferative verrucous leukoplakia include variants in NRXN3, SRGAP2B, INIP, MYO18A, and ATF7IP genes. Regarding variant analysis, two variants in the Syndecan 3 (SDC3) gene identified in proliferative verrucous leukoplakia have demonstrated enormous value and indicate an important biomarker for a differential diagnosis and to predict prognosis. Proliferative verrucous leukoplakia shows in miRNA analysis MIR1246 and MIR767 overexpression, with MIR135B being the most underexpressed. Our findings emphasize the intricate transcriptomic profiles in oral leukoplakia and proliferative verrucous leukoplakia development, laying the groundwork for future studies to enhance clinical management and patient outcomes in oral oncology. Syndecan 3 gene polymorphisms may represent a key point in proliferative verrucous leukoplakia differential diagnosis and prognostic prediction. Show less

Langya chickens, a Chinese indigenous breed, exhibit rich genetic resources but relatively low egg production performance. To investigate the genetic basis of egg production traits, we performed low-depth genome resequencing of 1,183 Langya hens and evaluated six phenotypic traits, including age at first egg (AFE), egg number at different laying stages-EN1 (from first egg to 26 weeks), EN2 (27-36 weeks), EN3 (37-43 weeks), total egg number at 43 weeks (E43), and maximal clutch length (MCL). Genetic parameter analysis revealed that MCL exhibited high heritability (0.42) and strong genetic correlations with both egg production and AFE, suggesting its potential as a more effective selection indicator for egg production traits. Genome-wide association studies identified a total of 245 SNPs associated with these traits. Notably, a 6.58 Mb region on chromosome 5 (GGA5, 40.03-46.61 Mb) was enriched for multiple traits and in strong linkage disequilibrium. Candidate genes in this core region, including TSHR, GTF2A1, DIO2, STON2, NRXN3, KCNK10, EML5, and FOXN3, were implicated in transcriptional regulation, thyroid hormone signaling, neuroendocrine modulation, and ovarian function. Additional trait-specific candidate genes, such as ATG2B for EN2, FMNL1 for EN1/EN2, TDP1 for E43, and TPMT for MCL, were also identified. Functional enrichment analyses highlighted pathways related to cellular processes, lipid metabolism, and signal transduction. These findings provide genomic insights into the molecular mechanisms underlying egg production traits and offer valuable candidate genes for marker-assisted breeding in Langya chickens. Show less

Body size traits serve as crucial phenotypic indicators of body conformation and growth, showing a close correlation with production performance. To elucidate the genetic basis of these traits and identify potential molecular markers in Saanen dairy goats, we analyzed low-coverage whole-genome sequencing (lcWGS) data from 635 individuals. Following genotype imputation based on an in-house goat reference panel, we obtained 14 million single-nucleotide polymorphisms (SNPs) and 45 thousand structural variants (SVs). Genetic parameters were estimated using SNP data. Subsequently, single-trait (ST) and multi-trait genome-wide association studies (MT-GWAS) were conducted using both SNP and SV datasets. Results indicated that body height, body length, and rump height possess moderate heritability, with positive genetic and phenotypic correlations observed among these traits. ST-GWAS identified 56 significant SNPs and 3 significant SVs, mapping to 30 candidate genes, including Show less

Neurexins (NRXNs) are presynaptic adhesion molecules essential for synaptic organization and the regulation of excitatory-inhibitory balance. The molecular diversity of NRXNs arises from alternative promoters and splicing, particularly at splice site 4 (SS4), which dictates ligand binding. Dysregulation of NRXNs has been linked to substance use disorders, but it remains unclear how the expression of NRXN isoforms responds to physiologically relevant amounts of ethanol. Human IMR-32 neuroblastoma cells were maintained in an undifferentiated (UnDiff) state or differentiated (Diff) with trans-retinoic acid (tRA) to promote an enrichment in parvalbumin (PV) expression. Cells were exposed to physiologically relevant ethanol concentrations (0, 7, or 35 mM) in vapor chambers. Quantitative polymerase chain reaction (qPCR) quantified mRNA levels of major NRXN transcripts (NRXN1, NRXN2, and NRXN3) and SS4 variants (+SS4, -SS4). Immunocytochemistry (ICC) was used to measure protein expression and overlap with neuroligin2 (NLGN2) and PV. Differentiation increased basal expression of several NRXN transcripts, including NRXN2α, NRXN2 +SS4, NRXN3α, NRXN3β, and NRXN3 -SS4. In Diff cells, ethanol-induced dose-dependent downregulation of NRXN2α, NRXN3α, NRXN3β, and NRXN3 -SS4 transcripts, while NRXN1 remained stable. In Diff cells, ICC confirmed isoform-specific protein reductions without changes in other markers (Tuj1 and PV). NRXN3β decreased at 7 and 35 mM; and NRXN1 and NRXN2 at 35 mM. Ethanol significantly reduced overall expression of NRXN3β at 7 and 35 mM; and NRXN1 and NRXN2 at 35 mM, along with NRXN3β-NLGN2 spatial overlap and NRXN1, 2, and 3β signal within PV-positive cells, indicating targeted disruption of inhibitory synaptic organization. Physiologically relevant ethanol exposure alters NRXN expression in an isoform-, splice site-, and differentiation-dependent manner, prominently affecting NRXN3 and the SS4 site. These coordinated transcriptional and proteomic changes suggest that ethanol perturbs NRXN3β-NLGN2 interactions and inhibitory synapse stability, revealing a molecular pathway where alcohol may compromise cortical network excitatory-inhibitory balance. Show less

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a globally prevalent disease, yet its genetic architecture remains incompletely characterized. We integrated genome-wide association study data from multiple cohorts totaling nearly 3 million individuals of European ancestry and applied cross-trait genomic modeling of hepatic fat and seven cardiometabolic traits to construct an MASLD-specific polygenic architecture. We identified 128 risk variants across 100 loci and prioritized 55 effector genes, including established (e.g., Show less

Schizophrenia (SZ) is characterized by excitation-inhibition (E-I) imbalance as a core pathophysiological feature, but its molecular underpinnings remain elusive. Susceptibility gene Roundabout2 (Robo2), which regulates E-I balance in the central nervous system, may play a critical role in the pathogenesis of SZ by contributing to this dysregulation. We conducted a transcriptomic analysis of Robo2 in postmortem brain tissues from patients with SZ and controls using the GEO/GSE datasets. The plasma levels of Robo2 were quantified in clinical cohorts via ELISA. We assessed the correlation between plasma Robo2 levels and clinical assessments (Positive and Negative Syndrome Scale [PANSS] and MATRICS Consensus Cognitive Battery [MCCB]) or neurophysiological measures (functional near-infrared spectroscopy [fNIRS] and event-related potentials). Rats with hippocampal Robo2 knockdown underwent comprehensive behavioral, electrophysiological, and ultrastructural (Golgi staining) assessments. Proteomic sequencing with pathway enrichment analysis was conducted to identify downstream molecular mediators. Hippocampal and plasma Robo2 expression were significantly downregulated in patients with SZ. The plasma levels of Robo2 were inversely correlated with PANSS scores and positively associated with MCCB performance. Neurophysiological correlations revealed positive associations between Robo2 and dorsolateral prefrontal cortex activation (fNIRS and P300 peak amplitude). Robo2-deficient rats exhibited anxiety-like behaviors, cognitive impairments, social withdrawal, and sensory gating abnormalities, accompanied by decreased dendritic spine density and increased hippocampal field potential power. Proteomics identified disrupted GABAergic/glutamatergic synaptic pathways, with neurexin-3 (Nrxn3) downregulation emerging as a potential downstream candidate. Our findings established Robo2-Nrxn3 deficiency as a potential molecular hub linking E-I imbalance to SZ-associated behavioral and neurophysiological deficits, highlighting novel therapeutic targets for E-I modulation. Show less

Vitiligo is an autoimmune disorder characterized by the destruction of melanocytes. We performed a rank-based meta-analysis of six independent transcriptomic studies (115 samples) spanning microarray, bulk, and single-cell RNA-seq platforms to identify consensus signatures of lesional skin. Robust rank aggregation identified 108 downregulated and 6 upregulated genes. Pathway analysis revealed consistent suppression of melanin synthesis and neural development pathways in vitiligo, whereas immune response activation was heterogeneous across studies. Re-analysis of single-cell data from three studies confirmed melanocyte depletion. The 108 downregulated genes were expressed exclusively in melanocytes. These include neural development genes (PLP1, GPM6B, NRXN3), consistent with melanocytes' neural crest origin. We also identified candidate melanocyte markers, such as CYB561A3 and QPCT, with high melanocyte specificity and consistent downregulation in vitiligo. These findings reveal a robust melanocyte-loss signature in vitiligo, detectable across different studies. Study-dependent immune activation, possibly influenced by sampling method and disease characteristics, warrants further study. Show less

In fishes and aquatic-stage amphibians, mechanosensory neuromasts are arranged in characteristic lines in the skin of the head and trunk, with afferent innervation from anterior or posterior lateral line nerves. In electroreceptive non-teleost jawed fishes and amphibians, fields of electrosensory ampullary organs flank some or all of the cranial neuromast lines, innervated by the anterior lateral line nerve. Like the mechanosensory hair cells found in neuromasts and the inner ear, electroreceptor cells in ampullary organs across vertebrates form specialised ribbon synapses with afferent nerve terminals. Ribbon synapses in hair cells are distinct from other glutamatergic synapses, including the ribbon synapses in photoreceptors: In hair cells, synaptic vesicles are loaded with glutamate by vGlut3 and otoferlin is the Ca Show less

Glaucoma is a leading cause of irreversible blindness, yet the circulating proteins and metabolic pathways that causally contribute to different glaucoma subtypes remain poorly defined. We analyzed baseline plasma proteomics in 1485 glaucoma cases (447 primary open‑angle glaucoma [POAG], 177 primary angle-closure glaucoma [PACG], 120 normal-tension glaucoma [NTG]) in the UK Biobank using Cox models with graded adjustment. We then integrated five independent protein quantitative trait loci resources with FINLAND R12 genome-wide association study data to perform two‑sample Mendelian randomization (MR) and cross‑cohort meta‑analysis for overall glaucoma and each subtype. To prioritize effector genes and pathways, we conducted summary-data-based Mendelian randomization (SMR) using eQTLGen and two‑step mediation MR using metabolite quantitative trait loci data for ∼1400 plasma metabolites from the Canadian Longitudinal Study on Aging cohort. In fully adjusted Cox models, 484 proteins were associated with incident glaucoma, 135 with NTG, 59 with POAG, and 1 with PACG (false discovery rate <0.05). Multicohort MR and meta‑analysis identified eight proteins with robust causal effects: NRP2, TSPAN1, and HAVCR2 for overall glaucoma; NRXN3 for PACG; MANSC4 for NTG; and LTBP2, CD69, and SMAD1 for POAG. SMR supported NRP2 (overall glaucoma) and SMAD1 (POAG) as causal genes. Mediation MR revealed that sphingomyelins, acylcarnitines, and bile acid-related metabolites partially mediated the effects of several proteins, defining shared (e.g., sphingolipid) and subtype‑specific metabolic pathways. By integrating epidemiologic, proteomic, genetic, and metabolomic data, we identify convergent systemic protein and metabolic signatures associated with glaucoma susceptibility and its clinical subtypes. These findings nominate NRP2, SMAD1, and related pathways as promising biomarkers and therapeutic targets and support a systems‑level view of glaucoma pathogenesis beyond intraocular pressure alone. Show less

Sleep is essential for health and regulated by genetic and environmental factors. We perform genome-wide association studies of device-measured sleep duration, efficiency, and accelerometer-derived rapid eye movement (REM) and non-rapid eye movement (NREM) sleep in 80,013 UK Biobank participants. We identify 20 autosomal loci, 12 of which have not been previously reported, including genome-wide significant associations for REM and NREM sleep duration. MEIS1 shows strong opposing effects on REM and NREM durations and is intolerant to loss-of-function mutations, suggesting an essential role in the regulation of REM/NREM sleep balance. Functional enrichment analysis identifies statistically significant pathways related to chromatin remodelling, lipid metabolism, and metal ion homeostasis while tissue enrichment analysis highlights significant signals in the hypothalamus and frontal cortex. Sex-stratified analyses identify distinct loci, including FOXP2 and NRXN3 in females and LRP1B, NPBWR2, and PABPC4 in males. Mendelian randomization supports associations between shorter sleep duration and higher cardiometabolic risk. These findings highlight sex- and phase-specific regulators of human sleep architecture, providing biological insights and potential therapeutic targets. Show less

White adipose tissue (WAT) expansion occurs through generation of new adipocytes from adipose progenitor cells (APC). The objective of this study was to characterize and validate a new transcriptional profile of APC. Single-cell (sc)/nuclei (sn) RNA-Seq was performed on nuclei from whole WAT (n = 20), cells from WAT stromal vascular fraction (n = 5), and cultured APC in vitro (n = 8) using ICELL8 smart-Seq technology. Additional snRNA-Seq was performed on WAT using 10x genomic platform. Pseudotime analyses and differentiation of hiPSCs was used to track the temporal patterns of novel gene signatures. Immunohistochemistry was performed to validate a new marker. A pre-adipocyte population was found across the four independent datasets that expressed known pre-adipocyte markers (ZNF423 and DLK1) in addition to genes typically associated with neurogenes (DPP10, PTRPT, CTNNA2, NRXN3, CTNNA2, PTPRD, CNTNAP2 and RBFOX1). The expression of these genes were temporally regulated with adipocyte differentiation. Immunohistochemistry analyses confirmed these pre-adipocytes are located in the neurovascular niche of WAT but are not neurons or endothelial cells. This work has defined a new transcriptional signature of pre-adipocytes in human subcutaneuous WAT that are distinct from mesencyhmal stem cell populations and represent novel targets for WAT expansion. Show less

Sex determination and differentiation are complex processes shaped by a wide variety of molecular factors. In contrast to teleost species, many aspects of these processes remain poorly understood in basal non-teleost fishes such as the Siberian sturgeon (Acipenser baerii). Genetic sexing of this important aquaculture species now enables studies of undifferentiated males and females to identify factors involved in early sexual differentiation. Twelve undifferentiated Siberian sturgeon (six males, six females) were genetically sexed at 2.5 months of age. High-quality RNA was extracted from gonad samples, and transcriptomes were assembled using a reference dataset. Bioinformatic analyses were performed to identify sex-biased genes through differential expression analysis, Gene Ontology (GO) enriched terms, and classification of coding and non-coding sequences. Genes potentially associated with sex differentiation were identified in gonadal tissue. Female-biased genes included classical estrogens production genes (hsd17b1, cyp19a1, foxl2) and immediate early response genes known to react rapidly to estrogens (jun-b, c-fos, egr1), as well as genes not previously linked to estradiol (di-ras2, ier2, aanat). The enriched Gene Ontology results suggested that melatonin signaling and hypothalamic pathways may also contribute to female differentiation. In males, the well-known factor tbx1 was upregulated along with novel candidates (plin1, nrxn3, chs2, mmp9). No sex-biased genes related to androgen production were identified. By 2.5 months of age, sex-specific gonadal differences are already apparent in Siberian sturgeon. This study highlights the estrogen response pathway, including immediate early response genes described here for the first time in the context of fish gonadal differentiation. At the same time, an estrogen-independent ovarian pathway cannot be ruled out. Male differentiation appears to involve tbx1 together with new candidates for testis regulation in the absence of sex-biased androgen-producing enzymes. These novel genes expressed near the onset of sex differentiation merit further investigation. Show less

Meningioma is a common primary central nervous system tumor that can cause a heavy burden on patients. Despite its well-established treatment modalities, pharmacological treatments are not sufficiently abundant. Therefore, we explored potential therapeutic targets for meningiomas by integrating genomic and proteomic data. We integrated meningioma data from the UK Biobank and Finnish databases and subsequently explored potential therapeutic targets for meningiomas through multi-omics data using bioinformatics techniques and Mendelian randomization. These targets were finally evaluated using phenotype-wide association group analysis. We found that BET1L, COL17A1, CFAP43, SH3PXD2A, TTC28, ZNRF3, SLK, AKR1C3, NRXN3, and RSPO3 can be potential therapeutic targets for meningiomas. This study provides evidence and explores the biological significance of BET1L, COL17A1, CFAP43, SH3PXD2A, TTC28, ZNRF3, SLK, AKR1C3, NRXN3, and RSPO3 as potential therapeutic targets for meningiomas, providing new insights into the development of targeted therapy for meningiomas. Show less

Decreased cerebrospinal fluid (CSF) levels of synaptic proteins, possibly reflecting impaired synaptic function, have been observed in major depressive disorder (MDD). To investigate the diagnostic utility of the soluble N-ethylmaleimide-sensitive-factor attachment receptor (SNARE) complex protein, synaptosomal-associated protein of 25 kDa (SNAP-25), for MDD. Overall, 208 participants with one of MDD, schizophrenia (SCZ) or bipolar disorder (BD), and healthy controls (HCs) were retrospectively enrolled. CSF levels of SNAP-25 were assessed relative to MDD characteristics and the diagnostic potential was analysed. In subgroups of patients, CSF levels of presynaptic neurexin 3 (NRXN3), postsynaptic neurogranin (NRGN) and Alzheimer's disease biomarkers were measured for comparison. SNAP-25 levels, but not the levels of the other synaptic markers, were significantly decreased in MDD compared with HCs, allowing for discrimination with 68% sensitivity and 67% specificity. SNAP-25 was not associated with MDD severity or antidepressant medication. Compared with HCs, SCZ also displayed decreased SNAP-25 enabling discrimination with 64% sensitivity and 77% specificity. There were strong correlations between levels of synaptic proteins and established Alzheimer pathology markers, with subtle differences in the association pattern between disorders. Our data suggest that SNAP-25, NRXN3 and NRGN versus beta-amyloid and phosphorylated tau protein 181 (ptau) are regulated differentially across psychiatric disorders and that SNAP-25 has a moderate diagnostic potential for MDD and SCZ. We propose that CSF SNAP-25 level might represent an integrated readout of reduced synaptic function, rather than of synaptic degeneration, in MDD. Further studies are needed to analyse whether this potential can be increased by using multimarker measurements and whether it will be possible to subtype psychiatric disorders according to synaptic involvement in pathophysiology. SNAP-25 and other synaptic proteins in CSF might aid diagnosis and subtyping of MDD and SCZ. The current development of sensitive methods to also determine synaptic proteins in blood samples from patients will advance the validation of the biomarker potential and contribute to understanding of synaptic involvement in the pathophysiology of MDD and SCZ. Show less

NGS (next-generation sequencing) has become a rapid advance in discovering the variants in the genomic data for disease diagnosis, prognosis, and therapeutic decision. However, the scope of detecting single nucleotide polymorphisms (SNPs) becomes limited by the availability of reliable high-throughput data. OUD (opioid use disorder) is a chronic condition marked by prolonged opioid misuse, leading to cycles of relapse and remission. The discovery of genetic variants associated with OUD is constrained by limited genomic data, making it crucial to identify these variants and their genetic factors. The identification of variants from RNA-seq (RNA-sequencing) data can become the representative of the SNP analysis that is generally preferred from the whole genome or exome sequencing data. This study aimed to identify variants from gene expression data downloaded from NCBI GEO with accession PRJNA492904 in postmortem ventral midbrain specimens of chronic opioid users. We hypothesized that the NRXN3 gene would exhibit the highest number of variants due to its significant role in neuronal synapse function and its association with opioid addiction and impulsivity. We utilized RNA-Seq data from OUD patients (PRJNA492904, NCBI SRA) to detect variants in expressed RNA, which can indicate functional protein changes. Eight genes were analyzed: BDNF, DRD2, DRD3, NRXN3, OPRD1, OPRM1, and NGFB, with a primary focus on NRXN3. Our findings revealed the highest number of variants in NRXN3 compared to the other genes, highlighting its potential importance in OUD and the robustness of RNA-Seq in variant detection. Show less

The study examined the association between body composition and beverage consumption and the risk of asthma and chronic obstructive pulmonary disease (COPD) and explored the single nucleotide polymorphisms (SNPs) involved in these associations by leveraging summary statistics from genome-wide association studies (GWAS) in nonoverlapping populations. The IEU OpenGWAS project was sourced for exposure datasets: body mass index, body fat percentage, fat-free mass, total body water mass, alcohol intake frequency, and coffee intake, and selected health outcome datasets: asthma and chronic obstructive pulmonary disease. Datasets were assessed and filtered using R, followed by a two-sample Mendelian randomization analysis. The MR Egger, weighted median, inverse variance weighted, simple mode, and weighted mode methods were used to examine the association between exposures and outcomes. Heterogeneity and pleiotropy analyses were used to evaluate the reliability of results. Additionally, SNPnexus was used to ascertain SNPs linked to established phenotypes, while SNP annotation was obtained from the Ensembl BioMart database via the biomaRt package. Genes belonging to overlapping groups were visualized using ComplexHeatmap. Higher body fat percentage (OR = 1.72, 95% CI: 1.23-2.41, Show less

Congenital heart disease (CHD) is associated with neurodevelopmental and cognitive impairments, but the underlying molecular mechanisms remain unclear. This study investigated cardiac neuronal genomics in CHD using single-nucleus RNA-sequencing data (GSE203274) from 157,273 cardiac nuclei of healthy donors and patients with hypoplastic left heart syndrome (HLHS), Tetralogy of Fallot (TOF), dilated (DCM), and hypertrophic (HCM) cardiomyopathies. The Uniform Manifold Approximation and Projection (UMAP) clustering identified major cardiac cell types, revealing neuron-specific transcriptional programmes. Neuronal populations showed enriched expression of neurodevelopmental disorder-linked genes ( Show less

This study aims to identify genetically influenced metabolites (GIMs) associated with SSBP and elucidate their regulatory pathways through metabolome genome-wide association studies (mGWASs). Untargeted metabolomics and genome-wide genotyping were performed on 54 participants from the Systematic Epidemiological Study of Salt Sensitivity (EpiSS). The mGWAS was conducted on 970 plasma metabolites, and their potential biological mechanisms were explored. The multivariable logistic regression model and mendelian randomization (MR) were employed to investigate the association and causal relationship between GIMs and SSBP. Metabolomic analysis was performed on 100 subjects in the replication analysis to validate the GIMs identified in the discovery set and their causal association with SSBP. The mGWAS revealed associations between 1485 loci and 18 metabolites. After performing linkage disequilibrium analysis, 368 independent mQTLs were identified and annotated to 141 genes. These functional genes were primarily implicated in the signal transduction of sinoatrial node and atrial cardiac muscle cells. Five key genes were identified using CytoHubba, including Show less

Mesenchymal cells constitute the primary structural support elements within endometriotic lesions, yet their pivotal roles in endometriotic pathogenesis remain largely uncharted. This study aimed to construct a single-cell atlas of endometriosis using samples from three ovarian tissues affected by endometriosis and three normal ovarian tissues. Through the utilization of scRNA-seq, we have unveiled six distinct mesenchymal subclusters in normal and endometriosis-afflicted ovaries, elucidating the diverse functions of mesenchymal populations in endometriosis. Our comprehensive analysis has revealed that mesenchymal cells predominantly engage in three key functions: ribosome-mediated protein synthesis and processing, cell adhesion facilitating intercellular support and communication, and a range of metabolic processes. Furthermore, our findings have identified several pivotal differentially expressed genes (e.g. C3, FN1, COL3A1, COL1A1, NRXN3), primarily associated with the complement and coagulation cascades, extracellular matrix (ECM) regulation, ECM receptor interactions, and cell adhesion molecules. In essence, our study provides a comprehensive transcriptomic dataset and novel insights into adhesive molecule and integrin networks within mesenchymal subclusters in endometriosis. This, in effect, has deepened the understanding of the pathomechanisms governing this condition. Show less

Neurexin 3 (Nrxn3) has a role in neuronal signaling. Previous reports indicated that reducing Nrxn3 expression in the central amygdala increased orofacial neuropathic pain. A common temporomandibular disorder is myofascial pain. Thus, we hypothesized that Nrxn3 would reduce myofascial hypersensitivity. To test this hypothesis Nrxn3 shRNA was infused into the central amygdala of male rats. Then a ligature of the tendon attachment of the anterior superficial portion of the masseter muscle was performed to induce inflammatory orofacial pain. Dark phase meal duration was measured continuously, and von Frey filament testing was completed every 7 days for 21 days to measure the nociceptive response. After testing tissues were collected and the amount of Nrxn3 was measured. Neuronal activity in the orofacial pain pathway was quantitated by c-Fos staining of the central amygdala, lateral parabrachial nucleus, trigeminal ganglia and trigeminal nucleus caudalis. Knockdown of Nrxn3 in the central amygdala significantly increased the pain response and increased the levels of c-Fos. This increased response was observed for greater than two weeks. The data suggests Nrxn3 expression within the central amygdala attenuates nociceptive orofacial pain by reducing neuronal activity. Show less

This study explores the cell fate reprogrammability of H3K27M-mutant pediatric high-grade gliomas (pHGG) using neuronal transdifferentiation as a potential targeted therapy. We treated the BT245 patient-derived glioma cell line with pharmacological combinations targeting neuronal differentiation pathways and performed bulk RNA sequencing to characterize gene expression patterns driving cell fate transitions. Our findings reveal that the drug combinations induce transcriptomic changes consistent with differentiation towards neuronal phenotypes, including the upregulation of synaptic and dendritic signaling genes and the downregulation of malignant signatures. In comparison, astrocytic differentiation media (DM) and H3K27M knockout (KO) promote residual astrocytic phenotypes, suggesting neuronal transdifferentiation as a more effective strategy for mitigating tumor aggressiveness and progression. Differentially expressed genes such as GRIK1, GRIN1, NRXN3, NRXN1, CALB2, SCGN, SLC32A1, SLC1A2, KCNC3, and neurodevelopmental regulators including WNT7A, DLX6, ERBB4, ARX, BCL11B, SEMA3C, and FGFBP3 were identified as key markers regulating the neuron-like lineage transition. This study demonstrates that pHGGs can be phenotypically redirected toward neuronal-like identities through modulating cell fate differentiation programs. These findings advance the concept of 'differentiation therapy' as a promising intervention to reduce phenotypic plasticity and malignancy in pHGG ecosystems. While these are early in vitro findings, the potential ability to steer and control glioma cells toward stable, less malignant fates offers promising translational potential for patient-centered targeted therapies. Show less

Neurexins (NRXNs), a complex family of synapse regulatory proteins, represent attractive candidate molecular mediators of retinal neuronal dysfunction in early diabetic retinal disease (DRD) given their roles in the central nervous system and recent work suggesting a potential link with diabetes mellitus (DM). As antibodies are unable to distinguish NRXN family members and isoforms, the purpose of this study was to investigate differential expression of individual NRXN transcripts in relevant retinal cell types in early DRD. RNAscope multiplexed fluorescent in situ hybridization was used to quantify transcripts of NRXNs in mouse and human retina. DM was induced in C57BL/6J mice using streptozotocin (STZ) and the retinal phenotype characterized by electroretinogram (ERG), optical coherence tomography (OCT), and optokinetic tracking (OKT) after 6 weeks. Retinal ganglion cells (RGCs) were generated in vitro by directed differentiation from human embryonic stem cells (hESCs), cultured in normal or high glucose, and NRXN expression assessed by qPCR and Western blot. All NRXN family members (NRXN1, NRXN2, and NRXN3) were enriched in inner retinal neurons in both human and mouse tissue. We identified decreased Nrxn3 transcripts, specifically the Nrxn3β isoform, in RGCs of diabetic mice at 6 weeks after STZ treatment. Interestingly, Nrxn3α and Nrxn3β were differentially expressed in inner retinal layers. Finally, we confirmed decreased Nrxn3β expression in hESC-RGCs cultured in high glucose in vitro. Our findings suggest that NRXNs may play cell-type-specific roles in the inner retina and associate decreased Nrxn3β expression in RGCs with inner retinal dysfunction in early DRD. Show less

Asthma severity assessment is essential for asthma management. Transcriptomics contributes substantially to asthma pathogenesis. Then, this study aimed to explore asthma severity-associated transcriptomics profile and promising biomarkers for asthma severity prediction. In discovery cohort, induced sputum cells from 3 non-severe and 3 severe asthma patients were collected and analyzed using RNA-seq. Multivariate analysis was performed to explore asthma severity-associated transcriptomics profile and differential expressed genes (DEGs). The Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) were used for pathway enrichment analysis. Subsequently, based on the previous study and clinical experience, the mRNA expressions of 6 overlapped asthma severity-associated DEGs and Distinct asthma severity-associated transcriptomics profile was identified in induced sputum cells in discovery cohort. Then, 345 DEGs were found, of which 38 terms and 32 pathways were enriched using GO and KEGG, respectively. In validation cohort, the mRNA expressions of Collectively, this study provides the first identification of the association between induced sputum cells transcriptomics profile and asthma severity, indicating the potential value of transcriptomics for asthma management. The study also reveals the promising value of serum C3 for predicting asthma severity in clinical practice. Show less

Colorectal cancer (CRC) is a prevalent digestive system malignancy accompanied by peritoneal metastasis occurring in 7% of cases. Methyltransferase-like 3 (METTL3) promoted the progression of CRC whereas its function in peritoneal metastasis was incompletely understood. Here, we found that METTL3 was upregulated in peritoneal metastasis tissues of CRC patients compared with CRC tissues. By sequencing the mRNA of above tissues, we discovered that METTL3-mediated N6-methyladenosine (m6A) modification regulated the downstream target Show less

The pathophysiology of tension-type headache (TTH) remains poorly understood, and current treatments are largely symptomatic. Identifying genetically supported, causally relevant proteins may provide insights into disease mechanisms and enable precision therapeutics. We conducted a proteome-wide Mendelian randomization (MR) analysis integrating large-scale plasma proteomic quantitative trait loci with genome-wide association study data for TTH. Phenome-wide MR, enrichment, protein-protein interaction (PPI), and mediation analyses were performed to identify druggable targets and clarify potential biological pathways. Thirteen plasma proteins exhibited significant causal associations with TTH (Bonferroni correction This integrative genetic analysis identified multiple plasma proteins with causal and pharmacologically relevant roles in NRXN3, CCL22, CLEC1B, and LRIG1 emerged as promising and potentially safe therapeutic targets. The online version contains supplementary material available at 10.1186/s10194-025-02235-5. Show less

Early-life stress (ELS) increases the risk of major depressive disorder in children and adolescents. However, the molecular and cellular mechanisms of major depressive disorder (MDD) induced by ELS are poorly understood. Here, we establish a stress model in rats in which maternal separation stress (MS) during the postnatal period increases susceptibility to restraint stress (RS) later in life. In terms of mechanism, MS causes long-lasting synaptic plasticity alterations in rats, which is accompanied by reduced branch and spine lengths in the hippocampus. We identified the role of the cell adhesion factor neurexin 3 (NRXN3) and its ligand neuroligin 1 (NLGN1) as mediators of these effects. NRXN3 and NLGN1 downregulation in the hippocampus occurred prior to the observed synaptic changes and depression-related behaviors. In conclusion, NRXN3 is involved in the development of depression induced by maternal separation, and the specific mechanism involves the NRXN3-NLGN1 complex, which can mediate synaptic plasticity and increase susceptibility todepression. Show less