Search Results (785)

Major depressive disorder (MDD) remains a leading cause of disability; however, monoaminergic models do not fully explain delayed treatment onset, incomplete remission, or rapid responses to glutamatergic interventions. In this study, we proposed a system-level ionic homeostasis framework for MDD. In this model, genetic susceptibility, chronic stress, metabolic burden, and neuroinflammation converge in neuronal and glial ion-channel systems, disrupting calcium, potassium, chloride, and purinergic homeostasis. These disturbances alter intrinsic excitability, synaptic integration, inhibitory tone, glial buffering, and neuron–glia signaling, thereby promoting excitation–inhibition imbalance, impaired plasticity, and corticolimbic network instability. We reviewed the evidence implicating the CACNA1C/Cav1.2, TREK-1, KCNQ, NKCC1/KCC2, HCN, transient receptor potential/acid-sensing ion channels, and glial mediators, including P2X7R, Kir4.1, and AQP4. We also discuss how ketamine-related mechanisms, chloride-restoring strategies, anti-inflammatory ion channel targeting, neuromodulation, EEG biomarkers, and AI/multiomics approaches support mechanism-informed precision therapeutics. MDD could be conceptualized as a distributed failure of ionic homeostasis that links neuroinflammation, E/I imbalance, network instability, and impaired adaptive plasticity. Full article

Fibrosis is a common extracellular matrix pathology characterized by increased scarring, representing a critical checkpoint toward cirrhosis and hepatocellular carcinoma. Its onset involves coordinated interplay among hepatocytes, Kupffer, and hepatic stellate cells (HSCs). Extracellular ATP and its derivates act as crucial damage-associated molecular patterns when released by injured liver cells, binding to specific purinergic receptors (P2X, P2Y, and P1) to establish an autocrine–paracrine signaling loop. The hepatic fibrotic response underlies the activation of ATP receptors that generate second messengers and cationic conductance. In parallel, extracellular nucleotidases hydrolyze ATP towards less phosphorylated intermediates and adenosine. This review focuses on the role of P2X and P2Y receptors in liver injury. The P2X7 receptor regulates the NLRP3 inflammasome in Kupffer cells and HSCs, while the P2X4 receptor is upregulated in myofibroblasts, modulating migration and matrix synthesis. Among P2Y receptors, P2Y2 drives inflammation and steatosis but promotes HIF-1α-mediated DNA repair. The P2Y6 receptor promotes alcohol-induced injury but restrains metabolic-dysfunction-associated steatohepatitis. P2Y2 and P2Y4 receptors maintain biliary homeostasis in cholangiocytes, whereas the P2Y1 receptor preserves HSC quiescence by blocking YAP translocation. Finally, UDP-glucose–P2Y14 induces HSC activation. Targeting these specific purinergic receptors or ecto-nucleotidases represents a promising pharmacological frontier against hepatic fibrosis. Full article

Background/Objectives: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are increasingly prescribed for diabetes and weight loss, with many breast reconstruction candidates being prescribed these medications. However, perioperative risks remain unclear. This study evaluated the association between GLP-1RA use and postoperative complications in implant-based and autologous tissue breast reconstruction. Methods: A retrospective analysis of TriNetX identified patients undergoing implant-based or autologous tissue breast reconstruction. Preoperative GLP-1RA users were compared to matched controls. Patients were propensity score matched (1:1 and 1:3) for demographics and comorbidities including body-mass index and timing of reconstruction (delayed vs. immediate). Ninety-day outcomes were assessed using logistic regression. Results: Between 2014 and 2024, 57,987 patients were identified, of which 823 were GLP-1RA users. Of those users, 326 patients undergoing implant-based reconstruction and 51 patients undergoing autologous reconstruction were matched to controls. In implant-based cohorts, GLP-1RA use was associated with increased odds of implant failure (1:1 OR 1.70, 95% CI 1.18–2.45, p = 0.0046), wound healing complications (1:1 OR 1.90, p = 0.027), and higher readmission/ED utilization (1:1 OR 1.80, 95% CI 1.04–3.21, p = 0.040). No significant differences were observed for hematoma, seroma, or thromboembolism. In autologous reconstruction, GLP-1RA use was not associated with increased risks. Conclusions: GLP-1RA use is linked to higher rates of implant failure, wound healing complications, and readmission in implant-based breast reconstruction only. These findings highlight the need for risk stratification and counseling of GLP-1RA users undergoing implant-based procedures and for further research investigating the implications of perioperative use of these agents in plastic surgery. Full article

Background: Atrial fibrillation (AF) and heart failure with preserved ejection fraction (HFpEF) usually coexist and are related to increased morbidity and mortality. Cardiovascular benefits have been demonstrated by drugs such as sodium-glucose cotransporter-2 inhibitors (SGLT2i) and GLP-1 receptor agonists including the dual GIP/GLP-1 receptor agonist tirzepatide (collectively, incretin-based therapies); however, their relative effectiveness in patients with concomitant AF and HFpEF remains undefined. Methods: We conducted a retrospective, propensity score-matched cohort study utilizing the TriNetX Global Collaborative Network. Adults with AF or atrial flutter with a diagnosis of HFpEF who initiated incretin-based therapies (GLP-1 receptor agonists or dual GLP-1/GIP receptor agonists) or SGLT2i were included; index medication was required to be initiated within 30 days of a qualifying AF/HFpEF diagnosis. 1:1 matching was performed based on baseline medications, demographics, and comorbidities. Co-primary outcomes were all-cause mortality, inpatient visits, and emergency department (ED) visits at 1 year. Secondary outcomes included myocardial infarction, ischemic stroke, acute kidney injury, transient ischemic attack, major adverse cardiovascular events (MACE; all-cause mortality/MI/stroke composite), and AF-related procedures. Agent-specific subgroup analyses were performed for semaglutide and tirzepatide separately. Sensitivity analyses were conducted at 6 months and 2 years. Results: 7624 patients were included in each cohort after matching (mean age: 70.8 years; 52% women). At 1 year, incretin-based therapy was associated with lower all-cause mortality (5.3% vs. 7.3%, HR 0.721, 95% CI 0.634–0.820; p < 0.001), fewer inpatient visits (30.0% vs. 37.4%, HR 0.743, 95% CI 0.702–0.787; p < 0.001), and no statistically significant difference in ED visits (27.0% vs. 28.0%; HR 0.946, 95% CI 0.888–1.007; p = 0.081) compared with SGLT2i. Incretin-based therapy was also associated with lower risk of MACE (HR 0.709), acute kidney injury (HR 0.751), myocardial infarction (HR 0.583), catheter ablation (HR 0.685), and electrical cardioversion (HR 0.472). No significant differences were observed in ischemic stroke or transient ischemic attack. These findings were broadly consistent at 6-month and 2-year follow-up, and directionally consistent in agent-specific subgroup analyses of semaglutide and tirzepatide. Conclusions: In this large propensity-matched cohort of patients with AF and HFpEF, initiation of incretin-based therapy (GLP-1 receptor agonists or dual GLP-1/GIP receptor agonists) was associated with lower all-cause mortality, fewer inpatient visits, and reduced cardiovascular events compared with SGLT2i. These findings, while subject to observational limitations, suggest potential benefits of incretin-based therapy in this high-risk population and support the need for prospective comparative trials. Full article

Autoimmune endocrine diseases constitute a group of disorders characterized by immune-mediated destruction or dysfunction of hormone-producing glands. The pathogenesis of these diseases reflects a breakdown of immune tolerance in which regulatory T cells (Tregs) play a key role. The transcription factor forkhead box P3 (FOXP3) is a master regulator of Treg differentiation and suppressive function. Also, it is central to maintaining self-tolerance. Genetic mutations in FOXP3, including those responsible for immune dysregulation, polyendocrinopathy, enteropathy X-linked (IPEX) syndrome, highlight the critical role of FOXP3 in endocrine immune tolerance. Emerging evidence suggests that autoimmune endocrine disorders may reflect organ-specific destabilization of FOXP3 expression rather than complete Treg deficiency. The reversibility or irreversible loss of FOXP3 gene expression represents a key determinant of Treg plasticity and the persistence of autoimmune inflammation. This review proposes an integrated genetic–epigenetic model of FOXP3 instability and examines how the endocrine microenvironment shapes Treg plasticity. Genetic or epigenetic alterations affecting FOXP3 expression can impair Treg activity and precipitate endocrine organ-specific autoimmunity. Epigenetic mechanisms such as DNA methylation, histone modifications, and non-coding RNA-mediated regulation that modulate FOXP3 transcriptional activity are discussed. From a translational perspective, the potential of FOXP3 as a biomarker for endocrine disease susceptibility and progression was summarized. Furthermore, therapeutic strategies employed for expanding or engineering functional FOXP3⁺ Tregs using antigen-specific vaccines, chimeric antigen receptors (CAR)-Tregs, gene therapy, or low-dose interleukin-2 (IL-2) were described. Full article

Acute liver failure (ALF) is characterized by a rapid decline in liver function, leading to metabolic and organ failure. This study employed liver metabolomics, Nuclear Factor kappa-B (NF-κB) signaling pathway analysis, and inflammatory factor profiling to investigate the therapeutic mechanisms of xanthoxylin in ALF. Xanthoxylin administration led to increased antioxidant levels and reduced markers of inflammation and tissue damage. Xanthoxylin downregulated the messenger RNA (mRNA) expression of Nitric Oxide Synthase (NOS), Interleukin-1β (IL-1β), Interleukin-6 (IL-6), Tumor Necrosis Factor-α (TNF-α), NF-κB, Inhibitor of NF-κB α (IκBα), and Toll-like receptor 4 (TLR4), and inhibited the protein expression of p-p38 and p-p65 while upregulating B-cell CLL/Lymphoma 2 (Bcl-2) and B-cell Lymphoma-x (Bcl-xl). Metabolomic analysis identified 41 differentially expressed metabolites, 20 of which showed strong correlations with pharmacodynamic parameters. These 20 candidate metabolite signatures are involved in amino acid and carboxylic acid metabolic pathways, with potential links to glycolysis and the tricarboxylic acid (TCA) cycle. Together, these findings suggest that xanthoxylin exerts therapeutic effects against ALF by modulating the IκBα/NF-κB signaling pathway and related metabolic pathways, providing a scientific basis for understanding its multi-target mechanism. Full article

Background: Endocrine therapy for hormone receptor-positive breast cancer is associated with accelerated bone loss and increased fracture risk. Vertebral fractures (VFs) are frequently asymptomatic and remain underdiagnosed, potentially leading to underestimation of fracture risk. Methods: We conducted a cross-sectional real-world study that included 172 women with breast cancer (mean age 58.2 ± 12.0 years), the majority receiving aromatase inhibitors. Vertebral fractures were assessed using vertebral fracture assessment (VFA) during dual-energy X-ray absorptiometry (DXA). Bone mineral density (BMD), trabecular bone score (TBS), quantitative ultrasound (QUS), and FRAX^® scores were evaluated. Results: Vertebral fractures were identified in 13% of patients, and 78% of these occurred in women with normal or osteopenic BMD. Age was independently associated with VFs, while conventional densitometric and non-densitometric parameters showed limited discriminatory ability. The incorporation of VFA-detected fractures into FRAX significantly increased estimated fracture risk (hip fracture risk: 0.8% vs. 4.1%, p = 0.008). Conclusions: Vertebral fractures are common and frequently unrecognized in women receiving endocrine therapy and are not adequately captured by BMD. Routine use of VFA during DXA substantially improves fracture risk assessment and leads to a clinically meaningful reclassification of FRAX estimates. These findings support a more comprehensive approach to skeletal risk evaluation in this population. Full article

Background: Urosepsis is a life-threatening condition accounting for approximately 20–30% of all sepsis cases and typically arises from ascending infection by uropathogenic Escherichia coli (UPEC). Disease progression is mediated by virulence factors, including adhesins, iron acquisition systems, and toxins. Among these, P fimbriae, particularly papGII adhesin subunit, have been implicated in the transition from uncomplicated urinary tract infection (UTI) to severe urosepsis. This study aimed to evaluate whether papGII carriage, alone or in combination with other UPEC virulence determinants and clinical risk factors, can predict urosepsis. Methods: A total of 60 paired Escherichia coli isolates from concurrent blood and urine samples of adults with clinical sepsis were collected between January and June 2024. Control isolates were obtained from patients with cystitis (n = 28) and pyelonephritis (n = 32). Polymerase chain reaction (PCR) assays were used to detect fifteen virulence-associated genes, including the pap operon (with papG allelic variants), the type 1 fimbriae (fimH), S fimbriae (sfaS), curli fimbriae (csgA), afa/Dr adhesin operon genes, cytotoxic necrotizing factor 1 (cnf1), and the aerobactin biosynthesis (iucD) and receptor (iutA) genes. Associations between gene carriage and clinical groups were analyzed using chi-square tests. Results: The incidence of urosepsis increased with age, peaking in the 60–69-year age group. Renal disease and catheterization were identified as significant risk factors (p < 0.05). More than 95% of UPEC isolates carried the csgA gene associated with biofilm formation and the iucD gene. The α- hemolysin toxin (hlyA) was significantly associated with urosepsis [X²(1, N = 120) = 6.62, p = 0.03]. No significant differences were observed in the carriage of papA, papC, or fimH. Although papGII was present in 65% of urosepsis-associated UPEC isolates, it did not demonstrate a statistically significant independent association with urosepsis [p = 0.1]. Conclusion: This study demonstrates that while papGII may contribute to the pathogenic potential of UPEC and facilitate systemic infection, it is not a reliable independent predictor of urosepsis. Full article

This research paper focused on the synthesis of 1-[2-hydroxy-3-(phenylcarbamoyloxy)propyl]-4-(R¹, R²-substituted phenyl)piperazin-1-ium chlorides (I)–(III), containing R¹, R² = H, Cl and/or OCH₃, and the evaluation of some of their physicochemical parameters. The in vitro biological investigation of these N-arylpiperazine (NAP) derivatives consisted in assessing their impact on purinergic P2X7-associated signaling, that is, the evaluation of antioxidant, anti-inflammatory and immunomodulatory characteristics. The ultraviolet type C (UVC) irradiation (λ = 254 nm, 0.954 kJ/m²) induced a pronounced stress response in human leukocytes without marked cytotoxicity while maintaining high cell viability (≥90%), as evidenced by increased interleukin (IL)-1β production (94%), elevated IL-1β mRNA expression, enhanced lipid peroxidation (66%), and increased intracellular adenosine 5′-triphosphate (ATP; 97%), respectively. Under basal conditions, these lipophilic NAPs, defined with logarithmic values of retention (capacity) factors corresponding to 100% water in isocratic elution RP-HPLC, i.e., k_w descriptors (varying from 2.3829 to 4.3689), and isocratic chromatographic hydrophobicity index (φ₀) parameters (ranging from 0.7578 to 0.8842), reduced IL-1β production (by 26–63%) and enhanced superoxide dismutase (SOD) activity (up to 64%) without inducing oxidative damage. Under UVC-induced stress, all evaluated compounds decreased lipid peroxidation (up to 45%) and significantly increased antioxidant enzyme activities, including SOD (up to 223%) as well as catalase (up to 145%). The observed effects were associated with changes in intracellular ATP levels and redox-related parameters. In the experiments described in this paper, intracellular ATP was measured so that no direct conclusions could be drawn regarding the extracellular ATP-dependent activation of purinergic receptors, including P2X7. Overall, the results demonstrated that variations within the structure of these NAPs significantly affected compounds’ biological activity, highlighting their potential for further optimization as cytoprotective and anti-inflammatory agents. Full article

Cross-presentation of exogenous antigens by dendritic cells (DCs) relies on the cytosolic pathway, enabling proteasomal processing and subsequent loading of antigenic peptides onto major histocompatibility complex class I (MHC-I) molecules. Although this pathway is central to CD8⁺ T-cell activation, the molecular mechanisms that regulate intracellular antigen processing and redistribution during cross-presentation remain incompletely defined. In this study, we investigated the contribution of the large-pore channel Pannexin-1 (Panx1) to antigen handling during cross-presentation. Using confocal microscopy and quantitative image analysis in granulocyte–macrophage colony-stimulating factor/interleukin-4 (GM-CSF/IL-4)-derived inflammatory bone marrow-derived dendritic cell (BMDC)-like cellsexposed to ovalbumin (OVA)–Alexa Fluor 488, we observed time-dependent changes in intracellular antigen distribution that were altered upon pharmacological inhibition of Panx1 with the blocking peptide 10Panx1. In parallel, functional assays revealed that Panx1 inhibition significantly reduced SIINFEKL peptide-dependentactivation of B3Z CD8⁺ T-cell hybridomas following pulsing with full-length OVA. Similar effects were observed in the cross-presentation-competent MUTU1940 dendritic cell line. Importantly, Panx1 inhibition did not significantly affect dendritic-cell viability or LPS-induced activation under the experimental conditions tested. In contrast, pharmacological inhibition or genetic deficiency of P2X7 receptor (P2X7) did not produce comparable reductions in cross-presentation, and combined inhibition did not result in additive effects under the experimental conditions tested. Together, these findings provide functional evidence supporting a role for Panx1 in regulating intracellular antigen redistribution associated with cross-presentation. While not establishing direct genetic causality, our data identify Panx1 as a modulatory component influencing antigen-processing events that culminate in CD8⁺ T-cell activation, thereby expanding the current framework of intracellular antigen-processing mechanisms involved in dendritic-cell-mediated cross-presentation. Full article

Background: Heart failure patients are frequently prescribed SGLT2 inhibitors, but the incremental real-world benefit of adding GLP-1 receptor agonists is uncertain. Methods: A retrospective propensity-matched cohort study was conducted using the TriNetX Global Collaborative Network (171 healthcare organizations). Adults aged ≥18 years with incident heart failure who initiated either dual SGLT2 inhibitor and GLP-1 receptor agonist therapy or SGLT2 inhibitor monotherapy within 1 month of the first heart failure diagnosis were compared. Outcomes over 365 days included all-cause mortality, all-cause hospitalization, acute myocardial infarction, atrial fibrillation/flutter, acute kidney failure, pulmonary edema, new-onset diuretic use, urinary tract infection, retinopathy, and laboratory hypoglycemia (glucose ≤ 70 mg/dL). Cox proportional hazards models were used; the proportional hazards assumption was formally tested. Bonferroni and Benjamini–Hochberg adjustments were applied for multiple comparisons. E-values quantified robustness to unmeasured confounding. Appendicitis was used as a negative control outcome. Results: After 1:1 propensity score matching, 3421 patients were included in each cohort. Cohorts were well-balanced (all standardized mean differences < 0.10). Over 365 days of follow-up, no significant differences were observed between dual therapy and monotherapy in all-cause mortality (HR 0.92, 95% CI 0.77–1.09), all-cause hospitalization (HR 1.16, 95% CI 0.96–1.40), acute myocardial infarction (HR 1.20, 95% CI 0.92–1.55), atrial fibrillation/flutter (HR 1.05, 95% CI 0.85–1.30), acute kidney failure (HR 1.05, 95% CI 0.89–1.26), new-onset diuretic use (HR 0.92, 95% CI 0.78–1.09), or urinary tract infection (HR 1.16, 95% CI 0.90–1.48). Dual therapy was associated with a significant increase in retinopathy (HR 2.66, 95% CI 1.81–3.93; Bonferroni p = 0.001; E-value 4.77, lower CI bound 3.01), and a modest increase in laboratory hypoglycemia (HR 1.22, 95% CI 1.04–1.44) and pulmonary edema (HR 1.35, 95% CI 1.06–1.70), both of which survived FDR but not Bonferroni adjustment. Prespecified subgroup analyses showed lower mortality with dual therapy in patients aged 18–64 (HR 0.64, 95% CI 0.43–0.93) and in women (HR 0.60, 95% CI 0.45–0.81). The negative control outcome (appendicitis) was non-significant. Conclusions: In a propensity-matched real-world cohort with a conservative cohort definition, dual SGLT2 inhibitor and GLP-1 receptor agonist therapy was not associated with significant differences in mortality or major cardiovascular outcomes compared with SGLT2 inhibitor monotherapy. Subgroup signals favoring dual therapy in younger and female patients, alongside safety signals for retinopathy and laboratory hypoglycemia, are hypothesis-generating and should be confirmed in prospective trials. Full article

Background/Objectives: Chimeric antigen receptor T-cell (CAR-T) therapy has transformed outcomes in relapsed or refractory hematologic malignancies, but long-term cognitive outcomes remain poorly understood. We compared the incidence and time course of cognitive impairment and associated neurological complications after CAR-T therapy compared with autologous stem cell transplantation (ASCT). Methods: This retrospective, propensity-matched cohort study utilized the TriNetX US Collaborative Network (January 2014–April 2025). To ensure concurrent comparisons, ASCT recipients were restricted to an index date beginning in August 2017 or later. CAR-T recipients were matched 1:1 to ASCT recipients for demographics, disease, comorbidities, prior and concomitant treatments, and laboratory parameters. The primary endpoint was time to cognitive impairment, as defined by ICD-10 codes. Results: After comparing 3067 CAR-T patients (median follow-up 634 days) with 3067 ASCT patients (median follow-up 713 days), CAR-T recipients had a higher risk of cognitive impairment (HR 1.58; 95% CI 1.39–1.80; p < 0.001). Because the risks were not proportional (Schaenfeld p < 0.001), the difference was also expressed as restricted median survival time (RMST): CAR-T recipients spent approximately 25 and 53 days fewer days without cognitive impairment at 1 and 2 years, respectively (both p < 0.001). The risk was greatest at 30 days (HR 4.22; 95% CI 3.23–5.53), but remained elevated in control analyses at 30 and 90 days that excluded the acute ICANS window (HR 1.30 and 1.25, respectively; both p < 0.05). Neurological dysfunction, particularly encephalopathy (HR 2.04; 95% CI 1.73–2.40), was more common after CAR-T. Conversely, CAR-T was associated with a reduced risk of secondary acute myeloid leukemia (HR 0.46; 95% CI 0.38–0.55; p < 0.001). Conclusions: CAR-T therapy is associated with a higher risk of cognitive impairment that persists beyond the acute phase. As these are observational, code-based data, they should be interpreted as associations rather than evidence of a specific mechanism, and they highlight the need for informed consent discussions, long-term neurocognitive monitoring, and the development of neuroprotective strategies. Full article

Spermatogenesis is a highly coordinated biological process in which diploid spermatogonia undergo mitotic expansion, meiotic division, and terminal differentiation into haploid spermatozoa. This process is tightly regulated by intrinsic germ cell programs and extrinsic signals from Sertoli cells within the seminiferous epithelium. Among the signaling pathways governing male germ cell development, all-trans retinoic acid (RA), a bioactive metabolite of vitamin A, has emerged as a master regulator of meiotic initiation and spermatogonial differentiation in mammals. RA functions through nuclear retinoic acid receptors (RARs) and retinoid X receptors (RXRs), which regulate transcriptional networks essential for germ cell progression, including the activation of Stimulated by Retinoic Acid 8 (STRA8), a key determinant of meiotic entry. Intratesticular RA homeostasis is maintained by a balance between synthesis via aldehyde dehydrogenase (ALDH) enzymes and degradation by cytochrome P450 family 26 (CYP26) enzymes, ensuring precise temporal and spatial control of germ cell development. While rodent models have defined core mechanisms of RA signaling, the canine testis provides a valuable comparative and translational system due to its physiological similarity to human spermatogenesis and relevance to reproductive management. Recent studies highlight conserved RA signaling pathways in dogs, including receptor-mediated transcriptional regulation, feedback control of RA metabolism, and post-transcriptional modulation via microRNAs. Importantly, pharmacological manipulation of RA signaling can reversibly disrupt spermatogenesis, supporting its potential applications in non-hormonal male contraception. This review integrates molecular, developmental, pharmacological, and comparative evidence and presents RA signaling as a central regulatory axis of spermatogenesis with important translational applications. Full article

Background: Vector-borne diseases (VBDs) caused by Borrelia spp., Bartonella spp., and Babesia spp. are associated with neuropsychiatric morbidity. Cerebral folate deficiency (CFD), primarily caused by folate receptor-α autoantibodies (FRAAs) impairing folate blood–brain barrier transport, is a treatable contributor to neurodevelopmental disorders including pediatric acute-onset neuropsychiatric syndrome (PANS) and autism spectrum disorder. Despite overlapping clinical manifestations, FRAA prevalence in VBD populations has not been investigated. This study aimed to determine the prevalence of FRAA in patients with confirmed VBDs. Methods: This retrospective cohort study included 68 VBD-positive patients with and without PANS evaluated at a single clinical practice. VBD testing was performed by IGeneX Laboratories; FRAA analysis including binding, blocking, and soluble folate receptor (sFR) testing was performed by Religen Laboratories (Plymouth Meeting, PA). Statistical associations were assessed using Fisher’s exact test with Wilson 95% confidence intervals. Results: Of the 68 VBD-positive patients, 42 (61.8%; 95% CI: 49.9–72.4%) were also FRAA-positive. Soluble folate receptor (sFR) was detected in eight patients (11.8%; 95% CI: 6.1–21.5%), all of whom were binding FRAA-positive, with 87.5% carrying confirmed evidence of Borrelia species infection. Neuropsychiatric symptoms were highly prevalent across both groups but did not significantly differentiate FRAA-positive from FRAA-negative patients (all p > 0.05). Conclusions: This study demonstrates a high prevalence of FRAA in a pediatric VBD cohort. The sFR was strongly associated with Borrelia species infection, suggesting a potential mechanistic link between spirochetal infection and folate receptor autoimmunity. These findings support the consideration of FRAA testing in patients with VBDs and warrant further investigation in larger prospective cohorts. Full article

Zoonotic tuberculosis (zoonotic TB) caused by Mycobacterium bovis (M. bovis) accounts for up to 10% of human tuberculosis cases in some regions, but the underlying pathogenic mechanisms remain incompletely understood, especially those involved in cellular pyroptosis. This study aimed to explore the regulatory roles of non-coding RNA (ncRNA) in the pyroptosis of human monocytic THP-1 cells induced by M. bovis infection. An in vitro pyroptosis model was established by infecting THP-1 cells with M. bovis, followed by whole-transcriptome sequencing to identify differentially expressed messenger RNA (mRNA), long non-coding RNA (lncRNA), microRNA (miRNA), and circular RNA (circRNA). Bioinformatics analysis was performed to construct an lncRNA–miRNA–mRNA regulatory network associated with infection-induced pyroptosis; in addition, overexpression, knockdown, and dual-luciferase reporter assays and quantitative PCR were conducted to verify the interactions and functions of metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), miR-20b-5p, and purinergic receptor P2X7 (P2RX7). Transcriptome analysis detected 741 mRNAs, 1049 lncRNAs, 25 circRNAs, and 40 miRNAs with significant differential expression in infected THP-1 cells. Specifically, MALAT1 and P2RX7 were upregulated, while miR-20b-5p was downregulated after infection. Knockdown of MALAT1 or P2RX7 and overexpression of miR-20b-5p relieved M. bovis-induced pyroptosis in THP-1 cells. Mechanistically, MALAT1 targeted miR-20b-5p, which directly targeted P2RX7, and overexpression of miR-20b-5p partially reversed P2RX7 upregulation mediated by MALAT1 overexpression. This study provides a transcriptomic characterization of M. bovis-induced pyroptosis in THP-1 cells and supports the MALAT1–miR-20b-5p–P2RX7 axis as a potential regulatory mechanism involved in this process, offering initial molecular insights into the pathogenesis of zoonotic TB. Full article