Search Results (223)

This study investigated the ethanolic leaf extract of Brazilian pepper tree (Schinus terebinthifolius Raddi) for its metabolite composition and effects on growth performance and intestinal immune gene expression in Nile tilapia (Oreochromis niloticus). Ultra-performance liquid chromatography-electrospray ionization-mass spectrometry (UPLC-ESI-MS/MS) in positive and negative modes revealed a diverse profile of 33 peaks in each polarity, identifying key compounds such as phenolic acids (e.g., gallic acid and ferulic acid), flavonoids (e.g., myricetin-O-glucoside and quercetin 3-O-glucoside), gallotannins (e.g., glucogallin and pentagalloylglucose), and triterpenoids (e.g., masticadienoic acid). A 60-day feeding trial with four groups (control and three extract doses; 0.5%; T0.5%, 1%; T1% and 2%; T2%) demonstrated dose-dependent enhancements in growth metrics, where final body weight increased by up to 106.9 ± 3.6 g, weight gain% by 197.3 ± 3.5%, and the growth rate got more than doubled in T2% (2.4 ± 0.1), alongside improved feed conversion ratio (1.24 ± 0.01) at 30 days and condition factor (stabilized at 2.1 ± 0.0) at 60 days post-feeding. Viscero- and gastro-somatic indices declined insignificantly in most feed groups, indicating improved muscle growth. Biphasic patterns were observed in intestinal gene expression as follows: over 60 days, the IL-1β gene upregulated at low doses but returned to normal at high doses. The IL-10 gene upregulated progressively, promoting an anti-inflammatory balance. In fish fed medium and high doses (T1% and T2%), the IgM gene is upregulated, supporting humoral immunity. These outcomes, linked to the extract’s previously described antioxidants, anti-inflammatory, and antimicrobial bioactive compounds, suggest that S. terebinthifolius is a promising natural feed additive for sustainable tilapia aquaculture and warrants further validation for commercial application. Full article

Background: Measles remains a global public health threat despite the availability of an effective vaccine and substantial progress toward elimination in many countries. Outbreaks in highly vaccinated settings suggest that waning vaccine-induced immunity, particularly among adults, may create silent susceptibility gaps capable of sustaining viral transmission. Aim: To evaluate age- and cohort-specific patterns of measles-specific antibody levels in Mexican adults and to examine evidence suggesting lower vaccine-induced antibody levels in younger vaccinated cohorts. Methods: A cross-sectional seroepidemiological study was conducted among 302 voluntary blood donors aged 18–70 years. Demographic, clinical, and vaccination data were collected through structured interviews. Serum anti-measles-virus (MV) IgG levels were quantified using a commercial ELISA. Antibody concentrations were analyzed according to age, sex, vaccination history, self-reported measles infection, and historical vaccination strategies. Multivariate linear models were applied to identify factors associated with IgG levels. Results: Anti-MV IgG seropositivity (>200 mIU/mL) was 67.2%, with a geometric mean concentration (GMC) of 270.43 mIU/mL. A positive correlation was observed between age and antibody levels (r_s = 0.161, p = 0.005). Individuals born before the introduction of the measles vaccine (pre-1970) had significantly higher GMCs (1096.63 mIU/mL) than younger cohorts. A history of natural infection tended to be associated with higher antibody levels (GMC: 428.38 vs. 257.24 mIU/mL; p = 0.051). In multivariate analysis, historical vaccination strategy emerged as the primary factor associated with antibody levels, whereas age alone was not significant. Conclusions: Cohort-specific differences in measles IgG levels suggest generational patterns of immunity and are consistent with diminished vaccine-induced antibody levels in younger adults in the absence of natural boosting. These findings highlight the importance of ongoing serological surveillance in post-elimination settings and underscore the need for targeted public health interventions. Full article

Background: Transferrin receptor-targeting monoclonal antibodies (TfRMAbs) enhance brain drug delivery by facilitating TfR-mediated transcytosis across the blood–brain barrier (BBB). Data suggest that chronic TfRMAb dosing reduces their plasma exposure in a dose- and fusion partner-dependent manner; however, the underlying mechanisms remain unclear. The neonatal Fc receptor (FcRn) extends IgG half-life via recycling, but its saturation after repeated doses may alter the pharmacokinetics (PK) of IgG fusion proteins. This study evaluated the role of the FcRn on the PK and biodistribution of TfRMAb fusion proteins. Methods: We examined TfRMAb alone and TfRMAb fused to erythropoietin (TfRMAb-EPO) or TNFα receptor (TfRMAb-TNFR) in wild-type (WT) and FcRn knockout (KO) mice following acute (single dose) or chronic (3× weekly for 4 weeks) subcutaneous administration at 3 mg/kg. Plasma levels, tissue biodistribution, and FcRn binding were measured using immunoassays. Results: Our results show that fusion partners influenced FcRn-mediated recycling and PK of TfRMAb fusion proteins. After acute dosing, TfRMAb-TNFR exhibited the greatest reduction in plasma exposure in FcRn KO versus WT mice, compared with TfRMAb and TfRMAb-EPO. Chronic dosing reduced the plasma persistence of all fusion proteins in WT mice. In FcRn KO mice, plasma exposure of TfRMAb and TfRMAb-EPO decreased with chronic dosing, whereas TfRMAb-TNFR showed no further reduction. Differences in FcRn binding affinity likely explain these patterns. Tissue distribution largely mirrored plasma concentrations. Conclusions: FcRn regulates plasma concentrations of TfRMAb fusion proteins in a fusion partner-dependent manner. While FcRn-mediated protection regulates plasma exposure with acute dosing, additional mechanisms beyond FcRn saturation appear to regulate plasma exposure during chronic dosing. Full article

Background/Objectives: Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by B-cell hyperactivation and excessive autoantibody production. Z-DNA binding protein 1 (ZBP1), an innate immune sensor involved in nucleic acid recognition and cell death signaling, has been implicated in antiviral and inflammatory responses. However, its role in B-cell dysregulation during SLE remains unclear. Methods: Integrative transcriptomic analyses were performed using public datasets (GSE61635, GSE235658, GSE136035, and GSE163497) to determine the expression pattern and biological functions of ZBP1 in SLE. Bulk RNA-seq and single-cell RNA-seq data were used to evaluate ZBP1 expression across B-cell subsets. Correlations between ZBP1 expression, disease activity, and immunological parameters were assessed. RNA-seq data following ZBP1 knockdown were analyzed to explore its potential downstream pathways and molecular networks. In addition, in vitro ZBP1 knockdown experiments were conducted to examine its effects on B-cell activation, plasma cell differentiation, and antibody production. Results: ZBP1 was significantly upregulated in peripheral blood and B cells from SLE patients and was enriched in pathways related to type I interferon signaling and cytokine-mediated immune responses. Single-cell transcriptomic profiling further revealed elevated ZBP1 expression across multiple B-cell subsets, including naïve B cells, memory B cells, age-associated B cells (ABCs), and plasma cells. Clinically, ZBP1 expression in peripheral B cells was positively correlated with CD86 mean fluorescence intensity (MFI), SLE Disease Activity Index (SLEDAI) scores, and serum IgG levels, suggesting a link between ZBP1 and B-cell activation. RNA-seq analysis following ZBP1 silencing demonstrated that ZBP1 regulates genes involved in the cell cycle, DNA replication, and p53 signaling, indicating its potential role in promoting B-cell proliferation and activation. Functionally, ZBP1 silencing impaired B-cell activation, reduced plasma cell differentiation, and decreased immunoglobulin production in vitro. Conclusions: Our study identifies ZBP1 as a molecule upregulated in SLE B cells and associated with B-cell activation and disease activity. Although direct causality remains to be established, the data indicate that ZBP1 may contribute to SLE pathogenesis by modulating cell cycle-related pathways and promoting aberrant B-cell responses, highlighting its potential as a biomarker and a candidate therapeutic target in SLE. Full article

Traditional statistical approaches identify group-level associations between biomarkers and rupture status in intracranial aneurysms (IAs) but often miss nonlinear interactions at the patient level. Methods: The authors retrospectively analyzed 35 saccular IAs in 35 patients (57.1% ruptured) from a single center (2021–2023). Demographics, detailed morphology (e.g., neck width, aspect ratio, VERTI, irregular shape), and multi-site inflammatory/immune markers (CRP; complement C3/C4; IgA/IgG/IgM) were included. After preprocessing (min–max scaling; one-hot encoding), five algorithms (DT, AdaBoost, GBM, XGBoost, RF) were evaluated with stratified five-fold CV and class balancing via random oversampling. The primary model (Random Forest) was tuned with Optuna and explained using global feature importance and LIME. The results showed that baseline RF achieved CV ROC-AUC 0.81 and test ROC-AUC 0.92 (test accuracy 0.857). The tuned RF (with oversampling and Optuna) yielded a mean CV accuracy of 0.85 ± 0.09 and CV ROC-AUC of 0.98 ± 0.07 while maintaining test ROC-AUC of 0.92. The average precision on the test PR curve was 0.97. The most influential predictors combined inflammatory markers (CRP, C3, C4) with morphology (neck width, irregular shape). LIME revealed consistent local patterns: low A.CRP/C.CRP and lower C3/C4 favored Not-Broken, whereas higher CRP/complement with smaller neck and irregular shape pushed toward Broken classifications. It can be concluded that an interpretable machine learning (ML) pipeline captured clinically plausible, nonlinear interactions between inflammation and aneurysm geometry. Integrating explainable ML with conventional statistics may enhance rupture risk stratification, enable patient-level rationale, and inform personalized management. These results could significantly contribute to the quality of treatment for patients with intracranial aneurysms. Full article

Optic neuritis (ON) has been recognized since antiquity, but its modern clinical identity emerged only in the late 19th century and was definitively shaped by the Optic Neuritis Treatment Trial (ONTT). The ONTT established the natural history, visual prognosis, association with multiple sclerosis (MS), and therapeutic response to corticosteroids, building the foundation for contemporary ON management. Subsequent discoveries—most notably aquaporin-4 IgG-associated ON (AQP4-ON), myelin oligodendrocyte glycoprotein antibody-associated ON (MOG-ON), and double-negative ON—have fundamentally transformed this paradigm, shifting ON from a seemingly uniform demyelinating syndrome to a group of biologically distinct disorders. These subtypes differ in immunopathology, clinical course, MRI features, retinal injury patterns, CSF profiles, and long-term outcomes, making early and accurate differentiation essential. MRI provides key distinctions in lesion length, orbital tissue inflammation, bilateral involvement, and chiasmal or optic tract extension. Optical coherence tomography (OCT) offers complementary structural biomarkers, including severe early ganglion cell loss in AQP4-ON, relative preservation in MOG-ON, and variable patterns in double-negative ON. CSF analysis further refines diagnosis, with oligoclonal bands strongly supporting MS-ON. Together, these modalities enable precise early stratification and timely initiation of targeted immunotherapy, which is critical for preventing irreversible visual disability. Despite major advances, significant unmet needs persist. Access to high-resolution MRI, OCT, cell-based antibody assays, and evidence-based treatments remains limited in many regions, contributing to global disparities in outcomes. The understanding of the pathogenesis of double-negative optic neuritis, the identification of reliable biomarkers of relapse and visual recovery, and the determination of standardized cut-off values for multimodal diagnostic tools—including MRI, OCT, CSF analysis, and serological assays—remain unresolved challenges. Future research must expand biomarker discovery, refine imaging criteria, and ensure equitable global access to cutting-edge diagnostic platforms and therapeutic innovations. Four decades after the ONTT, ON remains a dynamic field of investigation, with ongoing advances holding the potential to transform care for patients worldwide. Together, these advances expose a fundamental tension between historically MS-centered diagnostic frameworks and the emerging biological heterogeneity of ON, a tension that underpins the structure and critical perspective of the present review. Full article

Anti-p200 pemphigoid is an autoimmune blistering disease (AIBD) caused by autoantibodies against laminin β4 and/or γ1, and clinically resembles bullous pemphigoid (BP) as well as the inflammatory variant of epidermolysis bullosa acquisita (EBA). All three diseases show IgG and/or C3 deposition along the cutaneous basement membrane zone (BMZ). Although complement activation is central to BP and EBA pathogenesis, its role in anti-p200 pemphigoid remains unclear. To investigate this, we analyzed inflammatory infiltrates in lesional and perilesional skin from anti-p200 pemphigoid patients (n = 11), revealing a neutrophil-predominant pattern, with mixed neutrophil–eosinophil infiltrates in 81% of cases, which contrasted with the eosinophil-rich infiltrates typical of BP. Infiltrating neutrophils expressed C5aR1 and C5aR2. Complement fixation test (CFT) of patient sera demonstrated C3c deposition at the BMZ in 40% (20/50) of anti-p200 pemphigoid cases and 87% (13/15) of BP cases. Patients in both cohorts could be stratified into high, mild, and non-complement-fixating groups. Pharmacological inhibition of C1s (sutimlimab), C3 (compstatin), C5 (tesidolumab), or C5aR1 (avacopan) significantly blocked C3c or C5 deposition in vitro. These findings indicate that selective blockade of the classical, alternative, or terminal complement pathways effectively prevents BMZ complement deposition, highlighting pathway-specific complement inhibition as a potential therapeutic strategy for anti-p200 pemphigoid. Full article

This study investigates the glycosylation patterns of serum IgG antibodies in relation to COVID-19 infection and vaccination, highlighting the potential of specific glycan profiles as biomarkers for immune responses. Using Spearman correlation analysis, distinct associations among glycan levels and various clinical laboratory parameters were identified, revealing complex, non-linear interactions that influence immune dynamics. Significant differences were observed in sialylated glycan profiles across patient groups, indicating that vaccination and natural infection elicit unique immune mechanisms and suggesting that vaccination induces favorable glycosylation changes. Notably, high-mannose glycans were found to correlate with other glycan types, underscoring their critical role in the immune response and suggesting their potential as biomarkers to differentiate between infection- and vaccination-induced immunity. The findings suggest that understanding these glycosylation dynamics may enhance diagnostic and therapeutic strategies, providing valuable tools for differentiating between immune responses elicited by infection and vaccination. Overall, this study contributes to the understanding of glycosylation’s impact on immune function in the context of COVID-19, emphasizing the importance of specific glycan markers, such as sialylated and high-mannose structures, in clinical applications. Full article

B cells are key drivers of immune dysregulation across systemic autoimmune diseases. Among their progeny, plasmablasts occupy a uniquely revealing niche: short-lived, highly proliferative intermediates that mirror real-time B-cell activation. Their appearance in peripheral blood integrates antigenic stimulation, cytokine-driven differentiation, and aberrant germinal-center dynamics, transforming them into sensitive indicators of ongoing immunological activity. This review synthesizes current knowledge on plasmablast biology and highlights disease-specific phenotypes across systemic lupus erythematosus (SLE), primary Sjögren disease (pSjD), IgG4-related disease (IgG4-RD), ANCA-associated vasculitis (AAV), and rheumatoid arthritis (RA). We incorporate molecular insights from single-cell technologies that have uncovered previously unrecognized plasmablast subsets, metabolic states, and interferon-related signatures with prognostic and mechanistic value. Beyond descriptive immunology, plasmablasts are emerging as dynamic biomarkers capable of informing real-time clinical decisions. One of the most robustly supported applications is the prognostic interpretation of plasmablast kinetics following B-cell-depleting therapies, where early reconstitution patterns consistently predict relapse across multiple autoimmune conditions. As clinical immunology shifts from static serological markers toward kinetic, cell-based monitoring, plasmablast quantification offers a path toward precision immune surveillance. Integrating plasmablast dynamics into routine care may ultimately allow clinicians to anticipate disease flares, time therapeutic reinforcements, and transition from reactive management to preventive intervention. Full article

Background: Food allergy is a growing public health concern, and oral immunotherapy (OIT) has emerged as a promising approach to induce desensitization and potentially sustained unresponsiveness to allergenic foods. Changes in humoral immunity, particularly in allergen-specific immunoglobulin levels, play a central role in the immunological mechanisms underlying OIT. This review aims to summarize the current evidence on how OIT modulates allergen-specific immunoglobulin E (IgE), G (IgG) and A (IgA) responses in individuals with food allergy. Methods: We conducted a review of original research articles reporting longitudinal data on allergen-specific IgE, IgG, and/or IgA in patients undergoing OIT for common food allergens. Results: OIT was consistently associated with a transient increase in allergen-specific IgE levels during early phases, followed by a gradual decline. In contrast, Allergen-specific IgG4 levels showed a robust and sustained increase, correlating with desensitization and proposed to function as blocking antibodies. Several studies also reported an increase in allergen-specific IgA, particularly secretory IgA at mucosal sites, suggesting a potential role in enhancing mucosal tolerance and immune exclusion of allergens. Conclusions: Humoral immune responses during OIT are characterized by distinct and dynamic changes in immunoglobulin patterns. In particular, the rise in IgG4 and, in some cases, IgA suggests a role in promoting tolerance. Monitoring these biomarkers may offer insights into treatment efficacy and support individualized approaches to OIT. Full article

Background: Dengue is a growing mosquito-borne viral infection of global concern. It remains a major public health challenge in Nepal, where reliable biomarkers for disease staging and prognosis are lacking. In this study, we investigated circulating microRNA-1246 (miR-1246) as a potential diagnostic and prognostic marker in dengue infection. Methods: Serum samples from 21 dengue-positive patients and 20 healthy controls were analyzed by quantitative Reverse Transcription Polymerase Chain Reaction (RT-qPCR), with RNU6 as an internal control. Results: Dengue patients showed markedly elevated miR-1246 levels, with a mean 47-fold increase compared to controls (p = 0.001). Expression varied by disease stage, peaking in IgM positive cases, declining in weakly positive IgM patients, and reaching the lowest levels in IgG positive convalescent cases, a pattern consistent with clinical parameters such as platelet recovery. Receiver Operating Characteristic (ROC) analysis further highlighted diagnostic potential, yielding an Area Under the Curve (AUC) of 0.79, sensitivity of 95.24%, and specificity of 60.00%. Conclusions: These findings imply that miR-1246 is drastically dysregulated during dengue infection and could be a useful biomarker for tracking the intensity and course of the illness. Full article

Background/Objectives: Tuberculosis (TB) remains the leading cause of death from a single infectious agent worldwide. In line with the World Health Organization’s (WHO) goal to end TB by 2035, the rapid development and clinical implementation of new, effective vaccines is urgently needed. To support global TB control efforts, we developed a novel candidate subunit multistage vaccine. Methods: This vaccine incorporates multiple Mycobacterium tuberculosis antigens expressed during both dormant and active stages of infection, fused into a single recombinant protein (ESAT6-CFP10-Ag85A-Rv2660c-Rv1813c). The antigen was encapsulated in biodegradable poly(D,L-lactide-co-glycolide) (PLGA) nanoparticles along with the pattern recognition receptor (PRR) agonists monophosphoryl lipid A (MPLA) and muramyl dipeptide (MDP), which function as adjuvants. Results: Using a mixed intramuscular/nasal prime-boost regimen, the vaccine elicited a mixed Th1/Th17 cell-mediated immune response, as well as a robust humoral response characterized by sustained systemic IgG (lasting at least one year) and prominent local secretory IgA. The vaccine demonstrated protective efficacy as a prophylactic booster following BCG priming in both murine and guinea pig models and was also effective in a therapeutic setting in a murine infection model. Conclusions: The results of this study provide empirical evidence that multistage tuberculosis vaccines represent a promising strategy for achieving global TB control. Full article

Balancing tourism industry (TI) growth and ecological protection is critical for sustainable development in the Yellow River Basin (YRB), China’s vital ecological security barrier and economic belt. However, existing research lacks a spatial perspective on the coordinated development between TI and inclusive green growth (IGG), with limited understanding of cross-regional spillover mechanisms. Based on panel data from 75 cities in the YRB (2011–2023), this study constructs a comprehensive evaluation system encompassing the scale, structure, and potential dimensions of the TI and the economic, social, livelihood, and environmental dimensions of IGG. The study employs the coupling coordination degree (CCD) model, exploratory spatial data analysis (ESDA), and the Spatial Durbin Model (SDM) to examine spatiotemporal evolution and spillover effects. The results reveal an upward yet fluctuating coordination trend with pronounced spatial heterogeneity, characterized by a “downstream–midstream–upstream” gradient pattern, dual-core radiation centered on the Jinan–Qingdao and Xi’an–Zhengzhou agglomerations, and persistent High–High clusters in the Shandong Peninsula contrasted with Low–Low clusters in the upstream Qinghai–Gansu–Ningxia region. Critically, new-quality productive forces exert significant positive direct and spillover effects, while industrial structure and government intervention have inhibitory spatial effects on adjacent cities. Regional heterogeneity analysis confirms factor-endowment-driven differentiation across upstream, midstream, and downstream areas. These findings advance spatial spillover theory in river basin contexts and provide evidence-based pathways for balancing economic growth with ecological protection in ecologically sensitive regions worldwide, directly supporting multiple UN Sustainable Development Goals. Full article

Background: The link between clinical recovery and immune restoration after severe COVID-19 remains poorly defined. Although most survivors experience symptomatic improvement, persistent symptoms have been hypothesized to reflect ongoing immune dysregulation. Methods: This prospective cohort study followed 93 unvaccinated adults with RT-PCR-confirmed moderate-to-critical COVID-19 at 3, 6, and 12 months post-discharge. Clinical assessments used structured interviews to evaluate the persistent symptoms. Peripheral blood analyses were used to measure lymphocyte subsets, immunoglobulins, and complement components. Results: Clinical recovery was substantial; fatigue prevalence declined from 70.9% to 24.7% and dyspnea prevalence from 81.7% to 25.8% by 12 months (p < 0.001 for both). However, immune recovery exhibited divergent patterns. Activated T cells (CD3⁺HLA-DR⁺) decreased significantly (from 20% to 13%; p < 0.001), complement C3c levels paradoxically increased from 1.23 to 1.35 g/L (p < 0.001), and serum IgA increased by 32% (p = 0.003). NK cells remained stable overall but were persistently reduced in a subset (~25%) of patients, particularly among those with fatigue and dyspnea. Critical illness was associated with slower T-cell resolution, prolonged IgM elevation, and increased complement activity. Conclusions: One year after hospitalization, most patients achieved substantial clinical improvement, but immune reconstitution lagged behind. These findings highlight the dissociation between clinical and immunological recovery and suggest that persistent immune dysregulation may be associated with long COVID manifestations. Incorporating immune monitoring into post-COVID care may help identify patients at risk of prolonged sequelae and guide targeted therapeutic strategies. Full article

Background: Cholangiocarcinoma (CCA) has the highest incidence in Northeastern Thailand, where patients generally present with late diagnosis and poor prognosis. Opisthorchis viverrini (OV) infection is the major cause of CCA, with oxidative stress driving DNA mutations and genetic instability. Microsatellite instability (MSI) is a predictive biomarker in several cancers. This study aimed to investigate MSI status and its association with clinicopathological features and survival of CCA patients. Methods: Tissue and serum samples were collected from 25 surgical CCA patients. MSI status and mismatch repair (MMR) proteins were evaluated using an MSI scanner and immunohistochemistry (IHC). Serum OV IgG was assessed by ELISA, while tumor-infiltrating lymphocytes (TILs) were evaluated by two pathologists. Associations of MSI with clinicopathological features, OV status, MMR, and survival were analyzed. Results: Among CCA patients, 66.7% were MSI-high and 33.3% were MSI-low. MSI-high significantly correlated with age < 57 years, intraductal growth pattern, OV positivity, and early-stage disease. Patients with MSI-high and high TILs showed markedly improved median survival compared to MSI-low with low TILs (94.0 vs. 16.8 and 3.0 months; HR = 6.82 and 14.10; p = 0.004 and 0.001). Incorporation of MSI and TILs remained an independent prognostic factor in multivariate analysis (p < 0.05). Conclusions: MSI-high is highly prevalent in OV-associated CCA and is associated with intraductal growth, OV infection, and early-stage disease. Combined MSI and TIL status may serve as an independent prognostic factor, warranting validation in larger cohorts. Full article