Search Results (31,654)

Toll-like receptor 9 (TLR9) and Toll-like receptor 3 (TLR3), which are widely expressed in dendritic cells (DCs), function as key pattern recognition receptors (PRRs) in the immune system. Their primary roles involve specifically detecting pathogen-associated molecular patterns (PAMPs): TLR9 recognizes unmethylated CpG motifs predominantly found in bacterial and viral DNA, while TLR3 identifies viral double-stranded RNA (dsRNA), a molecular signature associated with viral replication. Their specific agonists [CpG ODN (a TLR9 agonist) and poly(I:C) (a TLR3 agonist)] can effectively activate DCs and enhance the expression of immune activation-related molecules. In this study, by establishing a mouse primary dendritic cell model and a glioma-bearing mouse model, and employing techniques such as transcriptome sequencing, we found that combined stimulation with CpG ODN and poly(I:C) significantly enhanced the anti-tumor function of DCs: in vitro, DCs subjected to combined stimulation showed upregulation of anti-tumor-related surface markers, enhanced migratory capacity, and a more effective activation of CD8⁺ T cells; in vivo, a DC vaccine loaded with tumor lysate antigen and stimulated with this combined regimen significantly delayed the progression of glioma in tumor-bearing mice. Further investigation revealed that the underlying mechanism for this enhanced effect may involve TLR9 activation promoting TLR3 upregulation through the p38 MAPK-ATF3 signaling axis. Consequently, we designed a sequential stimulation protocol (first CpG ODN then poly(I:C)), which demonstrated a stronger anti-glioma effect compared to simple combined stimulation. This study provides a new strategy for enhancing the immune efficacy of DC vaccines and has potential significance for promoting the clinical translation of DC vaccines. Full article

Alzheimer’s disease (AD) is the leading cause of dementia and is often prefaced by mild cognitive impairment (MCI). Detection of AD-related changes via blood-based biomarkers would enable critical therapeutic interventions early in disease progression. Neuronal enriched extracellular vesicle (NEEV) miRNAs regulate peripheral genes as a response to early AD brain changes and hence may have biomarker potential. Plasma NEEVs were captured from plasma samples of Mexican Americans (MAs) and Non-Hispanic Whites (NHWs) using an antibody against the neuronal surface marker CD171. miRNAs isolated from NEEVs were sequenced and analyzed using miRDeep2/DEseq2 and QIAGEN RNA-seq portal for differential expression between cognitively impaired (CI) and cognitively unimpaired controls. hsa-miR-122-5p was significantly underrepresented in the CI group in both MAs and NHWs compared to the healthy control. Other population-specific miRNAs (MAs: hsa-miR-26a-5p, hsa-let-7f-5p, and hsa-miR-139-5p, NHWs: hsa-miR-133a-3p, hsa-miR-125b-5p, and hsa-miR-100-5p) identified may have biomarker potential in AD precision medicine. Some of these differentially expressed miRNAs were associated with key AD-related comorbidities such as APOE genotype, age, and metabolic burden and were predicted to target genes within NF-κB -regulated inflammatory pathways. Together, these findings suggest that dysregulated miRNA networks may serve as a mechanistic link between comorbidity burden and AD-related neuroinflammation and neurodegeneration. Full article

Background/Objectives: Cytokine release during organ transplantation contributes to primary graft dysfunction and requires careful immunomodulation. CytoSorb, a hemoadsorption device developed to reduce circulating cytokine levels, is increasingly used in critically ill patients. However, its impact on concurrent immunosuppressive therapy remains unclear. Methods: In this ex vivo study, we investigated the adsorption of five immunosuppressants—cyclosporine A, tacrolimus, methylprednisolone, mycophenolic acid, and 6-mercaptopurine—using a scaled-down CytoSorb hemoadsorption circuit and compared results to chronic and acute dialysis. Additionally, a whole blood model was used to assess the functional impact of CytoSorb treatment on leukocyte activation, using LPS and anti-CD3 stimulation and subsequent cytokine measurement (TNF-α, IL-1β, IL-6, IL-8). Results: CytoSorb significantly reduced serum levels of methylprednisolone (92 ± 3%), mycophenolate (80 ± 2%), 6-mercaptopurine (65 ± 32%), and cyclosporine A (61 ± 16%), but had no significant effect on tacrolimus. Dialysis effectively removed methylprednisolone and 6-mercaptopurine, while strongly protein-bound drugs such as cyclosporine A and tacrolimus remained largely unaffected. In the whole blood model, CytoSorb treatment did not significantly alter cytokine release after immunostimulation, suggesting preserved immunosuppressive efficacy. Conclusions: CytoSorb treatment reduces the plasma concentration of selected immunosuppressants. However, short-term treatment appears to have minimal impact on immunosuppressive function. These findings support the cautious use of CytoSorb in transplant settings but highlight the need for in vivo confirmation. Full article

The current knowledge on the histological structure of the gastrointestinal tract (GIT) in cetaceans is based on general descriptions. The aim of this study was to characterize the histology and expression of immune cell markers in samples from the GIT and lymph nodes (LNs) in a harbour porpoise (Phocoena phocoena) bycaught in the Cantabrian Sea. The thickness of the histological layers of the GIT was measured, being greater in the stomach and anal canal, although no significant differences were found among any intestinal segment (p = 0.448). Variation in thickness, morphology of the folds, and the presence of Peyer’s patches allowed the duodenal ampulla and the distal segments to be distinguished from the rest of the intestine. An immunohistochemical technique was performed to identify the following markers: IBA1 for macrophages, CD3 for T lymphocytes, and CD20 for B lymphocytes. The distribution of immune cells varied significantly along the GIT, with higher percentages of all three cell types in the distal intestine and the anal tonsil. Within the LNs, B lymphocytes represented the predominant cell population. This study provides the first description of the histological structure of the GIT and associated lymphoid tissue in a harbour porpoise, which will be useful for future research studies. Full article

Inflammatory Bowel Diseases (IBDs), including Crohn’s disease (CD) and ulcerative colitis (UC), have become a growing global health concern in children and adolescents. Pediatric-onset IBD presents unique challenges compared with adult-onset forms, including more extensive disease, impaired growth, delayed puberty, and psychosocial difficulties. While biologic and targeted therapies have advanced disease control, nutritional interventions remain a central component of management. Exclusive enteral nutrition (EEN) is recognized as the first-line therapy for inducing remission in pediatric CD, offering comparable efficacy to corticosteroids with additional benefits for mucosal healing, nutritional status, and growth. Modified dietary approaches, such as partial enteral nutrition and the Crohn’s Disease Exclusion Diet (CDED), show promise for improving adherence and maintaining remission. However, dietary restrictions may lead to deficiencies and psychosocial stress, underscoring the importance of individualized, dietitian-supervised care. The role of nutrition in UC is less defined, but balanced, anti-inflammatory dietary patterns appear beneficial. This narrative review summarizes current evidence on nutritional strategies in pediatric IBD, highlighting their therapeutic potential, limitations, and integration with pharmacologic treatment within a multidisciplinary framework aimed at optimizing outcomes and quality of life. Full article

CIE recommendations for architectural exterior illumination provide general guidelines for highlighting building forms, with emphasis on edges, curvature, and spatial layering. However, they do not explicitly address luminance contrast disposition—specifically, whether elements further from the viewer should appear brighter or if those closer should be more intensely lit. Inspiration for addressing this problem can be drawn from the principles of Renaissance and Baroque paintings, where techniques of working with light evolved from dramatic contrasts to more rational and balanced approaches, offering valuable models for contemporary illumination design. This study compares the principles of painting from that period with eye-tracking and survey-based methods to investigate whether the arrangement of luminance contrasts of illuminated building facades significantly influences viewers’ visual attention, aesthetic judgment, and perception of depth. The verification was conducted in two stages using three lighting variants of a selected architectural object. These variants differed in the luminance contrast distribution between surfaces closer to and farther from the observer, while maintaining a constant average luminance level across the entire façade of 10 cd/m². The first stage analysed visual reactions of 116 (out of 178) participants to luminance changes across the multi-segmented façade, presented in a darkened room on a luminance-calibrated display. The second stage involved a survey in which 358 participants were asked about their lighting preferences. Participants—including both design professionals and laypeople—exhibited consistent perceptions regarding how different lighting configurations affected their impression of the building. The results revealed that luminance disposition significantly influenced the perceived volume of the structure, particularly the sense of depth. Eye-tracking data also indicated a strong positive correlation between subjective aesthetic assessments and patterns of visual attention. Full article

Background/Objectives: Primary central nervous system lymphoma (PCNSL) has a markedly high proliferation rate, making early diagnosis and prompt therapeutic intervention essential. To accelerate diagnosis, our institution adopted flow cytometry (FCM) in conjunction with conventional histopathology, and this study therefore evaluated the diagnostic performance of FCM for PCNSL. Methods: We retrospectively analyzed 67 consecutive patients with suspected PCNSL who underwent intraoperative FCM between 2010 and 2023 based on preoperative imaging. B-cell clonality was defined as ≥20% CD19/CD20-positive cells with a κ/λ ratio of >3.0 or <0.5. Results: Using histopathology, we confirmed the presence of PCNSL in 42 patients, all diagnosed as having diffuse large B-cell lymphoma. Six cases (14.3%) were discordant (FCM-D). The sensitivity, specificity, and positive predictive value of FCM were 85.7%, 100%, and 100%, respectively. T-cell markers were significantly elevated in FCM-D cases (p < 0.01), although these were pathologically diagnosed as diffuse large B-cell lymphoma based on histology and immunohistochemistry. Conclusions: FCM yields reliable diagnostic information within hours of tissue collection and supports early therapeutic decisions in PCNSL. Discordant results may reflect reactive T-cell infiltration. This is the first study to present detailed subset analyses in PCNSL using FCM in correlation with pathology, underscoring its utility as a rapid diagnostic tool. Full article

This study introduces a health-aware fuzzy logic (FL) energy management strategy (EMS) for fuel cell electric commercial vehicles (FCECVs) that aimed to improve energy efficiency and extending fuel cell system (FCS) lifespan. The FL-based EMS was developed using vehicle power demand and battery state of charge (SOC) as inputs, with the FCS power change rate as the output, aiming to mitigate degradation induced by abrupt load transitions. A multi-objective optimization framework was established to optimize the fuzzy logic controller (FLC) parameters, achieving a balanced trade-off between fuel economy and FCS longevity. The non-dominated sorting genetic algorithm-II (NSGA-II) was utilized for optimization across various driving cycles, with average Pareto-optimal solutions employed for real-time application. Performance evaluation under standard and stochastic driving cycles benchmarked the proposed strategy against dynamic programming (DP), charge-depletion charge-sustaining (CD-CS), conventional FL strategies, and a non-optimized baseline. Results demonstrated an approximately $38\%$ reduction in hydrogen consumption (HC) relative to CD-CS and over $75\%$ improvement in degradation mitigation, with performance superior to that of DP. Although the strategy exhibits an average $17.39\%$ increase in computation time compared to CD-CS, the average single-step computation time is only $2.1$ ms, confirming its practical feasibility for real-time applications. Full article

This study presents the design and application of an electrochemical sensor for selective detection of lead ions (Pb²⁺) based on ionophore-modified raspberry-like Fe₃O₄–Au nanostructures. The material was engineered with a magnetic Fe₃O₄ core, coated with polyethyleneimine (PEI) to facilitate nucleation, and subsequently decorated with Au nanoparticles, providing a raspberry-like (Fe₃O₄@PEI@AuNPs) nanostructure with high surface area and excellent electrochemical conductivity. Surface functionalization with Lead Ionophore IV (ionophore thiol) introduced Pb²⁺-selective binding sites, whose presence and structural evolution were verified by TEM and Raman spectroscopy. The Fe₃O₄ core endowed strong magnetic properties, enabling facile manipulation and immobilization onto screen-printed carbon electrodes (SPCEs) via physical adsorption, while the Au nanoparticles enhanced electron transfer, supplied thiol-binding sites for stable ionophore anchoring, and increased the effective electroactive surface area. Operational conditions were systematically optimized, with acetate buffer (HAc/NaAc, pH 5.7) and chronoamperometric preconcentration (CA) at −1.0 V for 175 s identified as optimal for differential pulse voltammetry (DPV) measurements. Under these conditions, the sensor exhibited a linear response toward Pb²⁺ from 0.025 mM to 2.00 mM with superior sensitivity and reproducibility compared to conventional AuNP-modified SPCEs. Furthermore, the ionophore-modified Fe₃O₄–Au nanostructure-based sensor demonstrated outstanding selectivity for Pb²⁺ over competing heavy metal ions (Cd²⁺, Hg²⁺, Cr³⁺), owing to the specific coordination interaction of Lead Ionophore IV with target ions. These findings highlight the potential of raspberry-like Fe₃O₄@PEI@AuNP nanostructures as a robust and efficient electrochemical platform for the sensitive and selective detection of toxic heavy metal ions. Full article

Celiac disease (CD) is a chronic autoimmune condition traditionally recognized for its gastrointestinal symptoms. However, growing evidence indicates that CD can also affect social and emotional health, particularly among children. This narrative review explores how the autoimmunity of CD may contribute to social–emotional dysregulation through mechanisms such as neuroinflammation, nutrient deficiencies, and disruption of the gut–brain axis. It summarizes the current literature on anxiety, attention-deficit/hyperactivity disorder (ADHD), oppositional defiant disorder (ODD), and autism spectrum disorder (ASD), highlighting how immune dysregulation may influence children’s social–emotional wellbeing. Delayed diagnosis, poor dietary adherence, and ongoing inflammation were recognized among children with social–emotional dysregulation. While digestive problems are commonly recognized and treated, social–emotional dysregulation among children with CD is frequently overlooked. However, a gluten-free diet without a confirmed diagnosis of CD is not sufficient to improve social–emotional outcomes. Children presenting with social–emotional dysregulation and clinical features suggestive of CD should be screened using standard serology and, when indicated, biopsy. Starting a gluten-free diet (GFD) without a confirmed diagnosis is not recommended. While mechanistic pathways are described, most evidence remains observational and clinically descriptive, underscoring the need for longitudinal and experimental studies to understand the intersectionality of CD with social–emotional dysregulation. Full article

The major histocompatibility complex (MHC) class I and class II molecules (abbreviated as MHC-I and MHC-II, respectively) are specialized in antigen presentation. Unlike the T cell receptors (TCRs), which have great variability, the MHC-I and MHC-II molecules essentially have no variability at all. It is apparent that the MHC-I and MHC-II molecules per se do not have the built-in ability to distinguish the huge populations of self-peptides from antigenic non-self-peptides. At present, the precise mechanism underlying the selective presentation of antigenic peptides by both MHC-I and MHC-II molecules is unclear. For an MHC-II molecule to gain the ability to selectively present antigenic (mostly foreign) peptides, it is hypothesized herein that all naïve CD4⁺ T cells in the body will release extracellular vesicles (EVs), which are specially designed for antigen-presenting cells (APCs); these EVs contain mRNAs that will be delivered to APCs and translated into an intracellular version of the TCR proteins (iTCR^II), which will help select antigenic peptides for presentation by the MHC-II molecules. Similarly, it is hypothesized that the fully activated CD4⁺ T cells will also release EVs, and these EVs contain different mRNAs for another intracellular version of the TCR proteins (iTCR^I), which will help pathogen-infected somatic cells to select the antigenic peptides (mostly from invading pathogens) for presentation by the MHC-I molecules. Understandably, while the iTCR^II proteins will work closely with the MHC-II molecules in the exogenous endocytic pathway, the iTCR^I proteins will work closely with the MHC-I molecules in the endogenous pathway. In this paper, a few other related hypotheses are also proposed, which jointly offer a plausible mechanistic explanation for the selective presentation of antigenic peptides by both MHC-I and MHC-II molecules. While the proposed hypotheses are partly supported by some experimental observations, it is hoped that these hypotheses will promote discussion and experimental testing of the mechanisms underlying the complex process of selective antigen presentation. Full article

Plasmacytoid dendritic cells (pDCs) are a unique subset of dendritic cells specialized in rapid and robust type I interferon (IFN) production, playing critical roles in the pathogenesis and pathomechanisms of many human diseases. Accurate identification of pDCs in peripheral blood mononuclear cells (PBMCs) is challenging due to dynamic and non-exclusive specific expression of surface markers such as blood dendritic cell antigen (BDCA)-2 and BDCA-4. Although BDCA-4 is generally more stably expressed than BDCA-2, prolonged stimulation or inflammatory conditions can induce its expression on multiple non-pDC cell types, reducing the accuracy of pDC identification. Here, we thoroughly investigated BDCA-4 expression dynamics on pDCs and other PBMC subsets following prolonged activation with Toll-like receptor (TLR) 7 and TLR9 agonists. Our flow cytometry analysis revealed a significant increase in BDCA-4-positive non-pDC populations after extended stimulation, primarily corresponding to CD14⁺ monocytes. To overcome this limitation, we performed a gating strategy combining BDCA-4 positivity with a cocktail of non-pDC markers, enabling the exclusion of non-pDCs and accurate identification of pDCs. This approach enables the reliable identification of pDCs within heterogeneous cell populations using only two fluorescent channels in healthy conditions and even during strong activation or pathological states characterized by chronic inflammation. Full article

In this research, we examined the potential sensor characteristics of branched polyethyleneimine (BPEI)-derived carbon dots (CDs) synthesized using BPEI as a nitrogen source and citric acid (CA) as a carbon source, specifically for the recognition of various metal ions. Among the BPEI CDs produced with different amounts of BPEI to CA BPEI:CA ratios of 0.5:1, 1:1, and 2:1 w/w, named as BPEI^0.5 CD, BPEI¹ CD, and BPEI² CD, respectively. The BPEI^0.5 CD, which contains the least BPEI, exhibited the highest fluorescence intensity: 50,300 a.u. in a 0.6 mg/mL solution were recorded as λ_em: 420 nm at λ_ex: 360 nm and 600 V PMT voltage with 5 nm of slit width for both excitation and emission. We investigated the fluorescence variations in BPEI CD-based CDs in 2 mL solutions containing Cd²⁺, Co²⁺, Cu²⁺, Ni²⁺, and Pb²⁺ metal ions at various concentrations. Amongst these metal ions, the most pronounced sensitivity was noted for Cu²⁺ ions with a limit of detection (LOD) value of 0.39 ppm. For BPEI CDs created with BPEI:CA ratios of 0.5:1, 1:1, and 2:1 w/w, the sensitivity to Cu²⁺ ions increased with a higher BPEI ratio, with a LOD value of 0.30 ppm recorded for BPEI² CDs. Moreover, Cu²⁺ ion solutions were prepared from various salts, including chloride, acetate, nitrate, and sulfate; aside from some fluorescence variation observed for BPEI^0.5 CDs, no significant difference in BPEI CD fluorescence change was observed with the use of the various salt solutions of Cu²⁺ ion. In quenching experiments conducted on mixtures of Cd²⁺, Co²⁺, Cu²⁺, Ni²⁺, and Pb²⁺ metal ions with Cu²⁺, it was noted that BPEI CDs displayed selectivity for Cu²⁺ ions. Furthermore, the structures of BPEI CDs have been effectively utilized in real water samples, such as tap water and seawater, demonstrating a quenching capability of over 65% in the presence of 50 ppm Cu²⁺ ions. Full article

This study proposes a novel framework for analyzing Vehicle-Integrated Photovoltaic (VIPV) systems, integrating optical, thermal, and electrical models. The model modifies existing fixed PV methodologies for VIPV applications to assess received irradiance, PV module temperature, and energy production, and is available as an open-source MATLAB tool (VIPVLIB) enabling simulations via a smartphone. A key innovation is the integration of meteorological data and real-time driving, dynamically updating vehicle position and orientation every second. Different time resolutions were explored to balance accuracy and computational efficiency for optical model, while the thermal model, enhanced by vehicle speed, wind effects, and thermal inertia, improved temperature and power predictions. Validation on a minibus operating within the University of Palermo campus confirmed the applicability of the proposed framework. The roof received 45–47% of total annual irradiation, and the total yearly energy yield reached about 4.3 MWh/Year for crystalline-silicon, 3.7 MWh/Year for CdTe, and 3.1 MWh/Year for CIGS, with the roof alone producing up to 2.1 MWh/Year (c-Si). Under hourly operation, the generated solar energy was sufficient to fully meet daily demand from April to August, while during continuous operation it supplied up to 60% of total consumption. The corresponding CO₂-emission reduction ranged from about 3.5 ton/Year for internal-combustion vehicles to around 2 ton/Year for electric ones. The framework provides a structured, data-driven approach for VIPV analysis, capable of simulating dynamic optical, thermal, and electrical behaviors under actual driving conditions. Its modular architecture ensures both immediate applicability and long-term adaptability, serving as a solid foundation for advanced VIPV design, fleet-scale optimization, and sustainability-oriented policy assessment. Full article

In this study, we review the use of cyclodextrin-based formulations to develop oral tablets of cladribine by enhancing its bioavailability and to improve the solubility and stability of retrometabolic chemical delivery systems (CDSs) in general and estredox, a brain-targeting estradiol-CDS, in particular. Cyclodextrins (CDs), cyclic oligosaccharides that can form host–guest inclusion complexes with a variety of molecules, are widely utilized in pharmaceuticals to increase drug solubility, stability, bioavailability, etc. The stability of the complex depends on how well the guest fits within the cavity of the CD host; a model connecting this to the size of the guest molecules is briefly discussed. Modified CDs, and particularly 2-hydroxypropyl-β-cyclodextrin (HPβCD), provided dramatically increased water solubility and oxidative stability for estredox (estradiol-CDS, E₂-CDS), making its clinical development possible and highlighting the potential of our brain-targeted CDS approach for CNS-targeted delivery with minimal peripheral exposure. A unique HPβCD-based formulation also provided an innovative solution for the development of orally administrable cladribine. The corresponding complex dual CD-complex formed by an amorphous admixture of inclusion- and non-inclusion cladribine–HPβCD complexes led to the development of tablets that provide adequate oral bioavailability for cladribine, as demonstrated in both preclinical and clinical studies. Cladribine–HPβCD tablets (Mavenclad) offer a convenient, effective, and well-tolerated oral therapy for multiple sclerosis, achieving worldwide approval and significant clinical success. Overall, the developments summarized here underscore the importance of tailored cyclodextrin-based approaches for overcoming barriers in drug formulation for compounds with challenging physicochemical properties, and demonstrate the versatility and clinical impact of CD inclusion complexes in modern pharmaceutical development. Full article