Search Results (3,496)

Bovine viral diarrhea virus (BVDV) is a major pathogen inflicting substantial economic losses on the global cattle industry. To develop a more effective vaccine, we constructed two novel bicistronic recombinant adenoviruses, rAdV-I E0+I E2 and rAdV-I E2+II E2, and systematically evaluated their immunogenicity and protective efficacy in BALB/c mice. Both vaccine candidates, particularly rAdV-I E2+II E2, provoked a robust and rapid neutralizing antibody response that was significantly superior to a commercial inactivated vaccine. They also elicited a potent Th1-skewed cellular immune response, as indicated by significantly higher IFN-γ secretion, and a balanced profile of BVDV-specific IgG and its subclasses. Upon BVDV challenge, immunization with both recombinant vaccines, especially rAdV-I E2+II E2, resulted in a comprehensive reduction in viral loads across all tested tissues (blood, spleen, lungs, kidneys, and small intestine), demonstrating broader protection than the inactivated vaccine. Concordantly, histopathological analysis confirmed that vaccination preserved the normal architecture of the duodenum and spleen, preventing the significant pathological damage observed in the rAdV-empty negative control group. Our findings demonstrate that these adenovirus-vectored vaccines, particularly rAdV-I E2+II E2, induce a multifaceted and protective immune response, highlighting their promise as superior candidates against BVDV. Full article

Cancer immunoprevention leverages the immune system’s surveillance mechanisms to mitigate tumor development. Vaccines that constitute a tumor antigen and an immune adjuvant are perceived as immunoprevention modalities. However, relevant tumor antigens are unknown for non-viral cancers, which constitute most human cancers. Our group has recently shown that SA–4–1BBL, a novel agonist of CD137 receptor, but not antibodies, shows immunoprevention efficacy against various tumors. Advanced bioinformatics analyses of bulk RNA-seq data were conducted to elucidate mechanisms underlying cancer immunoprevention. Mice received subcutaneous injections of SA–4–1BBL or agonistic 3H3 antibody, and the injection-site tissue (IS) and draining lymph nodes (LN) were analyzed for differential gene expression. SA–4–1BBL induced a compartmentalized and temporally dynamic immune program characterized by early effector activation at IS and sustained immune regulation in draining LN. K-means clustering of 4564 DEGs identified eight functionally distinct clusters. IS-enriched clusters contained activation genes for CD4⁺ T and NK cells, including Cd28, Klra1, Cd4, Cd40, and Cd40l, while LN clusters were enriched for regulatory genes (Tnfaip3, Irf5, Col1a2) that ensure immune priming and homeostatic restraint for a balanced response. SA–4–1BBL generated a more selective and durable activation of adaptive immunity, TCR signaling, Th1/Th2 differentiation, and NK cytotoxicity. 3H3 activated broader innate inflammatory programs, including Toll-like receptor and neurodegeneration-linked pathways. IMPRes analysis showed that SA–4–1BBL activates sequential immune-regulatory circuits centered on Stat1, Cd247, and Ifng and modulates the CD151–TGF-β axis. These findings demonstrate that SA–4–1BBL elicits a balanced immune response, ensuring both safety and efficacy in preventing cancer development. Full article

Allergic conditions have surged to unprecedented levels globally, affecting approximately 30% of the global population. Fungi are among the most significant sources of allergens, accounting for approximately 6% of respiratory issues in the general population. However, identifying the precise cause of respiratory allergies remains challenging. We investigated the potential of two rust species, Tranzschelia pruni-spinosae and Phragmidium rubi-idaei, which infect common fruit plants, to induce inflammatory and asthmatic responses in mouse models of both acute and chronic asthma. Mice were sensitized and administered intranasal challenges with extracts from T. pruni-spinosae and P. rubi-idaei. Levels of pro-inflammatory cytokines (IL-4, IL-5, IL-13, TNF-α, and TGF-β) were measured via ELISA. Additionally, specific IgE production was assessed via ELISA and lung histology was examined using hematoxylin-eosin staining. Both fungal extracts induced significant increases in all tested cytokines, elevated specific IgE levels, and histological changes characteristic of acute and chronic asthma progression in the lungs. The microfungi T. pruni-spinosae and P. rubi-idaei possess strong proinflammatory and asthma-inducing capabilities, suggesting their potential as previously unrecognized fungal allergens. Full article

Background/Objectives: Brucella is a major global One Health threat, causing an estimated 2.1 million human infections and substantial livestock losses annually, with no vaccine currently available for humans, underscoring the urgent need for a safe and effective vaccine. Methods: Employing a reverse vaccinology approach, a novel 175-mer multiepitope vaccine (Mvax) targeting Brucella FrpB was computationally designed in this study, incorporating two B-cell, two MHC class I (MHC-I), and three MHC class II (MHC-II) epitopes selected for their high predicted antigenicity, safety, and IFN-γ-inducing potential. Human β-defensin-3 (hBD3) was fused to the N-terminus as an adjuvant, followed by comprehensive in silico evaluation of the construct. Results: Population coverage analysis predicted 99.59% global MHC class I/II coverage for selected epitopes. In silico analyses predicted that Mvax has high solubility (Protein-SOL score: 0.808), a high antigenicity score (VaxiJen: 1.06), and a negative GRAVY index (−0.881), indicating favorable predicted physicochemical characteristics. iMODS, CABS-Flex 3, and molecular dynamics simulations suggested theoretical stability trends for the modeled vaccine complexes. C-ImmSim immune simulations further predicted elevated Th1 cell populations and associated cytokines (IL-12, IFN-γ, IL-2) following both single and multiple simulated Mvax exposures. Conclusions: The computational analyses described here provide a theoretical modeling basis for an antivirulence multi-epitope vaccine design against human brucellosis, with predicted metrics and simulated immune responses requiring empirical validation. Full article

Background: The pancreatic beta-cell hormone insulin regulates the metabolism of carbohydrates, as well as fats and protein. While the insulin response to a carbohydrate challenge is well defined in normoglycaemic as well as dysglycaemic (prediabetes and type 2 diabetes (T2DM)) individuals, the response of co-secreted beta-cell products (C-peptide, proinsulin and proinsulin intermediates) is less well defined. This analysis aimed to establish the expected glycaemic and pancreatic beta-cell responses to a standardised mixed meal in individuals with impaired glucose tolerance (IGT) and T2DM alongside reference ranges established in normoglycaemic individuals (NGT). Methods: A total of 743 adults (104 NGT, 85 IGT and 554 T2DM) were included, none of whom were on any anti-diabetic medication at the time of initial testing. All attended following a 10 h fast, before consuming a 500 kcal solid mixed meal (calorie contribution: 58% carbohydrates, 22% fat and 20% protein). Blood samples were collected every 30 min for the 4.5 h duration of the test for the determination of plasma glucose, insulin, C-peptide and intact and total proinsulin. Median profiles with corresponding 2.5th and 97.5th percentile lines to display the expected range were calculated and plotted for the three participant groups. Results: Median profiles with ranges over a 4.5 h meal period have been created for glucose, insulin, C-peptide and intact and total proinsulin, along with respective fasting and post-meal intervals in the three participant groups with differing glycaemic status. Conclusions: The resulting profiles and ranges allow for comparison in responses to a carbohydrate challenge in individuals across the glycaemic spectrum. Full article

Background/Objectives: Anaphylaxis is a rare occurrence in dental practice, yet when it happens, it demands swift management, as untreated cases can be fatal. The aim of this study is to evaluate the level of knowledge among dental students and residents regarding the symptoms and management of anaphylactic emergencies in dental surgery. Methods: The study involved a sample of 236 students from the 3rd and 5th years, and residents in their 1st and 2nd years of the General Dentistry programme at the Faculty of Dental Medicine in Iași, Romania. The response rate to the invitation was 85.8%. Knowledge was assessed using a self-administered questionnaire consisting of 18 questions organised into three sections, which were tested for internal consistency, yielding a Cronbach’s alpha value of 0.731. Results: Statistically significant differences in the responses provided by the three categories of participants were observed for the following items: management of patients with an allergic background (p = 0.033), factors aggravating allergic predisposition (p = 0.001), the correct dose of epinephrine (p = 0.001), secondary medication (p = 0.001), and the timing of treatment initiation (p = 0.009). Questions where answers indicated moderate to low levels of knowledge (25–50% correct answers) concerned the therapeutic approach for patients with an allergic background, the site of adrenaline administration, and secondary medication. Conclusions: Overall, it can be observed that students demonstrated a high level of knowledge in questions related to the symptomatology of anaphylaxis and the therapeutic management of allergic patients, whereas residents showed better performance in questions addressing the therapeutic management of anaphylaxis. However, significant knowledge gaps were identified across all participant categories, suggesting that there must be periodic supplementary training. 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

The rapid development of large language models (LLMs), including ChatGPT, Gemini, and Copilot, has led to their increasing use in health communication and patient education. However, their growing popularity raises important concerns about whether the language they generate aligns with recommended readability standards and patient health literacy levels. This review synthesizes evidence on the readability of medical information generated by chatbots using established linguistic readability indices. A comprehensive search of PubMed, Scopus, Web of Science, and Cochrane Library identified 4209 records, from which 140 studies met the eligibility criteria. Across the included publications, 21 chatbots and 14 readability scales were examined, with the Flesch–Kincaid Grade Level and Flesch Reading Ease being the most frequently applied metrics. The results demonstrated substantial variability in readability across chatbot models; however, most texts corresponded to a secondary or early tertiary reading level, exceeding the commonly recommended 8th-grade level for patient-facing materials. ChatGPT-4, Gemini, and Copilot exhibited more consistent readability patterns, whereas ChatGPT-3.5 and Perplexity produced more linguistically complex content. Notably, DeepSeek-V3 and DeepSeek-R1 generated the most accessible responses. The findings suggest that, despite technological advances, AI-generated medical content remains insufficiently readable for general audiences, posing a potential barrier to equitable health communication. These results underscore the need for readability-aware AI design, standardized evaluation frameworks, and future research integrating quantitative readability metrics with patient-level comprehension outcomes. Full article

Neoadjuvant chemoimmunotherapy has emerged as a promising treatment strategy for head and neck squamous cell carcinoma (HNSCC). There is an urgent need to improve patient responses to this approach. In this study, we aim to elucidate the mechanisms underlying poor response to neoadjuvant chemoimmunotherapy and to identify strategies to enhance therapeutic efficacy in HNSCC. We identified a cancer stem-like cell (CSC) population enriched in patients with partial response (PR) to neoadjuvant chemoimmunotherapy, characterized by high CD80 expression. CD80 was likewise highly expressed in ALDH^highCD44⁺ and BMI1⁺ populations. Functionally, CD80 knockdown attenuated tumor-sphere-forming capacity and reduced the migration and invasion of tumor cells, whereas CD80 overexpression potentiated these pro-tumorigenic activities. Moreover, CD80 inhibition activated signaling pathways of Th1 immune responses and IL-2 production. CD80 blockade enhanced T cell cytotoxicity. In preclinical HNSCC models, inhibition of CD80 significantly decreased tumor burden, accumulated CD8⁺ T cells, and increased the production of cytotoxic effector molecules. Our data demonstrated that CD80 modulated tumor-cell stemness and malignant phenotype while restraining antitumor T cell immunity. Targeting CD80 augments antitumor immunity and provides a compelling strategy to enhance treatment responses to neoadjuvant chemoimmunotherapy in HNSCC. Full article

Accurate segmentation of ischemic stroke lesions from multimodal magnetic resonance imaging (MRI) is fundamental for quantitative assessment, treatment planning, and outcome prediction; yet, it remains challenging due to highly heterogeneous lesion morphology, low lesion–background contrast, and substantial variability across scanners and protocols. This work introduces Tri-UNetX-2D, a large-kernel and scale-aware 2D convolutional network with explicit boundary refinement for automated ischemic stroke lesion segmentation from DWI, ADC, and FLAIR MRI. The architecture is built on a compact U-shaped encoder–decoder backbone and integrates three key components: first, a Large-Kernel Inception (LKI) module that employs factorized depthwise separable convolutions and dilation to emulate very large receptive fields, enabling efficient long-range context modeling; second, a Scale-Aware Fusion (SAF) unit that learns adaptive weights to fuse encoder and decoder features, dynamically balancing coarse semantic context and fine structural detail; and third, a Boundary Refinement Head (BRH) that provides explicit contour supervision to sharpen lesion borders and reduce boundary error. Squeeze-and-Excitation (SE) attention is embedded within LKI and decoder stages to recalibrate channel responses and emphasize modality-relevant cues, such as DWI-dominant acute core and FLAIR-dominant subacute changes. On the ISLES 2022 multi-center benchmark, Tri-UNetX-2D improves Dice Similarity Coefficient from 0.78 to 0.86, reduces the 95th-percentile Hausdorff distance from 12.4 mm to 8.3 mm, and increases the lesion-wise F1-score from 0.71 to 0.81 compared with a plain 2D U-Net trained under identical conditions. These results demonstrate that the proposed framework achieves competitive performance with substantially lower complexity than typical 3D or ensemble-based models, highlighting its potential for scalable, clinically deployable stroke lesion segmentation. Full article

Heat-killed Enterococcus faecalis EF-2001 (EF-2001) is a postbiotic preparation reported to modulate host immunity. However, its specific impact on host immune responses and virological outcomes during the early phase of influenza infection remains insufficiently characterized. Female BALB/c mice received oral EF-2001 (16 mg/kg/day) for either 4 days or 14 days prior to intranasal inoculation with influenza A/H3N2 (A/Aichi/2/68). On day 2 post-infection, splenic T-cell subsets (CD3⁺, CD4⁺, CD8⁺) were quantified by flow cytometry. Cytokines released from PMA/ionomycin-stimulated splenocytes were measured using a cytometric bead array assay to assess functional polarization. Lung viral titers (TCID₅₀) and interferon-α (IFN-α) concentrations were assessed to evaluate local antiviral efficacy. EF-2001 administration significantly increased the proportions of splenic CD3⁺ T cells, including both CD4⁺ and CD8⁺ subsets, compared to controls. The 14-day pretreatment regimen significantly enhanced IFN-γ production while reducing IL-10, IL-4, and IL-2 secretion, consistent with a distinct systemic Th1-skewed immune activation. In contrast to these systemic effects, EF-2001 did not significantly reduce lung viral titers (difference < 0.2 log₁₀ TCID₅₀) and did not increase lung IFN-α concentrations at day 2 post-infection. Oral EF-2001 pretreatment promoted systemic immune activation characterized by T-cell expansion and a Th1-biased cytokine profile. However, this systemic priming showed no detectable antiviral effect on lung viral burden at the early evaluation time point. EF-2001 may be better positioned as an adjunctive immunomodulatory approach rather than a direct antiviral agent, warranting further studies that include clinical outcomes and multi-time-point antiviral and mucosal immune assessments. Full article

Between the 15th and 17th centuries, as the Northern Hemisphere entered the Little Ice Age, the scale and frequency of hailstorms increased. In Ming Dynasty China, following the Han Dynasty’s “Interaction Between Heaven and Mankind” doctrine and the pre-Qin Confucian classic Zuo Zhuan’s interpretation that “when a sage rules, there is no hail,” linked these disasters to the moral conduct of the emperor. Others took a more agnostic, naturalistic approach, but in both cases, scapegoating was largely avoided. Building on existing Western scholarship on the link between witch hunts and hail, this paper will use Chinese classical interpretations, historical records of hail events from the Ming Dynasty, and the reactions of emperors and Confucian scholars as a point of reference. It aims to compare and contrast the different understandings and responses to hail disasters in Ming China and Europe. Full article

Background/Objectives: The dopaminergic system regulates motivation, executive functions, motor learning, and emotional responses—processes that are key in both sport and esports. Although many studies analyse dopaminergic gene polymorphisms, their impact on psychophysical predispositions remains unclear. This narrative review aims to summarise current knowledge about the mechanisms of dopamine action and genetic determinants that may influence athletic and cognitive performance. Methods: The PubMed, Scopus, and Web of Science databases (publications from January 2010 to December 2025) were searched using keywords related to the DRD1–DRD5, COMT, SLC6A3/DAT1, and TH genes, as well as the terms ‘sport’ and ‘esport.’ Studies of athletes were included in which the relationship between dopaminergic polymorphisms and motivational and personality traits was assessed, and the results of neuroimaging and epigenetic studies were also considered. Results: Dopaminergic polymorphisms are associated with differences in reward processing, cognitive flexibility, motivation, and stress resilience. The most essential critical effects concern the DRD2 and DRD4 variants, which are associated with novelty seeking, reward dependence, and coping with stress. The COMT Val158Met polymorphism affects dopamine levels in the prefrontal cortex, modulating executive functions. The effects of individual polymorphisms are moderate, and conclusions regarding esports remain speculative due to limited research in this area. Conclusions: Dopaminergic predispositions involve interactions among genetics, neural activity, and the environment. However, current evidence is limited by small sample sizes, a predominance of European populations, scarce data on esports players, and difficulties in separating genetic effects from training-related adaptations. Full article

Background: A major challenge in developing effective immunological damage-control therapies for traumatic hemorrhage (TH) is the lack of animal models that accurately reproduce the immune and pathophysiological responses observed in humans. In this study, we established a clinically relevant rat model that combines blast injury with hemorrhagic shock in a simulated prolonged damage control resuscitation environment. Methods: Male Sprague Dawley rats were anesthetized and subjected to moderate blast overpressure, followed by controlled hemorrhage equivalent to 40% of the estimated total blood volume. Animals then received hypotensive resuscitation with Plasma-Lyte A at twice the shed blood volume. Plasma-Lyte A was used in our study to correct hypovolemia and electrolyte imbalances, thereby helping to standardize the traumatic hemorrhage model. Results: Four of six rats in the blast-plus-hemorrhage (B + H) group survived the 25 h observation period. During resuscitation, mean arterial pressure remained markedly below baseline for at least 4 h. The B + H insult triggered a rapid innate immune response, characterized by elevated circulating HMGB1, terminal complement activation, and increased myeloperoxidase levels. Complement deposition (C4d, C5a, and C5b-9) was evident in lung tissue, accompanied by multi-organ histopathological injury, including pronounced inflammatory cell infiltration, hemorrhage, and cellular degeneration, apoptosis, or necrosis. Metabolic disturbances, including acidosis, hyperkalemia, and dilutional anemia, were also observed. Conclusions: Overall, this model reproduced key features of inflammation-driven multi-organ dysfunction syndrome seen in human polytrauma, supporting its utility for studying TH-related immunopathology and therapeutic interventions during prolonged damage control resuscitation. Full article

Prolonged tooth loss causes alveolar ridge atrophy, complicating implantation, especially in patients with impaired mineral metabolism. This study aimed to develop a personalized titanium mesh for guided bone regeneration and qualitatively evaluate its local tissue response in a vitamin D3-deficient rabbit model. A titanium mesh design has been developed in the form of a plate-shaped profile frame of a truncated pyramid with a solid upper base and perforated side faces. For testing in a rabbit model with vitamin D3 deficiency, a bone defect was created and repaired in the mandible using hydroxyapatite, an individual titanium mesh and a collagen membrane. Histological analysis was performed in the Laboratory of Digital Microscopic Analysis. The optimized geometry and parameters of the mesh openings contributed to effective vascularization and osteogenesis. In the postoperative period (3, 5 and 7 days), moderate edema and hyperemia were noted with their complete leveling by the 7th day (p < 0.05). According to the histological examination, 3 months after the installation of the titanium mesh, the formation of dense connective tissue with signs of active osteogenesis was observed in the defect area, including zones of mineralized bone trabeculae, osteocytes and osteon elements. The findings of this study indicate acceptable biocompatibility of the developed titanium structure and suggest osteoconductive potential, which, however, needs to be confirmed in controlled, quantitatively powered studies. Full article