Search Results (246)

Both epidemiological studies and prior work in animal models suggest that moderate-dose alcohol reduces disease severity across several autoimmune conditions, including multiple sclerosis (MS). However, the mechanisms underlying the potentially beneficial effects of alcohol and how these effects may change with alcohol dose in autoimmunity remain underexplored. In this study, we characterize the effects of chronic, high-dose ethanol consumption in experimental autoimmune encephalomyelitis (EAE), a murine model of MS, by examining EAE disease severity, gut microbial composition, and peripheral cell immunophenotypes. We found that high-dose ethanol-fed males exhibited a significant amelioration in peak EAE disease severity, in association with decreased T cell activation and B cell proportions. Concurrently, we observed proinflammatory shifts in gut microbiota and hepatic lipid accumulation. Our results suggest that high dose ethanol may benefit autoimmune neuroinflammation in EAE through immunosuppressive effects on adaptive immunity, however its toxic systemic effects preclude the use of alcohol as an immunomodulator in MS. Overall, our findings reveal a mechanistic basis for alcohol’s beneficial properties in autoimmunity and could inform the development of more targeted disease modifying therapies that recapitulate these benefits without alcohol-associated toxicity. Full article

Multiple sclerosis (MS) is a highly disabling chronic autoimmune disease of the central nervous system with neuroinflammatory and neurodegenerative alterations found in the white and grey matter of the brain. The pathogenesis of MS is complex and not fully understood. Mitochondrial dysfunctions are suspected to play an important role. The visual system is often affected in MS. Optic neuritis is a frequent symptom, but also the retina itself, including retinal synapses appear compromised in MS independent from demyelination of the optic nerve. A previous study demonstrated synapse-specific alterations of mitochondria in photoreceptor synapses in the Experimental Autoimmune Encephalomyelitis (EAE) mouse model of MS at day 9 after injection, an early time point in pre-clinical EAE. In the present study, we analysed even earlier stages of pre-clinical EAE for possible alterations of synaptic mitochondria. For this purpose, we performed qualitative and quantitative immunolabelling analyses of the mitochondrial cristae organising protein MIC60 at retinal synapses and functional analyses by measuring synaptic mitochondrial membrane potential (during rest and depolarisation-induced exocytosis) and visually guided behaviour (optometry analyses). At day 3 after injection, morphological and functional data were indistinguishable between MOG/CFA-injected EAE mice and CFA-injected control mice. But already on day 5 after injection, we observed a decreased expression of the mitochondrial MIC60 protein at synaptic mitochondria, a decreased synaptic mitochondrial membrane potential at rest, an enhanced drop of mitochondrial membrane potential during stimulated exocytosis and a decreased visual performance of the respective EAE mice. These data argue that synaptic pathology in the EAE retina begins as early as day 5 after injection. Our data propose that dysfunctions of mitochondria play an important role already at the very early stages of synaptic pathology in EAE. Full article

The growing complexity of maritime navigation creates safety challenges that drive the shift toward autonomous systems. Maritime vessel behaviour modelling is critical for safe and efficient autonomous operations. Representation learning offers a systematic approach to learn feature embeddings encoding vessel behaviour for improved situational awareness and decision-making. We introduce a three-stage representation learning pipeline evaluating six architectures on real-world AIS trajectories. Grouped Masked Autoencoder (GMAE)-Risk Extrapolation (REx) combines group-wise masked autoencoding at the semantic feature level with risk extrapolation regularisation, forcing encoders to learn cross-group dependencies between temporal, kinematic, spatial, and interaction features. DAE and EAE provide robust and uncertainty-aware baselines. Evaluation uses a dual-pipeline framework on two years of Kiel Fjord AIS data (176,787 trajectories, 527,225 segments). Pipeline 1 applies three-stage representation learning using vessel-type classification as encoder selection probe. GMAE-REx achieves 86.03% validation accuracy, outperforming DAE (85.63%), EAE (85.56%), and baselines Transformer (84.93%), TCN (76.27%), LiST (85.12%). Pipeline 2 applies unsupervised clustering to discover intrinsic behavioural structure. Learnt representations consistently outperform expert features on DBCV, conductance, and modularity metrics, organising trajectories by operational context rather than vessel type. This behaviour-oriented organisation enables cross-vessel knowledge transfer for autonomous navigation, VTS monitoring, and safety analysis. Full article

Multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE) are autoimmune inflammatory demyelinating diseases of the central nervous system (CNS). For decades, oligodendrocytes were regarded as passive targets of autoimmune inflammation in these conditions. However, recent studies challenge this view, revealing that oligodendrocytes are active participants—not just passive targets—in the pathogenesis of MS and EAE. In this review, we summarize recent research that highlights the active and dynamic roles of oligodendrocytes in these diseases. Full article

Al–Al₄C₃ composites exhibit promising mechanical properties including high specific strength, high specific stiffness. However, high reinforcement contents often promote brittle behavior, making it necessary to understand the mechanisms governing their limited toughness. In this work, a microstructural and mechanical study was carried out to evaluate the energy storage capacity in Al–Al₄C₃ composites fabricated by mechanical milling followed by heat treatment using X-ray diffraction (XRD) and Convolutional Multiple Whole Profile (CMWP) fitting method, the microstructural parameters governing the initial stored energy after fabrication were determined: dislocation density (ρ), dislocation character (q), and effective outer cut-off radius (R_e). Compression tests were carried out to quantify the elastic energy stored during loading (Es). The energy absorption efficiency (EAE) in the elastic region of the stress–strain curve was evaluated with respect to the elastic energy density per unit volume stored (Ee), obtained from microstructural parameters (ρ, q, and Re) present in the samples after fabrication and determined by XRD. A predictive model is proposed that expresses Es as a function of Ee and q, where the parameter q is critical for achieving quantitative agreement between both energy states. In general, samples with high EAE exhibited microstructures dominated by screw-character dislocations. High-resolution transmission electron microscopy (HRTEM) analyses revealed graphite regions near Al₄C₃ nanorods—formed during prolonged sintering—which, together with the thermal mismatch between Al and graphite during cooling, promote the formation of screw dislocations, their dissociation into extended partials, and the development of stacking faults. These mechanisms enhance the redistribution of stored energy and contribute to improved toughness of the composite. Full article

Background/Objectives: Tinnitus affects approximately 15% of the population and lacks a universally effective treatment. Tinnitus Retraining Therapy (TRT) is widely used but requires 6–8 h of daily sound exposure for 1–2 years, limiting accessibility and adherence. This study evaluated the clinical feasibility and therapeutic effectiveness of Enriched Acoustic Environment therapy (EAE), a streamlined alternative using individualized sound stimulation with a markedly reduced treatment burden, and compared its time efficiency with published TRT outcomes. Methods: 82 adults with chronic tinnitus received standardized counseling and completed one of two EAE protocols (continuous or sequential). Participants listened to their personalized stimulus for 1 h/day over four months. Tinnitus severity (THI, TFI) and time-efficiency metrics (improvement per 10 listening hours) were assessed and compared with TRT studies reporting baseline and post-treatment THI. Results: EAE produced clinically relevant and statistically significant improvements, with 51.6% THI and 49.8% TFI reduction (p < 0.001). Both stimuli achieved similar outcomes with high responder rates. EAE yielded ~2.3 THI-point improvement per 10 h (~4.3% relative gain), demonstrating substantially greater time efficiency—approximately 20 times higher than values reported for standard TRT protocols. Conclusions: EAE achieved robust symptom reduction with dramatically lower treatment burden, high adherence, and strong clinical feasibility. These findings support EAE as an accessible, time-efficient alternative to TRT. Controlled long-term studies are warranted. Full article

Background: Multiple sclerosis (MS) is an autoimmune neurodegenerative disease with a higher prevalence in women. While puberty appears to act as a trigger for MS, menopause has no clear effects on disease progression. Many studies have shown that transcranial magnetic stimulation (TMS) is a potential antioxidant treatment for MS, but the sexual hormones have been identified as a potential factor affecting TMS response by affecting cortical excitability and possibly clinical outcomes. Methods: The aim of this study was to test the effect of estrogen, progesterone, and testosterone hormonal supplementation as adjuvants to TMS treatment of experimental autoimmune encephalomyelitis (EAE), an experimental model of MS. The effects of the three hormones were also tested as replacement therapy in ovariectomized rats treated with TMS. Clinical signs of the disease, as well as disease-induced oxidative stress and antioxidant defenses of the glutathione system, were evaluated. Results: TMS alone, without supplements or replacement therapies, is effective against oxidative stress caused by EAE. Estrogen and progesterone replacement therapy is useful to enhance the role of TMS in ovariectomized rats, activating antioxidant defenses and improving clinical signs of the disease. Conclusions: TMS is effective in the treatment of MS, but its role could be enhanced, using hormone replacement therapy with estrogens and/or progesterone. Full article

Multiple sclerosis (MS) is a complex disease marked by chronic neuroinflammation and reactive oxygen species (ROS) toxicity in the central nervous system (CNS). Based on this ROS-driven mechanism, we tested whether PrC-210—a new aminothiol ROS scavenger—could lessen MS symptoms in mice with experimental autoimmune encephalomyelitis (EAE)-induced MS. Our goals were to assess the role of ROS in MS and evaluate the potential benefits of PrC-210 for managing MS. Mice with EAE received varying doses of PrC-210 under preventive and therapeutic protocols. Disease progression was measured using clinical scores and spinal cord histology. Safety was assessed by comparing the gastrointestinal and hematological toxicity between PrC-210 and dimethyl fumarate (DMF, Tecfidera’s active agent). PrC-210 reduced MS severity by up to 62% in paralysis scores versus those in the controls (p = 0.0001), whether used preventively or at the onset of paralysis. The group with the greatest decrease also showed the best spinal cord preservation and least demyelination. DMF caused toxicity at a dose that was ineffective, while PrC-210 showed no toxicity at effective levels. These findings suggest that the systemic administration of PrC-210 may offer a safe, effective MS treatment when started at symptom onset. Full article

Background: Current disease-modifying therapies (DMTs) for multiple sclerosis (MS) attenuate pathogenic immune responses but are limited by safety and tolerability concerns. Antigen-specific tolerance approaches provide targeted immunomodulation yet remain constrained by their dependence on known autoantigens. LPX-TI641, an orally bioavailable, clinical-stage small-molecule agonist of Tim-3/4, represents an antigen-independent strategy to restore immune tolerance by expanding regulatory T cells (Tregs). Methods: LPX-TI641 was evaluated in vitro for its ability to induce Treg populations in murine splenocytes. Therapeutic efficacy was assessed in vivo using MOG_35–55- and PLP_139–151-induced experimental autoimmune encephalomyelitis (EAE) mouse models. Ex vivo, peripheral blood mononuclear cells (PBMCs) from people with MS (PwMS) were analyzed for Treg phenotype and function in response to LPX-TI641. Results: LPX-TI641 induced dose-dependent expansion of CD4⁺Foxp3⁺ and CD4⁺Foxp3⁺Tim-3⁺ Tregs in vitro. In EAE models, treatment significantly reduced disease severity, prevented relapses, and maintained clinical benefit after discontinuation. In PBMCs from patients with MS, LPX-TI641 restored diminished Tim-3⁺ Treg populations and reversed Treg dysfunction in recall assays. Efficacy in animal models was comparable to or exceeded that of high-efficacy DMTs, including natalizumab. Conclusions: LPX-TI641 promotes antigen-independent immune tolerance through Tim receptor agonism and Treg expansion. These findings support its potential as a novel therapeutic candidate for MS, addressing the limitations of current DMTs. Full article

Enteropathogenic Escherichia coli (EPEC) is a significant diarrheagenic pathotype responsible for severe gastrointestinal infections, particularly in vulnerable populations. The aim of this study is to utilize genome-based in silico analysis to study the structural and functional characteristics of the Type III Secretion System (T3SS) and its core effector proteins in EPEC strains. Representative proteins were selected, with particular interest placed on EscV and EscD as major parts of the export apparatus and the basal body, while the EspA effector protein forms the filamentous structure. Several in silico-based techniques were employed, revealing key structural proteins, core effectors, and adhesion-related proteins among the sequenced isolates. Of the 27 isolates analyzed, only 3 (11%) were found to carry LEE-encoded proteins associated with T3SS structural components (escV, escN, escD, and escU) and core effector proteins (espA, espD, espG, and eae). Structural predictions and Ramachandran plot validations suggested stability and potential functional conservation of T3SS proteins, with EscV and EspA selected for detailed 3D structural modelling. Insights into transmembrane domains, protein–protein interaction, and secondary structures were obtained, providing a comprehensive understanding of T3SS assembly and function. These findings suggest that the T3SS in EPEC consists of stable proteins that enable the system to remain functional. The structural and functional properties of the LEE genes encoding the T3SS in the EPEC pathotype represent promising targets for developing virulence blockers to disrupt the pathogenesis of a broad range of bacteria. This study is the first to report EPEC strains with functional T3SS in South Africa, emphasizing the importance of continued surveillance and molecular characterization of EPEC strains. The findings contribute to the development of targeted interventions to mitigate foodborne infections and improve public health. Full article

The inflammatory and metabolic complexity of colitis necessitates therapies that act on multiple immune pathways. Using serum proteomic profiling, the present study evaluated the systemic immunomodulatory profile of Epilobium angustifolium lyophilized methanol-aqueous extract rich in oenothein B (EAE) in a dextran sulfate sodium (DSS)-induced mouse model of ulcerative colitis in a comparative manner to dexamethasone (DXM). DSS exposure triggered robust inflammatory activation, evidenced by elevated chemokines (CXCL9, CXCL10, CCL11), proinflammatory cytokines (IL-1α, IL-12, PAI-1, RAGE) and metabolic stress mediators (leptin, resistin, FGF-21). Treatment with EAE significantly attenuated this inflammatory profile, notably reducing Th2-skewed chemokines and eosinophil recruitment. In contrast to DXM, EAE uniquely normalized pro-thrombotic and tissue-remodeling markers, including PAI-1 and RAGE, both implicated in intestinal barrier dysfunction and chronic inflammation. Furthermore, EAE demonstrated superior modulation of inflammation-associated growth factors (IGFBP-5, HGF, Flt3L) and adipokines (leptin, resistin), indicating a broader therapeutic scope that includes metabolic dysfunctions. Collectively, our data reveal that EAE exerts a distinct immunoregulatory profile, modulating both innate and adaptive immune pathways while simultaneously addressing metabolic pathologies. These multifaceted actions underscore its promise as a phytotherapeutic candidate for the management of ulcerative colitis and other inflammatory conditions, with potential advantages over conventional steroid treatment. Full article

Stimulator of interferon genes (STING) is a cytosolic DNA sensor that activates type I interferon (IFN) signaling, which plays a key role in neuroinflammation. Although the role of STING in experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis (MS), remains debated, its involvement in the development of CNS lesions, particularly within localized pathology, modeled here by targeting the corpus callosum, has yet to be explored. Using a focal EAE model, we compared the induction of lesions in wild-type and STING-deficient (STING^gt/gt) mice. Lesions were analyzed by immunohistochemistry, flow cytometry, and transcriptomics. STING-deficient mice had significantly larger demyelinated lesions, reduced ISG expression, and modified immune cell infiltration. STING signaling limits lesion severity in focal EAE by promoting IFN responses and regulating immune infiltration. These findings position STING as a potential target for MS therapy. Full article

Multiple sclerosis (MS) is a chronic autoimmune disease characterized by sustained neuroinflammation and demyelination within the central nervous system (CNS). Vesatolimod (VES), a selective Toll-like receptor 7 (TLR7) agonist, has demonstrated both antiviral and immunomodulatory properties; however, its potential therapeutic value in neuroinflammatory contexts remains poorly understood. In this study, we evaluated the efficacy of VES in the experimental autoimmune encephalomyelitis (EAE) model of MS and elucidated its mechanisms of action. EAE was induced in mice by immunization with myelin oligodendrocyte glycoprotein (MOG_35–55). The therapeutic effects of VES were assessed through clinical scoring, body weight monitoring, histopathology, flow cytometry, quantitative proteomics, and Western blot analysis. Additionally, an in vitro model of lipopolysaccharide (LPS)-induced microglial activation was employed to investigate cell-autonomous mechanisms. Results showed that VES administration significantly ameliorated disease severity, reduced weight loss, and enhanced neurological function in EAE mice. Treatment with VES inhibited the differentiation of pro-inflammatory Th1 and Th17 cells while expanding regulatory T cell (Treg) populations. It also preserved blood–brain barrier (BBB) integrity, attenuated demyelination, and modulated microglial activation phenotypes within the CNS. At the molecular level, VES activated the Nrf2/HO-1 antioxidant pathway, thereby enhancing the expression of cytoprotective proteins. Proteomic profiling further revealed the downregulation of inflammation-related proteins, specifically those associated with TNF, IL-17, and NOD-like receptor signaling pathways. Collectively, these findings demonstrate that VES alleviates neuroinflammation in EAE through multimodal mechanisms—including peripheral and central immune regulation, BBB protection, and activation of endogenous antioxidant defenses—supporting its further development as a promising therapeutic candidate for MS. Full article

Short fiber-reinforced polymer (SFRP) has been extensively applied in structural engineering due to its exceptional specific strength and superior mechanical properties. Its mechanical behavior under medium strain rate conditions has become a key focus of ongoing research. A comprehensive understanding of the response characteristics and underlying mechanisms under such conditions is of critical importance for both theoretical development and practical engineering applications. This study proposes an innovative three-dimensional (3D) multiscale constitutive model that comprehensively integrates mesoscopic fiber–matrix interface effects and pore characteristics. To systematically investigate the dynamic response and damage evolution of SFRP under medium strain rate conditions, 3D-printed SFRP porous structures with volume fractions of 25%, 35%, and 45% are designed and subjected to drop hammer impact experiments combined with multiscale numerical simulations. The experimental and simulation results demonstrate that, for specimens with a 25% volume fraction, the strain rate strengthening effect is the primary contributor to the increase in peak stress. In contrast, for specimens with a 45% volume fraction, the interaction between damage evolution and strain rate strengthening leads to a more complex stress–strain response. The specific energy absorption (SEA) of 25% volume fraction specimens increases markedly with increasing strain rate. However, for specimens with 35% and 45% volume fractions, the competition between these two mechanisms results in non-monotonic variations in energy absorption efficiency (EAE). The dominant failure mode under impact loading is shear-dominated compression, with damage evolution becoming increasingly complex as the fiber volume fraction increases. Furthermore, the damage characteristics transition from fiber pullout and matrix folding at lower volume fractions to the coexistence of brittle and ductile behaviors at higher volume fractions. The numerical simulations exhibit strong agreement with the experimental data. Multi-directional cross-sectional analysis further indicates that the initiation and propagation of shear bands are the principal drivers of structural instability. This study offers a robust theoretical foundation for the impact-resistant design and dynamic performance optimization of 3D-printed short fiber-reinforced polymer (SFRP) porous structures. Full article

Adipose stem cells (ASCs) are a subset of mesenchymal stem cells with validated immunomodulatory and regenerative capabilities that make them attractive tools for treating neurodegenerative disorders, such as multiple sclerosis (MS). Several studies conducted on experimental autoimmune encephalomyelitis (EAE), the animal model of MS, have clearly shown a therapeutic effect of ASCs. However, controversial data on their efficacy were obtained from I- and II-phase clinical trials in MS patients, highlighting standardization issues and limited data on long-term safety. In this context, ASC-derived extracellular vesicles from (ASC-EVs) represent a safer, more reproducible alternative for EAE and MS treatment. Moreover, their physical characteristics lend themselves to a non-invasive, efficient, and easy handling of intranasal delivery. Using an in vitro setting, we first verified ASC-EVs’ ability to cross the human nasal epithelium under an inflammatory milieu. Magnetic resonance corroborated these data in vivo in intranasally treated MOG35-55-induced EAE mice, showing a preferential accumulation of ASC-EVs in brain-inflamed lesions compared to a stochastic distribution in healthy control mice. Moreover, intranasal treatment of ASC-EVs at the EAE onset led to a long-term therapeutic effect using two different experimental protocols. A marked reduction in T cell infiltration, demyelination, axonal damage, and cytokine production were correlated to EAE amelioration in ASC-EV-treated mice compared to control mice, highlighting the immunomodulatory and neuroprotective roles exerted by ASC-EVs during EAE progression. Overall, our study paves the way for promising clinical applications of self-administered ASC-EV intranasal treatment in CNS disorders, including MS. Full article