Search Results (8,331)

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder, which has recently been found to be closely associated with neuroinflammation. As an anti-inflammatory drug, triptolide (TP), a natural diterpenoid from Tripterygium wilfordii, was selected in the current study for treating PS19 (tau^P301S transgenic) mice, tauopathy AD mice. In addition, we have previously found that TP had the ability to reduce the level of cholesterol. However, the roles and mechanisms of TP in the above processes are not clear. To this end, we found that elevated cholesterol in serum and brain tissues upregulated the expression of apolipoprotein E (APOE) and sialic acid-binding Ig-like lectin 3 (CD33), leading to the activation of SH2-containing protein tyrosine phosphatase 1 (SHP-1). The activation of SHP-1 inhibits the signaling pathways of Janus kinase 1 (JAK1) and signal transducer and activator of transcription 6 (STAT6), which results in inhibition of the M2 polarization of microglia, which exacerbates neuroinflammation and cognitive decline in high-cholesterol diet (HCD)-fed mice. Conversely, TP treatment significantly inhibited the hepatic sterol regulatory element-binding protein 2 (SREBP2)/3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) pathway, which reduced the cholesterol levels in the serum and brain. By depressing the levels of cholesterol, the axis of CD33 and SHP-1 was suppressed, which resulted in restoration of the activity of JAK1 and STAT6 pathways, leading to the transition of microglia from the M1 to the M2 phenotype. Of note, these observations demonstrate that TP alleviates the cognitive impairment of PS19 mice via depressing neuroinflammation. Altogether, our results revealed the mechanisms of TP in treating AD via CD33/SHP-1/JAK1/STAT6 pathways in a cholesterol-dependent manner. Full article

Urban navigation in dynamic environments remains a challenging problem for blind and visually impaired users due to the presence of unpredictable obstacles and the limitations of conventional navigation systems, which rely primarily on static map-based information and lack real-time environmental awareness. This paper presents a real-time sensor-driven navigation system based on a multi-agent architecture incorporating a reinforcement-learning navigation policy for assistive mobility in urban environments. The proposed system integrates GPS-based global localization with vision-based perception to enable continuous fusion of global route planning and local obstacle detection. This integration allows the system to dynamically adjust navigation strategies in response to changing environmental conditions. The architecture is designed as a modular multi-agent system comprising agents for perception, navigation, sensor fusion, personalization, safety arbitration, interface management, and system monitoring. The reinforcement learning component formulates local navigation as a sequential decision-making problem, where the navigation policy is trained to balance path efficiency, obstacle avoidance, and safety constraints through interaction with simulated environments. Prototype implementation is developed and evaluated in both simulation and controlled real-world scenarios. Experimental results demonstrate that the proposed system shows improved obstacle avoidance performance and navigation stability under the evaluated conditions while maintaining low-latency responsiveness compared to baseline navigation approaches. The system also exhibits robust behaviour under varying environmental conditions, supporting its potential applicability to assistive navigation tasks in controlled urban environments. The proposed approach contributes to a scalable architecture that integrates a reinforcement-learning navigation policy within a multi-agent coordination framework and real-time sensor perception, providing a foundation for the development of intelligent and deployable assistive navigation systems. Full article

Endotoxemia represents a life-threatening clinical disorder driven by an aberrant host immune response to pathogenic infection, often resulting in severe multiple organ dysfunction. Among its most devastating complications are acute lung injury (ALI) and endotoxemia-associated encephalopathy (EAE), both of which are associated with elevated mortality and currently lack effective targeted interventions. This study evaluated the therapeutic efficacy and underlying molecular mechanisms of recombinant human thymosin β4 (rhTβ4) in a murine model of lipopolysaccharide (LPS)-induced endotoxemia. Our results showed that treatment with rhTβ4 markedly enhanced survival rates and diminished the systemic overproduction of diverse proinflammatory cytokines and chemokines in endotoxemic mice. These systemic protective actions were achieved through the inhibition of the TLR4/NF-κB signaling cascade, the reduction in M1 macrophage polarization, and the simultaneous alleviation of mitochondrial impairment and oxidative stress. Moreover, rhTβ4 treatment significantly rescued EAE-related cognitive deficits and attenuated neuronal damage, primarily through the suppression of neuroinflammation and microglial overactivation. Integrative transcriptomic profiling and functional assays identified lysophosphatidic acid receptor 3 (LPAR3) as an important contributor, suggesting that rhTβ4 suppresses microglial-mediated neurotoxicity at least in part through LPAR3 downregulation. In conclusion, rhTβ4 confers robust multi-organ protection against endotoxemic injury by orchestrating the inhibition of systemic and central neuroinflammatory cascades, positioning it as a promising candidate for the treatment of endotoxemia-induced ALI and EAE. Full article

Background/Objectives: Iron deficiency early in life can impair infant growth and cognitive development. Here, we follow infants’ plasma ferritin levels—an indicator of iron stores—over the first year of life and relate these to birth characteristics, maternal characteristics, and infant feeding. Methods: Children and their mothers enrolled in the Swedish birth cohort NICE (ClinicalTrials.gov identifier: NCT05809479) were followed from pregnancy to twelve months postpartum. Plasma ferritin was quantified in umbilical cord blood at birth (n = 345), in venous plasma at four months after birth (mother–infant dyads, n = 133), and at twelve months of age (n = 158), using sandwich ELISA. Perinatal and postnatal growth, together with infant and maternal characteristics, were extracted from medical birth records. Breastfeeding and formula feeding were assessed using repeated monthly questionnaires during the first year. Longitudinal changes were analyzed using linear mixed-effects models, and factors associated with ferritin concentrations were examined using Spearman correlations, linear regression models, and segmented generalized additive models. Results: The ferritin concentration declined over time (birth: 267 ng/mL; four months: 146 ng/mL; twelve months: 30 ng/mL). Boys had lower ferritin levels than girls at all timepoints. Ferritin status at four and twelve months was positively associated with ferritin concentrations in cord blood and with gestational age. Breastfeeding and formula feeding were not associated with ferritin concentrations. Conclusions: Infant sex, cord ferritin concentrations, and maternal ferritin concentrations were independently associated with infant ferritin concentrations across the first year of life, whereas neither breastfeeding nor formula feeding was associated with ferritin concentrations in the present analyses. Infant sex, cord ferritin, and maternal ferritin measured four months postpartum may help identify children at risk of low iron stores, with maternal ferritin potentially offering a less intrusive alternative to repeated infant sampling. However, the clinical relevance and potential use of maternal ferritin as a proxy for infant ferritin concentrations require further investigation. Full article

Background: As survival improves in transfusion-dependent β-thalassemia, long-term adult morbidity, including cognitive dysfunction, has become increasingly relevant. Adult data remain limited, particularly in Eastern Europe, and many studies rely on single screening tools with limited control for confounding. Methods: We conducted a single-center case–control study (2024–2025) at the Congenital Hemolytic Anemia Treatment Center, University Hospital “Sv. Georgi” Plovdiv, Bulgaria. Fifty adults with transfusion-dependent β-thalassemia (86% thalassemia major; 14% transfusion-dependent intermedia) and 30 frequency-matched healthy controls completed a multi-domain cognitive battery: Montreal Cognitive Assessment (MoCA), Mini-Mental State Examination (MMSE), Clock Drawing Test (CDT), Trail Making Test (TMT-A/B), and timed verbal fluency. Associations between thalassemia status and cognitive outcomes were estimated using three prespecified models: unadjusted, adjusted for age and sex, and a doubly robust model combining covariate balancing propensity score inverse probability weighting (balancing BMI, smoking, education, and comorbidity) with age/sex regression adjustment. Results: Patients performed worse than controls on global cognition and executive/visuospatial measures. MoCA scores were lower in patients (−2.26 unadjusted, p = 0.016; −2.83 doubly robust, p = 0.001), as were MMSE scores (−1.64, p = 0.015; −1.87, p = 0.002). CDT performance was consistently poorer (OR ≈ 0.28–0.30 across models). Patients were slower on TMT-B (time ratio 1.35 unadjusted, p = 0.003; 1.42 doubly robust, p < 0.001); TMT-A reached significance only after weighting (ratio 1.32, p = 0.001). Verbal fluency was modestly lower with borderline significance (p ≈ 0.05–0.06). Conclusions: Transfusion-dependent β-thalassemia in adults is associated with poorer cognitive performance, particularly in global cognition and executive/visuospatial domains, with results robust across adjustment strategies. Routine multi-domain cognitive screening may be warranted in adult thalassemia care. Full article

Glucose is the principal energy substrate for the brain. Hypo- and hyperglycemic episodes frequently occur in senescent people, contributing to functional and structural impairment of brain neurons and causing cognitive deficits in this population. In this study, we investigate whether long-term changes in the extracellular concentration of glucose affect viability and transmitter functions of septum-derived SN56 cholinergic neuronal cells through alterations in acetyl-CoA availability. Cells with low cholinergic expression (NCs) and cAMP/retinoic acid-induced high cholinergic expression (DCs) were investigated. Hypoglycemia brought about similar (approximately 20–30%) decreases in pyruvate dehydrogenase complex (PDHC) and ATP-citrate lyase (ACLY) activities and a 65% decline in lactate dehydrogenase (LDH) activity in NCs and DCs. Choline acetyltransferase (ChAT) and LDH activities in DCs were about 3–8 and 1.7–2.4 times higher than in NCs over the tested glucose concentration range, respectively. DCs appeared to be more resistant than NCs to hypoglycemia, as evidenced by lower glucose IC₅₀ values for cell count and intracellular LDH activity. On the other hand, some of functional properties of DCs, such as the cholinergic phenotype and their plasma membrane functions (trypan blue exclusion, TB+), were found to be more sensitive to hypoglycemia than those of NCs, as demonstrated by the higher IC₅₀ for glucose in DCs. Acetyl-CoA levels in DCs were 40% lower than in NCs, and decreased by about 25% with increasing hypoglycemia in both cell types. The cytotoxic effects of amyloid-β_25–35 (Aβ) and sodium nitroprusside (SNP; NO generator) were also tested. In 25 mM glucose medium, these toxic compounds exerted greater detrimental effects on DCs than on NCs. In contrast, in 1 mM glucose, more evident cytotoxicity of SNP and Aβ was observed in NCs. These data suggest that the higher rate of glycolysis in differentiated cholinergic septal neurons may be a protective mechanism against hypoglycemia. Full article

Alzheimer’s disease (AD) is a progressive, multifactorial neurodegenerative disorder ranking first as cause of dementia in the elderly. It is characterized by the progressive deterioration of the central nervous system, leading to impaired cognitive function and reduced ability to perform daily activities. Pathological hallmarks of AD include the accumulation of β-amyloid plaques and neurofibrillary tangles which ultimately cause neuronal death and synaptic loss. The vast majority of AD cases are sporadic, with aging representing the primary non-modifiable risk factor contributing to disease susceptibility and progression. However, several factors encompassing genetic predisposition, systemic inflammation, chronic diseases, infections, traumatic brain injury, lifestyle factors, and environmental exposures may affect AD onset. This work aims to describe and discuss the main molecular pathways involved in AD pathophysiology and to examine how these mechanisms cross-interact in promoting neurodegeneration and disease progression. Full article

Whether learned cognition can affect evolutionary outcomes remains a long-standing question. This study addresses a narrower mechanism: whether a model-based planner benefits from learned rules that explicitly condition on the action just taken. The testbed is a spatial artificial ecology with plants, shelters, a predator, reproduction, and a day/night cycle. Five rule-use arms are evaluated on matched simulation seeds. At age 200, agents switch to a weaker learned-lite planner that relies more strongly on learned rule predictions. The pre-specified hypothesis is that access to filtered action-conditioned rules improves outcomes relative to an otherwise identical no-rule-policy baseline, in which rules are still induced and stored but are not used for action selection. In thirty paired replicates under the default reproductive gates, the action-conditioned arm outperforms the no-rule baseline on all four pre-specified primary endpoints. The strongest effect is behavioural: the action arm produces 91.4 additional successful post-switch eating events per run ($d_z=1.56$, 93.3% paired win rate, $p<{10}^{-4}$). It also produces 10 additional crystallized clean-causal rules per replicate ($d_z=0.58$, $p_t=0.0034$). All four primary paired-tp-values remain significant after Bonferroni correction across the four-endpoint family. A diagnostic check shows that omitting reproductive cooldown from the planner’s rollout reverses the arm ordering on the same paired seeds; reinstating cooldown recovers the reported result. Two exploratory checks delimit the claim: broad unfiltered rule access can impair foraging, and a means–ends extension shifts behaviour toward reproduction without producing a robust whole-life fitness gain. Within this simulation, access to action-conditioned rules has a measurable effect on post-switch behaviour that is distinct from passive environmental prediction and from clean-crystallized rules alone. Full article

Background/Objectives: Post-COVID syndrome (PCS) is frequently associated with persistent cognitive complaints such as fatigue and impaired concentration, yet objective markers related to cognitive dysfunction are lacking. Pupillary oscillation metrics have emerged as non-invasive indicators of task-related cognitive load and autonomic regulation. This study investigated the Index of Pupillary Activity (IPA) and the Low/High Index of Pupillary Activity (LHIPA) in a large cohort of patients with PCS compared with healthy controls. Methods: In this cross-sectional study, 526 participants (397 PCS patients, 129 controls) performed a standardized virtual reality-based stereoscopic task at three disparity levels: 275 arcsec (high difficulty), 550 arcsec (medium difficulty), and 1100 arcsec (low difficulty), using a head-mounted display with integrated eye tracking. Continuous pupillometry data were recorded, and IPA and LHIPA were calculated. Linear mixed-effects models with random intercepts for participants were applied, adjusting for age, sex, and task difficulty. Results: Both IPA and LHIPA were significantly lower in PCS patients than in controls at all three task difficulty levels in post hoc model-based contrasts. In adjusted mixed-effects models, PCS was also associated with lower overall IPA ($\beta =-0.111$, 95% CI $-0.160$ to $-0.062$, $p<0.001$) and lower overall LHIPA ($\beta =-0.164$, 95% CI $-0.253$ to $-0.074$, $p<0.001$). Lower task difficulty was associated with higher values of both metrics: for IPA, $\beta =0.164$ at 550 arcsec and $\beta =0.287$ at 1100 arcsec (both $p<0.001$); for LHIPA, $\beta =0.161$ at 550 arcsec and $\beta =0.254$ at 1100 arcsec (both $p<0.001$), relative to 275 arcsec. Thus, both indices showed an inverse association with task difficulty. Age was negatively associated with both metrics, whereas male sex was positively associated with both. No significant interaction between cohort and task difficulty was observed. Conclusions: PCS was associated with reduced IPA and LHIPA during a standardized stereoscopic task. These findings indicate altered task-related pupillary dynamics in PCS and may reflect altered cognitive-load processing and autonomic regulation. LHIPA, and with caution also IPA, may contribute to the objective assessment of task-related pupillary alterations in PCS. Full article

Multiple Sclerosis (MS) is a chronic, immune-mediated disorder of the central nervous system characterized by leukocyte infiltration, inflammation, demyelination, and progressive neurodegeneration. Susceptibility to MS is influenced by genetic factors, including variants within the human leukocyte antigen (HLA) region, (notably HLA-DR15), and multiple single nucleotide polymorphisms that modulate T cell function and immune regulation. Clinically, early manifestations such as visual disturbances, sensory deficits, fatigue, and impaired coordination often precede more advanced features, including cognitive decline and bladder or bowel dysfunction. Although experimental and genetic models of neuroinflammation have facilitated the development of therapies that reduce relapse rates and slow disease progression, the underlying pathological mechanisms remain incompletely understood. Emerging evidence points to the importance of cytoskeletal organization and membrane-associated signaling platforms in maintaining neuronal and immune cell function. Disruption of these systems may contribute to demyelination and neuroinflammatory cascades. Within this context, a systems biology perspective is particularly valuable, as it emphasizes the integration of multiple, interdependent pathways rather than isolated mechanisms. Caveolin-1 (Cav-1), an integral membrane protein of caveolae, has gained attention as a potential central regulator due to its role in coordinating signaling processes across diverse cellular compartments. In this review, we examine the potential genetic and functional contributions of Cav-1 to MS pathophysiology, with a focus on its involvement in oxidative stress, inflammation, blood–brain barrier integrity, and autophagy. By framing these processes as components of an interconnected network, we highlight Cav-1 as a context-dependent modulator that may influence both disease progression and severity. However, despite its mechanistic relevance, the translational potential of Cav-1 remains uncertain, and further studies are required to clarify its precise role and evaluate its suitability as a therapeutic target in MS. Full article

Incretin receptor agonists (IRAs) such as GLP-1-based therapies improve metabolic and cognitive outcomes and enhance brain insulin signaling. One way that IRAs could have these actions is by affecting the blood–brain barrier (BBB); however, IRA-BBB interactions are poorly studied. Here, we examined the ability of insulin and IRAs to affect each other’s transport across the BBB in lean mice. We found that intracerebroventricular (ICV) administration of the insulin receptor antagonist S961 did not affect the blood-to-brain transport of the bioactive fragment of the IRA, ¹²⁵I-dulaglutide (BAF). In contrast, ¹²⁵I-dulaglutide (BAF) co-administered with intravenous (IV) insulin significantly enhanced ¹²⁵I-dulaglutide (BAF) BBB transport into whole brain, olfactory bulb, parietal cortex, and pons, demonstrating insulin-dependent modulation of IRA BBB transport. Regional transport rates for ¹²⁵I-dulaglutide (BAF) across the brain varied by ~2.5-fold, with the fastest transport into the olfactory bulb, frontal cortex, cerebellum, and pons. Co-administration of IV dulaglutide (BAF) did not alter ¹²⁵I-insulin BBB transport rates (K_i) but did reduce reversible insulin binding (V_i) at the BBB by >50%, suggesting rapid effects on BBB insulin receptors. To explore the effects of chronic IRA administration, lean mice were treated with semaglutide for two weeks. Body weight and food intake were unchanged, but female mice showed reduced fasting levels of serum insulin and GLP-1 and decreased insulin transport into whole brain, while male mice showed a reduction in insulin binding at the BBB. Chronic semaglutide also reduced ¹²⁵I-insulin BBB transport in female mice when studied with in situ perfusion, a procedure that removes the immediate influence of serum factors. Together, these findings demonstrate reciprocal and female-selective interactions between IRAs and insulin at the BBB. Acute insulin enhances the BBB transport of an IRA in female mice, whereas chronic IRA exposure selectively impairs insulin BBB transport in females, highlighting the BBB as a dynamic and hormone-sensitive interface with implications for long-term treatment in mouse models and potential for translation impact in humans. Full article

Background: Oncology nurses are highly vulnerable to impaired mental health and reduced quality of life due to the emotionally demanding nature of their work. Although mental health is a well-established determinant of quality of life, the mechanisms underlying this relationship remain insufficiently understood. Objective: This study examined the effect of the mental health continuum on quality of life among oncology nurses and tested the serial mediating roles of exercise self-efficacy and psychological resilience. Methods: A cross-sectional design was conducted with 604 oncology nurses in Türkiye. Data were collected using the Mental Health Continuum—Short Form, the Exercise Self-Efficacy Scale, the Psychological Resilience Scale, and the WHOQOL-BREF. Serial mediation analysis was performed using PROCESS Model 6 with 5000 bootstrap resamples. Results: The mental health continuum had a significant positive effect on exercise self-efficacy (a1 = 0.08, p < 0.001) and psychological resilience (a2 = 0.05, p < 0.001). Exercise self-efficacy significantly predicted psychological resilience (d1 = 0.51, p < 0.001). Both exercise self-efficacy (b1 = 0.88, p < 0.001) and psychological resilience (b2 = 1.60, p < 0.001) were significant predictors of quality of life. The direct effect of the mental health continuum on quality of life remained significant (c′ = 0.65, p < 0.001), indicating partial mediation. Bootstrap results further confirmed that all indirect effects were statistically significant, as their 95% confidence intervals did not include zero. Conclusions: Quality of life is influenced not only by mental health but also by sequential cognitive and adaptive processes. Interventions targeting exercise self-efficacy and psychological resilience may enhance well-being among oncology nurses. Full article

Background: Sjögren’s disease (SjD) is a chronic systemic autoimmune disorder primarily characterized by lymphocytic infiltration of exocrine glands, leading to xerostomia and xerophthalmia. Beyond glandular involvement, the disease frequently presents with a broad spectrum of systemic and neuropsychiatric manifestations that significantly affect patients’ quality of life. Methods: A review of the literature was conducted to identify studies addressing neuropsychological symptoms in patients with SjD. Relevant publications describing cognitive dysfunction, mood disorders, sleep disturbances, fatigue, and sexual dysfunction, as well as potential underlying mechanisms and therapeutic approaches, were included and analyzed. Results: Available evidence indicates that neuropsychological symptoms are common among patients with SjD. Cognitive impairment, often described as “brain fog”, may involve deficits in memory, attention, and executive functioning. Depression and anxiety appear to occur more frequently than in the general population and may interact with chronic fatigue and sleep disturbances, contributing to functional impairment. While somatic causes of sexual dysfunctions such as vaginal dryness are well recognized, psychological and psychosexual aspects, including reduced sexual desire, have received comparatively little attention. The pathogenesis of these manifestations is likely multifactorial and may involve immune-mediated processes, cytokine dysregulation, neuroendocrine alterations, microvascular changes, and psychosocial factors. Conclusions: Neuropsychological manifestations represent a significant component of the overall disease burden in SjD. Increased awareness and multidisciplinary management strategies may help improve symptom recognition, patient care, and quality of life. Full article

Background: A significant percentage of patients with major depressive disorder (MDD) fail to achieve remission with antidepressant monotherapy and frequently experience residual mood and cognitive symptoms that impair their functional recovery. Thus, an augmentation with vortioxetine, a multimodal antidepressant with reported cognitive benefits, might be a useful strategy for such patients. Methods: We conducted a 12-week naturalistic, prospective observational study in a Malaysian university hospital; 40 adults with MDD and inadequate response to at least eight weeks of antidepressant therapy received either adjunctive vortioxetine or optimization of their existing antidepressant as part of treatment-as-usual care. Depressive symptoms were assessed using the Montgomery–Åsberg Depression Rating Scale (MADRS), cognitive symptoms using the Perceived Deficits Questionnaire-5 (PDQ-D5), and global improvement using the Clinical Global Impressions—Improvement (CGI-I) scale. Results: Both groups demonstrated significant improvements in MADRS and PDQ-D5 scores over 12 weeks (p < 0.001). Remission rates at Week 12 were high in both groups (93.8% adjunctive vortioxetine vs. 86.7% control). Both groups demonstrated significant improvements in depressive and cognitive symptoms over 12 weeks. Although between-group differences were not statistically significant, descriptive trends toward earlier symptomatic improvement were observed in the adjunctive vortioxetine group in several core depressive symptoms, including apparent sadness, suicidal ideation, and appetite disturbance. Greater clinician-rated global improvement was observed in the vortioxetine group at Week 12 (87.5% vs. 40.0%, p < 0.001). Conclusions: In this outpatient clinical setting, adjunctive vortioxetine was associated with earlier improvement of core depressive symptoms and greater global clinical improvement compared with optimization of existing antidepressant therapy. Collectively, these findings suggest adjunctive vortioxetine as a clinically relevant option for patients with MDD who show an inadequate response to antidepressant monotherapy; however, findings are exploratory and not causal, and thus larger RCTs are needed for affirmation. Full article

Cognitive impairment is common in Post-COVID-19 Condition (PCC), yet full neuropsychological testing remains resource-intensive. Because eye movements are known to be altered in certain cognitive disorders, Eye-Tracking (ET) offers a fast, non-invasive complementary approach for large-scale screening. This study aimed to predict neuropsychological test scores of participants with PCC from ET metrics using machine and deep learning models. ET data was collected from 172 participants performing a battery of visual tasks designed to elicit smooth pursuit and fixational eye movements, as well as pupil responses to light. Cognitive performance was assessed through established neuropsychological tests. We applied regression and classification models (e.g., Random Forest, XGBoost, and deep neural networks) to predict neuropsychological performance. Models were trained using ET data alone and in combination with the Montreal Cognitive Assessment (MoCA) scores, a widely used neuropsychological test for global cognitive screening. Although predicting individual test scores was challenging, combining them into a global composite measure improved performance. Model sensitivity and specificity reached 88% and 34% using ET data alone, and 87% and 60% when integrating ET with MoCA. This last trained model outperformed the conventional MoCA, highlighting the potential of ET as a rapid screening support tool for cognitive assessment. Full article