Search Results (498)

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder marked by amyloid-β (Aβ) plaques, neurofibrillary tangles, blood–brain barrier dysfunction, oxidative stress (OS), and neuroinflammation. Current treatments provide symptomatic relief, but do not halt the disease’s progression. OS plays a crucial role in AD pathogenesis by promoting Aβ accumulation. Nuclear factor erythroid 2-related factor 2 (NRF2) is a key regulator of the antioxidant response, influencing genes involved in OS mitigation, mitochondrial function, and inflammation. Dysregulation of NRF2 is implicated in AD, making it a promising therapeutic target. Emerging evidence suggests that adherence to a Mediterranean diet (MD), which is particularly rich in polyphenols from extra virgin olive oil (EVOO), is associated with improved cognitive function and a reduced risk of mild cognitive impairment. Polyphenols can activate NRF2, enhancing endogenous antioxidant defenses. This study employs a computational approach to explore the potential of bioactive compounds in EVOO to modulate NRF2-related pathways in AD. We analyzed transcriptomic data from AD and EVOO-treated samples to identify NRF2-associated genes, and used chemical structure-based analysis to compare EVOO’s bioactive compounds with known NRF2 activators. Enrichment analysis was performed to identify common biological functions between NRF2-, EVOO-, and AD-related pathways. Our findings highlight important factors and biological functions that provide new insight into the molecular mechanisms through which EVOO consumption might influence cellular pathways associated with AD via modulation of the NRF2 pathway. The presented approach provides a different perspective in the discovery of compounds that may contribute to neuroprotective mechanisms in the context of AD. Full article

In modern medical education, a robust understanding of statistics is essential for fostering critical thinking, informed clinical decision-making, and effective communication. This paper explores the synergistic value of early and continued statistical education for medical students and residents, particularly in relation to the expanding field of sports supplementation and its impact on athletic performance. Early exposure to statistical principles enhances students’ ability to interpret clinical research, avoid cognitive biases, and engage in evidence-based practice. Continued statistical learning throughout residency further refines these competencies, enabling more sophisticated analysis and application of emerging data. The paper also addresses key challenges in integrating statistics into medical curricula—such as limited curricular space, student disengagement, and resource constraints—and proposes solutions including interactive learning, case-based teaching, and the use of public datasets. A unique emphasis is placed on connecting statistical literacy to the interpretation of research in sports science, particularly regarding the efficacy, safety, and ethical considerations of sports supplements. By linking statistical education to a dynamic and relatable domain like sports performance, educators can not only enrich learning outcomes but also foster lasting interest and competence in quantitative reasoning. This integrated approach holds promise for producing more analytically proficient and clinically capable physicians. Full article

Semantic modeling of legal reasoning is an important research direction in the field of artificial intelligence and law (AI and law), aiming to enhance judicial transparency, fairness, and the consistency of legal applications through structured semantic representations. This paper proposes a semantic judicial reasoning framework based on the “Data–Information–Knowledge–Wisdom–Purpose” (DIKWP) model, which transforms the conceptual expressions of traditional legal judgment into DIKWP graphs enriched with semantics. The framework integrates the objective content of legal norms with stakeholders’ subjective cognition through a DIKWP×DIKWP bidirectional mapping mechanism, achieving “semantic justice”. Specifically, we define a DIKWP-based legal knowledge representation method and design a mapping algorithm from traditional legal concepts to the DIKWP semantic structure. To validate the effectiveness of the framework, we use a real administrative law case as an example and construct DIKWP (normative content) and DIKWP (subjective cognition) graphs to model legal rules, evidence, and various perspectives. The results indicate that the intention-driven semantic transformation mechanism can harmonize legal reasoning with stakeholders’ cognitive backgrounds, thereby enhancing the interpretability and fairness of judicial interpretation. Case analysis further demonstrates that reasoning within the DIKWP semantic space can reveal underlying assumptions, bridge cognitive gaps, and promote judicial fairness by aligning legal intentions. This study provides new theoretical and methodological support for the explainable reasoning of intelligent judicial systems. Full article

Virtual reality (VR) can enrich neuropsychological testing, yet the ergonomic trade-offs of its input modes remain under-examined. Seventy-seven healthy volunteers—young (19–29 y) and middle-aged (35–56 y)—completed a VR Trail Making Test with three pointing methods: eye-tracking, head-gaze, and a six-degree-of-freedom hand controller. Completion time, spatial accuracy, and error counts for the simple (Trail A) and alternating (Trail B) sequences were analysed in 3 × 2 × 2 mixed-model ANOVAs; post-trial scales captured usability (SUS), user experience (UEQ-S), and acceptability. Age dominated behaviour: younger adults were reliably faster, more precise, and less error-prone. Against this backdrop, input modality mattered. Eye-tracking yielded the best spatial accuracy and shortened Trail A time relative to manual control; head-gaze matched eye-tracking on Trail A speed and became the quickest, least error-prone option on Trail B. Controllers lagged on every metric. Subjective ratings were high across the board, with only a small usability dip in middle-aged low-gamers. Overall, gaze-based ray-casting clearly outperformed manual pointing, but optimal choice depended on task demands: eye-tracking maximised spatial precision, whereas head-gaze offered calibration-free enhanced speed and error-avoidance under heavier cognitive load. TMT-VR appears to be accurate, engaging, and ergonomically adaptable assessment, yet it requires age-specific–stratified norms. Full article

Background/Objectives: Oxidative stress constitutes a principal pathophysiological mechanism driving neurodegeneration and brain aging. α-Ketoglutarate (AKG), a key intermediate of the tricarboxylic acid (TCA) cycle, has shown potential in longevity and oxidative stress resistance. However, the role of AKG in oxidative stress-induced neuronal senescence and its interaction with the mTOR signaling pathway during neuronal aging remain poorly understood, posing a key challenge for developing senescence-targeted therapies. Methods: We investigated the neuroprotective effects of AKG using H₂O₂-induced senescence in HT22 cells and a D-galactose-induced brain aging mouse model. Assessments encompassed SA-β-gal staining, EdU incorporation, mitochondrial membrane potential (JC-1), and ROS measurement. Antioxidant markers, ATP levels, and the NAD⁺/NADH ratio were also analyzed. Proteomic profiling (DIA-MS) and KEGG/GSEA enrichment analyses were employed to identify AKG-responsive signaling pathways, and Western blotting validated changes in mTOR signaling and downstream effectors. Results: AKG significantly alleviated H₂O₂-induced senescence in HT22 cells, evidenced by enhanced cell viability, reduced ROS level, restored mitochondrial function, and downregulated p53/p21 expression. In vivo, AKG administration improved cognitive deficits and vestibulomotor dysfunction while ameliorating brain oxidative damage in aging mice. Proteomics revealed mTOR signaling pathways as key targets for AKG’s anti-aging activity. Mechanistically, AKG suppressed mTOR phosphorylation and activated ULK1, suggesting modulation of autophagy and metabolic homeostasis. These effects were accompanied by enhanced antioxidant enzyme activities and improved redox homeostasis. Conclusions: Our study demonstrates that AKG mitigates oxidative stress-induced neuronal senescence through suppression of the mTOR pathway and enhancement of mitochondrial and antioxidant function. These findings highlight AKG as a metabolic intervention candidate for age-related neurodegenerative diseases. Full article

Parkinson’s disease (PD) is the second most common neurodegenerative disease. It primarily affects the motor system but is also associated with a range of cognitive impairments that can manifest early in disease progression, indicating its multifaceted nature. In this paper, we performed a meta-analysis of transcriptomics and proteomics data using MultiOmicsIntegrator to gain insights into the post-transcriptional modifications and deregulated pathways associated with this disease. Our results reveal differential isoform usage between control and PD patient brain samples that result in enriched alternative splicing events, including an extended UTR length, domain loss, and the upregulation of non-coding isoforms. We found that Inositol-Requiring Enzyme 1 (IRE1) is active in PD samples and examined the role of its downstream signaling through X-box binding mRNA 1 (XBP1) and regulated IRE1-dependent decay (RIDD). We identified several RIDD candidates and showed that the enriched alternative splicing events observed are associated with RIDD. Moreover, in vitro mRNA cleavage assays demonstrated that OSBPL3, C16orf74, and SLC6A1 mRNAs are targets of IRE1 RNAse activity. Finally, a pathway enrichment analysis of both XBP1s and RIDD targets in the PD samples uncovered associations with processes such as immune response, oxidative stress, signal transduction, and cell–cell communication that have previously been linked to PD. These findings highlight a potential regulatory role of IRE in PD. Full article

Owing to the need for a brain supplement targeting neuroprotection against age-related brain disorders and the known effect of carotenoids on brain function, we aimed to assess the effect of consuming carotenoid-rich functional congee for 8 weeks on cognitive function and age-related serum biomarkers. Both males and females (60–70 years old) were randomly assigned to consume either placebo or carotenoid-rich functional congee containing dried tomato powder at doses of 200 and 400 mg per day. Cognitive function, working memory, and serum biomarkers including alpha-synuclein and PARK7, together with serum oxidative stress parameters and neurotransmitters, were assessed prior to consumption and every 4 weeks throughout the study period. The contents of Lactobacillus and Bifidobacterium spp. in feces were also determined. Both doses of carotenoid-enriched congee enhanced cognitive function (P300), but only low doses improved working memory and decreased the activity of MAO-A and serum alpha-synuclein. The high-dose congee-treated group exhibited an increase in the density of Lactobacillus spp. in feces. Taking all data together, the carotenoid-enriched congee enhances cognitive function and working memory. The mechanisms may partly involve the increase in monoaminergic function, while the modulation of the gut–brain axis may require further confirmation. Full article

Objectives: To identify cognitive domains predictive of dynamic balance performance in older adults and inform targeted cognitive-motor interventions aimed at improving balance and reducing fall risk. Methods: This cross-sectional study used hierarchical multiple regression to analyze relationships between cognitive domains and dynamic balance among 62 community-dwelling older adults (≥65 years). Balance was assessed using the Y Balance Test (YBT) and Timed Up and Go Test (TUG), while cognitive function was measured using the Mini-Mental State Examination (global cognition), Stroop Test (inhibition), N-back Test (working memory), and Deary–Liewald Reaction Time Test (processing speed). Statistical analyses were conducted using SPSS, version 28, with significance set at p < 0.05. Results: Although all cognitive domains correlated with dynamic balance, regression analyses indicated that only global cognition and inhibition were significant predictors. Specifically, global cognition significantly predicted both TUG and YBT performance, whereas inhibition uniquely predicted YBT performance (all p < 0.05). Conclusions: Our findings suggest global cognition and inhibition are key cognitive predictors of dynamic balance in older adults. Assessing these domains could identify individuals at risk of impaired balance, facilitating the design of targeted, personalized cognitive-motor interventions. Future research should investigate cognitively enriched exercise programs, including digital therapeutics and wearable technologies, to effectively target these cognitive domains, enhance balance outcomes, and promote sustained physical activity adherence in aging populations. Full article

Alzheimer’s disease (AD) is characterized by progressive cognitive decline strongly associated with impaired adult hippocampal neurogenesis (AHN). Mounting evidence suggests that this impairment results from both the intrinsic dysfunction of neural stem cells (NSCs)—such as transcriptional alterations in quiescent states—and extrinsic niche disruptions, including the dysregulation of the Reelin signaling pathway and heightened neuroinflammation. Notably, AHN deficits may precede classical amyloid-β and Tau pathology, supporting their potential as early biomarkers of disease progression. In this review, we synthesize recent advances in therapeutic strategies aimed at restoring AHN, encompassing pharmacological agents, natural products, and non-pharmacological interventions such as environmental enrichment and dietary modulation. Emerging approaches—including BDNF-targeted nanocarriers, NSC-derived extracellular vesicles, and multimodal lifestyle interventions—highlight the translational promise of enhancing neurogenesis in models of familial AD. We further propose the Neurogenesis Impairment Index (NII)—a novel composite metric that quantifies hippocampal neurogenic capacity relative to amyloid burden, while adjusting for demographic and cognitive variables. By integrating neurogenic potential, cognitive performance, and pathological load, NII provides a framework for stratifying disease severity and guiding personalized therapeutic approaches. Despite ongoing challenges—such as interspecies differences in neurogenesis rates and the limitations of stem cell-based therapies—this integrative perspective offers a promising avenue to bridge mechanistic insights with clinical innovation in the development of next-generation AD treatments. Full article

PDE11A is a little-studied phosphodiesterase sub-family that breaks down cAMP/cGMP, with the PDE11A4 isoform enriched in the memory-related hippocampal formation. Age-related increases in PDE11A expression occur in human and rodent hippocampus and cause age-related cognitive decline of social memories. Interestingly, age-related increases in PDE11A4 protein ectopically accumulate in spherical clusters that group together in the brain to form linear filamentous patterns termed “PDE11A4 ghost axons”. The biophysical/physiochemical mechanisms underlying this age-related clustering are not known. Here, we determine if age-related clustering of PDE11A4 reflects liquid–liquid phase separation (LLPS; biomolecular condensation), and if PDE11A inhibitors can reverse this LLPS. We show human and mouse PDE11A4 exhibit several LLPS-promoting sequence features, including intrinsically disordered regions, non-covalent pi–pi interactions, and prion-like domains that were particularly enriched in the N-terminal regulatory region. Further, multiple bioinformatic tools predict PDE11A4 undergoes LLPS. Consistent with these predictions, aging-like PDE11A4 clusters in HT22 hippocampal neuronal cells were membraneless spherical droplets that progressively fuse over time in a concentration-dependent manner. Deletion of the N-terminal intrinsically disordered region prevented PDE11A4 LLPS despite equal protein expression between WT and mutant constructs. 1,6-hexanediol, along with tadalafil and BC11-38 that inhibit PDE11A4, reversed PDE11A4 LLPS in HT22 hippocampal neuronal cells. Interestingly, PDE11A4 inhibitors reverse PDE11A4 LLPS independently of increasing cAMP/cGMP levels via catalytic inhibition. Importantly, orally dosed tadalafil reduced PDE11A4 ghost axons in old mouse ventral hippocampus by 50%. Thus, PDE11A4 exhibits the four defining criteria of LLPS, and PDE11A inhibitors reverse this age-related phenotype both in vitro and in vivo. Full article

Cross-sectional research suggests associations between enrichment and cognitive skills in toddlerhood. There are no prospectively designed longitudinal studies that investigate the link between early home literacy activities and subsequent mechanisms that explain the putative cognitive benefits. This study tests long-term associations between toddler literacy enrichment and later student engagement across key academic transitions, from kindergarten to the end of high school. Using the Quebec Longitudinal Study of Child Development (QLSCD) population-based birth cohort data, we examined whether parent-reported experiences of shared reading, looking at picture books or illustrated stories, and pretend writing at age 2 years predict later teacher- and self-reported student engagement at ages 6, 12, and 17 years. The results from multiple regression models, stratified by sex and adjusted for pre-existing and concurrent child and family characteristics, revealed significant associations between early literacy enrichment and later engagement. For boys and girls, literacy enrichment in toddlerhood predicted increases in classroom engagement from kindergarten to the end of high school. These findings highlight the lasting influence of early literacy exposure on subsequent learning-related behaviors, both in and beyond the classroom. They underscore the importance of promoting enrichment in early childhood as a family strategy toward individual readiness to learn, a cornerstone of crystalized intelligence. Full article

Background: Recent studies indicate that physical activity (PA) may improve executive functions (EFs) in children with Autism Spectrum Disorder (ASD). The Enriched Motor Program (EMP), which combines aerobic and cognitive exercises, shows potential for enhancing EFs in these children. The EMP was originally created for typically developing preschoolers and includes locomotor and fine motor activities enriched by cognitive stimuli to help the development of EFs in children with ASD. The current study aims to adapt a shorter version of EMP for these children’s needs. Methods: The research will use a cross-sectional, quasi-experimental design with a forecasted sample of 40 children, with the age ranging from six to eight, with a diagnosis of ASD. The children’s working memory and inhibitory control will be measured before and after the intervention. Results: According to the literature, the experimental group should obtain higher scores, especially in working memory tasks. Discussion: This is the first implementation of EMP, which merges physical activities with cognitive stimuli to enhance EFs in children with ASD. It could be used by specialized centers and clinicians to support EFs through engaging activities, and it could be potentially recommended as a best practice for EF treatments in children with ASD. Full article

Addressing the escalating complexity of global sustainability challenges requires interventions that are not only technically effective but also cognitively and philosophically grounded. While the leverage points perspective has provided a useful framework for understanding systemic change, it can be enhanced through more operational coherence and cultural pluralism. This paper introduces the Deep and Shallow Sustainability Intervention (DSSI) framework, a novel conceptual model that integrates Taoist philosophical insights with contemporary systems thinking and the leverage points literature. Structured across five interconnected Taoist-inspired domains and ten leverage points, the framework extends and enriches Meadows’ leverage point theory by integrating pre-paradigmatic meta-cognitions, systemic momentum, and context-sensitive action. It emphasizes that sustainable transitions require the dynamic interplay between foundational source-code shifts and operational implementation. This framework contributes to the growing field of transformative sustainability science by (1) embedding non-Western epistemologies into systems transformation theory, (2) offering a structured yet flexible model for multi-level intervention design, and (3) enabling transdisciplinary dialogue between philosophy, paradigmatic shift, meta-systemic logic, governance, and practice. Preliminary applications in European rural transition contexts suggest its potential to enhance context-sensitive action and value-aligned systems innovation. The DSSI framework thus offers a timely and integrative approach for guiding long-term, systemic, and culturally responsive sustainability transitions. Full article

The early diagnosis of dementia, a progressive condition impairing memory, cognition, and functional ability in older adults, is essential for timely intervention and improved patient outcomes. This study proposes a novel multiclass classification that differentiates dementia from other comorbid conditions, specifically cardiovascular diseases, including heart failure and aortic valve disorder, by leveraging the “blessing of dimensionality” to enhance predictive performance while ensuring feature accessibility. Using a dataset of 26,474 electronic health records from two hospitals in Chiang Rai, Thailand, the proposed framework introduced clinically informed feature augmentation to enhance model generalizability. Furthermore, the borderline synthetic minority oversampling technique was employed to address class imbalance, enhancing the model’s performance for minority classes. This study systematically evaluated a suite of machine learning models, including extreme gradient boosting, gradient boosting, random forest, support vector machine, decision trees, k-nearest neighbors, extra trees, and TabNet, across both the original and enriched datasets, with the latter integrating augmented features and synthetic data. Predictive performance was assessed using accuracy, precision, recall, F1 score, area under the receiver operating characteristic curve, and area under the precision–recall curve. The results revealed that all the models exhibited consistent performance improvements with the enriched dataset, affirming the value of dimensionality when guided by domain expertise. Full article

Background: Docosahexaenoic acid (DHA) is the most important fatty acid (FA) for the development and function of brain and retina. Mother’s milk is the predominant source of DHA for the baby’s postnatal life, and the omega 3 FA content of a mother’s diet is highly correlated with the cognitive and visual functions of the infant. However, clinical trials aimed at increasing the DHA content of mother’s milk and thereby improving infant cognitive function have been inconclusive. Methods: In this study, we tested the hypothesis that the molecular form of dietary DHA is important in enriching DHA in mother’s milk as well as in pup tissues. Lactating dams were fed defined diets containing DHA either in the form of triacylglycerol (TAG) or lysophosphatidylcholine (LPC), and the FA composition of mother’s milk and pup tissues was determined on postnatal day 16. Results: The results showed that LPC-DHA was 5-fold more efficient than TAG-DHA in enriching milk DHA. Moreover, DHA content was increased by 31% in the brain, 56% in the retina, and 14% in the liver of the pups by LPC-DHA in the maternal diet, whereas no increases were observed with TAG-DHA. The DHA content of the pup adipose tissue, however, was increased equally by the DHA supplements. Conclusions: These results show that dietary LPC-DHA is a promising new strategy to increase milk DHA content and to potentially improve brain and retinal health in infants. This strategy may be more important in the care of premature infants who miss the critical prenatal period of DHA accretion in the last trimester of pregnancy. Full article