Search Results (554)

Background: Hyperphosphorylated tau accumulation and neurofibrillary tangles (NFTs) are hallmarks of tauopathies, including Alzheimer’s disease (AD), and are strongly associated with cognitive decline. The rTg4510 mouse model, which expresses mutant human tau (P301L), develops progressive tauopathy in the absence of amyloid-β pathology, providing a valuable tool for investigating tau-driven neurodegeneration. Previous studies have demonstrated spatial and object-recognition memory deficits at six months of age, which can be prevented by doxycycline (DOX)-mediated suppression of tau expression. However, it remained unclear whether non-spatial hippocampal learning, particularly temporal associative learning, would be similarly affected. Methods: We evaluated six-month-old rTg4510 mice with or without DOX treatment. To control for potential motor confounds, we first assessed spontaneous home cage activity. We then tested hippocampus-dependent non-spatial learning using two paradigms: trace eyeblink conditioning (500-ms trace interval) and contextual fear conditioning. Results: General motor function remained intact; however, rTg4510 mice without DOX treatment exhibited increased rearing behavior. These mice demonstrated significant deficits in trace eyeblink conditioning acquisition, with particularly clear impairment on the final day of training. Contextual fear conditioning showed milder deficits. Analysis of response peak latency revealed subtle temporal processing abnormalities during early learning. Two months of DOX treatment initiated at four months of age prevented these learning deficits, confirming their association with tau overexpression. Conclusions: Our findings demonstrate that rTg4510 mice exhibit deficits in non-spatial temporal associative learning alongside previously reported spatial and object-recognition impairments. Trace eyeblink conditioning serves as a sensitive behavioral assay for detecting tau-related hippocampal dysfunction, and the prevention of learning deficits by DOX treatment highlights its potential utility as a translational biomarker for evaluating tau-targeted interventions. Full article

Background/Objectives: As the global population ages, the prevalence of disorders associated with memory dysfunction (e.g., Alzheimer’s disease) continues to increase. There is a need for novel interventions that can enhance memory and support affected individuals. Non-invasive brain stimulation provides a promising approach to engage circuits within the hippocampal network, a group of brain regions critical for episodic memory, and thereby improve cognition. Methods: Twenty healthy participants completed a single-blind, within-subject crossover study over four sessions. In each session, they received one of four interventions whilst viewing pictures of real-world objects: 40 Hz synchronised audiovisual stimulation (AVS), theta burst stimulation (TBS), a combination of synchronised 5 Hz repetitive transcranial magnetic stimulation with AVS (rTMS + AVS), or sham rTMS. Electroencephalography (EEG) was recorded to measure associated brain activity changes. Following each intervention, participants completed a recognition memory task. Results: Mixed-effect repeated measure models (MRMMs) revealed no significant differences in recognition memory performance or theta (5 Hz) activity across conditions. However, both TBS and rTMS + AVS significantly increased gamma (40 Hz) activity compared to sham rTMS, and TBS induced a widespread increase in theta-gamma phase-amplitude coupling during picture viewing. Conclusions: While the neuromodulatory interventions did not enhance memory performance, the observed increase in gamma activity, particularly following rTMS-based stimulation, suggests potential engagement of neural processes associated with memory. These findings warrant further investigation into the role of gamma oscillations in memory and cognitive enhancement. Full article

Background: Mammalian orthoreovirus is a ubiquitous double-stranded RNA virus that causes mild respiratory and enteric infections, primarily in infants and young children. Its significant environmental stability and association with conditions like celiac disease highlight an unmet medical need, as no licensed vaccine or antiviral treatment currently exist. Methods: An immunoinformatics-driven approach was employed to design a multi-epitope vaccine. The highly antigenic inner capsid protein Sigma-2 was used to predict cytotoxic T lymphocyte (CTL), helper T lymphocyte (HTL), and linear B cell epitopes using NetCTL, NetMHCpan, NetMHCIIpan, and IEDB tools. Selected epitopes were fused with appropriate linkers. The construct’s antigenicity, allergenicity, and physicochemical properties were evaluated. The tertiary structure was predicted with AlphaFold2, refined, and validated. Molecular docking with TLR2 and TLR4 was performed using HDOCK, and immune response simulation was conducted with C-ImmSim. Finally, the sequence was codon-optimized for E. coli expression using JCat. Results: The final vaccine construct comprises one CTL, four HTLs, and one B cell epitope. It is antigenic (VaxiJen score: 0.5026), non-allergenic, and non-toxic and possesses favorable physicochemical properties, including stability (instability index: 32.28). Molecular docking revealed exceptionally strong binding to key immune receptors, particularly TLR2 (docking score: −324.37 kcal/mol). Immune simulations predicted robust antibody production (elevated IgM, IgG1, and IgG2) and lasting memory cell formation. Codon optimization yielded an ideal CAI value of 0.952 and a GC content of 57.15%, confirming high potential for recombinant expression. Conclusions: This study presents a novel multi-epitope vaccine candidate against reovirus, designed to elicit broad cellular and humoral immunity. Comprehensive in silico analyses confirm its structural stability, potent interaction with innate immune receptors, and high potential for expression. These findings provide a strong rationale for further wet-lab studies to validate its efficacy and advance it as a promising prophylactic candidate. Full article

Neonicotinoid pesticides, including imidacloprid (IMI), are widely used in agriculture and as household insecticides. IMI displays strong affinity for insect nicotinic acetylcholine receptors (nAChRs); however, neonicotinoids still partially bind to mammalian nAChRs. Relatively little is known about how neonicotinoid exposure alters learning, memory or mood, even though nAChRs play a role in these mechanisms. We tested the hypothesis that developmental exposure to IMI impairs performance on memory tasks, and anxiety- and depressive-like behavior. We orally dosed pregnant CD-1 mice from gestation day 10 to birth with vehicle or IMI at 0.5 mg/kg/day or 5.7 mg/kg/day. When exposed animals were adults, we examined cognitive and emotional behaviors and we examined the effect of IMI on α7 and α4 nAChR subunit mRNA expression using qPCR. For both sexes, IMI exposure was associated with impaired striatal-dependent procedural learning task and hippocampal-dependent spatial learning but had no effect on hippocampal-dependent working memory. Males, but not females, displayed increased anxiety-like behavior, with low dose subjects displaying more pronounced effects, suggesting a non-linear dose response. In males, we found lower α7 subunit mRNA expression in the hippocampus and amygdala and lower α4 mRNA expression in the striatum compared to controls. Thus, exposure to IMI during a critical period is associated with disruptions to cognitive and anxiety-like behaviors. Additionally, in males, IMI exposure is associated with reduced expression of nAChR subunits in relevant brain regions. Full article

Although associative interference has traditionally been attributed to retrieval competition, emerging evidence suggests that interference may also arise from encoding-based representational processes. The present study examined whether retroactive interference (RI) and proactive interference (PI) can occur in the absence of explicit retrieval competition and whether they reflect distinct underlying mechanisms. Participants studied two lists of word–picture pairs in an AB/AC associative learning paradigm, followed by a non-competitive two-alternative forced-choice (2AFC) associative recognition test and a source memory task. Across both frequentist and Bayesian analyses, recognition accuracy revealed a significant RI effect—lower accuracy for earlier A-B pairs relative to non-overlapping controls—whereas PI manifested as longer reaction times (RTs) for later A-C pairs, despite comparable accuracy. Source judgments showed faster correct responses for overlapping than for non-overlapping pairs, suggesting that cue overlap facilitated more fluent retrieval rather than confusion. These findings indicate that interference can emerge independently of retrieval competition and that RI and PI are supported by dissociable mechanisms: RI reflects encoding-related reorganization that weakens earlier associations, whereas PI reflects increased retrieval effort following differentiation of overlapping traces. Together, the results support a process-interaction framework in which encoding-based reactivation and reorganization shape later retrieval dynamics, demonstrating that associative interference arises from the interplay between encoding and retrieval processes rather than retrieval competition alone. Full article

Background. Cancer treatment-related cognitive impairment (CTRCI) is a frequent and persistent consequence of systemic cancer therapy, adversely affecting quality of life and independence among cancer survivors. Methods. To clarify the relative effectiveness of available treatments, we conducted a systematic review and network meta-analyses of randomized controlled trials evaluating psychological, pharmacological, and other interventions for established CTRCI in adult survivors of non-central nervous system cancers. Eligible trials reported objective outcomes in one or more of eight cognitive domains, including learning, memory, processing speed, word generation, cognitive flexibility, attention, working memory, and abstraction. Results. Eighteen studies met inclusion criteria, with 14 trials (n = 1100) contributing to network meta-analyses of immediate post-intervention effects across seven domains. A therapist-guided group intervention combining patient education and cognitive rehabilitation consistently ranked highest and was associated with significantly improved learning, memory, processing speed, attention, and working memory compared with a waitlist control, although the certainty of evidence (CoE) was low to very low and largely based on a single trial. Mindfulness-based interventions were also associated with improved processing speed (low CoE). Donepezil was associated with no benefit versus placebo for any domain. Conclusions. While findings suggest that structured multimodal group interventions may represent the most promising strategy for CTRCI, CoE was low, and additional rigorous, standardized trials are required. Full article

Suicidality is a complex multifactorial phenomenon strongly associated with major depression and other psychiatric disorders. Building on evidence implicating the Major Histocompatibility Complex (MHC) in modulating the immune and inflammatory processes characterizing psychiatric disorders, we hypothesized that specific HLA-DQB1 and HLA-DRB1 variants may contribute to an increased genetic susceptibility to suicidal behavior. Human Leucocyte Antigen (HLA) typing by sequence-specific primers (PCR-SSP) was performed on a sample of 196 individuals, including 70 non-lethal suicide attempters, 28 cases of completed suicide, and matched controls. The *HLA-DQB1 02/06 (RR 1.60, CI95% 1.22–2.09, p = 0.03 *) and *HLA-DRB1 11/15 (RR 1.70, CI95% 1.3–2.24, p = 0.04 *) genotypes and the HLA-DRB115~DQB103 haplotype (RR 1.58, CI95% 1.22–2.04, p = 0.03 *) were found to favor suicidal behavior. Psychosocial determinants associated with an increased suicidal risk were bereavement of close relatives (linked with HLA-DQB1*02), memory dysfunction (HLA-DQB1*06), disillusionment (HLA-DRB1*07 and HLA-DRB1*15), and self-harm (HLA-DRB1*15). Our findings support the contributory role of HLA polymorphisms in shaping susceptibility to suicidal behavior. Full article

Objectives: This study investigated the effects of healthy aging on sentence production in narrative discourse and examined the role of cognitive abilities and Lifelong Learning (LLL) in mitigating age-related decline. Methods: Three hundred and seven Italian-speaking adults (26–89 years) completed a narrative task elicited from five picture stimuli, alongside assessments of verbal working memory, sustained attention, and inhibitory control. Morphological and morphosyntactic measures (morphological errors and omissions of content and function words) and syntactic variables (complete sentences, subordinate clauses, and passive sentences) were analyzed. Results: Aging was associated with increased morphological and morphosyntactic errors and reduced syntactic complexity. These effects were non-linear for the % of morphological errors, the % of omission of content words, and the % of complete sentences and were more pronounced after age 70. LLL was negatively associated with morphological and morphosyntactic errors and positively associated with sentence production. Verbal working memory and sustained attention explained additional variance only for omissions of function words, whereas the passive component of verbal working memory only explained additional variance for complete sentence production. Conclusions: These findings suggest that aging affects both simple and complex sentence production, with declines related to morphological errors and omissions. LLL appears to buffer against some grammatical declines, suggesting a role for educational engagement in maintaining syntactic abilities. Clinically, assessing complex sentence production and considering LLL may improve diagnosis and intervention for language disorders in older adults. Full article

Intestinal ischemia and reperfusion injury (IRI) can lead to multiple organ dysfunction, including the central nervous system (CNS), where a neuroinflammatory response may develop. Hyaluronan, a glycosaminoglycan component of the extracellular matrix, has been shown to modulate enteric neuronal and immune function during in vivo IRI in the rat small intestine. The aim of this study was to investigate the potential involvement of hyaluronan in the alterations induced by in vivo intestinal IRI in the rat hippocampus and striatum. Mesenteric ischemia was induced in anesthetized adult male rats for 60 min, followed by 24 h of reperfusion. Injured (IRI group), sham-operated (SHAM group), and non-injured (CTR group) animals were treated with the hyaluronan synthesis inhibitor 4-methylumbelliferone (4-MU; 25 mg/kg). In the hippocampus and striatum of the IRI group, levels of both hyaluronan and neurocan, a proteoglycan primarily found in the central nervous system extracellular matrix, as well as the hyaluronan synthesizing enzyme Has2, were significantly downregulated compared to the CTR and SHAM groups. These changes were associated with alterations in the TLR4-NFκB-pIκB pathway, with the effects being more prominent in the hippocampus than in the striatum. Increased levels of IL6, co-localizing with the microglial marker S100β, were observed in both regions and were attenuated by 4-MU only in the hippocampus. Overall, these findings suggest that intestinal IRI may disrupt extracellular matrix homeostasis and induce hyaluronan-mediated enhancement of local proinflammatory signaling, primarily involving IL6 and microglial cells, mainly in the hippocampus. Such changes may contribute to the development of cognitive deficits and memory dysfunction associated with intestinal IRI. Full article

Background: Despite effective antiretroviral therapy, HIV-associated neurocognitive disorders (HANDs) remain prevalent, highlighting the need for sensitive biomarkers of early brain alterations. Trace-weighted diffusion spectroscopic imaging offers a non-invasive means to assess microstructural changes in brain metabolites in a single shot by measuring apparent diffusion coefficients (ADCs) of total N-acetylaspartate (tNAA), total creatine (tCr), total choline (tCho), and water. Methods: In this study, we used trace-weighted single-shot diffusion-weighted radial echo-planar spectroscopic imaging (DW-RESPI) to investigate metabolite diffusion and relative concentrations in the brains of people living with HIV (PLWH). Using a 3T MRI scanner, we studied 16 PLWH and 15 healthy controls (HCs), and we collected two sets of data with low and high b-values from which metabolite ADCs were computed. Metabolite ratios were derived from the low b-value spectra. A brief neuropsychological assessment evaluated attention, executive function, and memory in a subset of subjects. Cognitive and affective performance was quantified using domain-specific deficit scores, as well as depression and anxiety assessments, offering a comprehensive evaluation of neurobehavioral function. In the male subgroup (N = 15) of PLWH, we calculated the correlations between ADC values and neuropsychological domain scores. Results: tNAA, tCr, tCho, and water ADC values were significantly elevated in multiple gray and white matter regions in PLWH compared to HC, with the most pronounced differences observed in the superior precuneus, anterior cingulate cortex, and corona radiata. Notably, regional ADC values and metabolite ratios showed significant correlations with neuropsychological domain scores. Conclusions: These findings indicate the potential of metabolite and water diffusion metrics as biomarkers for HIV-associated microstructural brain alterations and cognitive impairment. However, the small sample size and preliminary nature of this data warrant further investigation to validate these findings. Full article

Associative learning is a fundamental neural mechanism in human memory and cognition. It has attracted considerable attention in neuromorphic system design owing to its multimodal integration, fault tolerance, and energy efficiency. However, prior studies mostly focused on single inputs, with limited attention to multibit pairs or recall under non-orthogonal input patterns. To address these issues, this study proposes a bidirectional associative learning system using paired multibit inputs. It employs a synapse–neuron structure based on spiking neural networks (SNNs) that emulate biological learning, with simple circuits supporting synaptic operations and pattern evaluation. Importantly, the update and read functions were designed by drawing inspiration from the operational characteristics of emerging synaptic devices, thereby ensuring future compatibility with device-level implementations. The proposed system was verified through Cadence-based simulations using CMOS neurons and Verilog-A synapses. The results show that all patterns are reliably recalled under intact synaptic conditions, and most patterns are still robustly recalled under biologically plausible conditions such as partial synapse loss or noisy initial synaptic weight states. Moreover, by avoiding massive data converters and relying only on basic digital gates, the proposed design achieves associative learning with a simple structure. This provides an advantage for future extension to large-scale arrays. Full article

Within the context of urban sustainability, the renewal and activation of communities have received growing attention. Public art, as a common approach to community revitalization, has long been regarded as an effective means of addressing urban and community issues. Basic human senses serve as a bridge between residents and community spaces, offering an effective entry point for creating human-oriented spaces. This study addresses the challenge of insufficient spatial vitality in community spaces by examining how sensory interventions can enhance residents’ participation in public art and thereby contribute to the revitalization of communities. To guide this inquiry, a theoretical framework was constructed based on sensory marketing theory and the Stimulus–Organism–Response (SOR) model, focusing on three core dimensions: sensory stimuli, perceptual responses, and behavioral intention. The study further investigated the relationship between public art and residents’ willingness to participate through five types of sensory stimuli, using a measurement scale and Structural Equation Modeling (SEM), with eight public art installations in Shanghai serving as case references. It also assessed the relative strength of each effect. Participant interviews and non-participatory observations were subsequently conducted for validation and supplementary analysis. The results show that residents’ participation willingness in community public art is directly influenced by perceptual responses (emotional fluctuations, cognitive memory, and physiological responses), and indirectly influenced by different sensory stimuli. Cognitive memory, shaped mainly by olfactory and visual stimuli, emerged as the most important factor in encouraging participation. Participation willingness also varies across generations, and different sensory stimuli are associated with distinct participation patterns. Based on empirical data from Shanghai’s community activation practices, the study proposes implementation strategies guided by the Theory of Planned Behavior (TPB) to enhance spatial vitality, promote community activation, and support sustainable development. Full article

This study investigated how encoding strength and consolidation shape proactive interference (PI) in associative memory. Using a Modified Modified Free Recall (MMFR) paradigm, participants studied overlapping (A-B, A-C) and non-overlapping (E-F, G-H) pairs. The encoding strength of List 1 was manipulated (one vs. three study repetitions), while List 2 was held constant. Cued recall was tested immediately and after a 24-h delay. Results showed that increasing List 1’s encoding strength enhanced overall recall for both overlapping and non-overlapping pairs, indicating more effective learning, but did not alter the magnitude of PI. Instead, PI was strongly modulated by retention interval. At immediate test, robust PI emerged across conditions, reflecting cue-based retrieval competition. After a 24-h delay, PI was reduced or absent when List 1 was weakly encoded but persisted in attenuated form when List 1 was strongly encoded, suggesting differential consolidation trajectories for overlapping and non-overlapping associations. Co-retrieval analyses further revealed reliable associative dependency between B and C across all conditions, consistent with representational linkages that promote cooperative retrieval. These findings highlight the dual influence of cue overlap: at the representational level, overlapping pairs form integrated structures that foster co-retrieval, whereas at the retrieval-processing level, cue overload induces competition and PI. Taken together, the results indicate that although initial encoding strength enhances overall recall of List 2, the persistence of proactive interference is influenced by consolidation processes. Full article

Autopsy studies have shown that Alzheimer’s disease (AD) often coexists with cerebrovascular injury, affecting cognitive outcomes and the effectiveness of anti-amyloid-beta (Aβ) drugs. No fluid biomarkers of cerebrovascular injury have been identified yet. We investigated the association between white matter hyperintensities (WMH) severity and fluid biomarkers, including cerebrospinal fluid (CSF) neurofilament light chain and plasma placental growth factor (PlGF) levels. This study included 242 patients from memory clinics. Magnetic resonance imaging (MRI), CSF, and plasma samples were collected. Patients were classified as AD+ or non-AD based on the CSF Aβ42/Aβ40 ratio. In the discovery cohort (79 AD+ and 20 non-AD patients with 3D-T1 images), we analyzed the association between WMH volume and plasma PlGF. In the validation cohort (54 AD+ patients without 3D-T1 images), we analyzed the association between WMH grading and plasma PlGF. Among AD+ patients in the discovery cohort, plasma PlGF levels remained significantly associated with WMH volume and grading after adjusting for age, sex, and global cognition. Among the AD+ patients in the validation cohort, the high-PlGF (above median) group had significantly greater WMH volumes and a higher number of patients with a high WMH grading than the low-PlGF (below median) group. Plasma PlGF is a promising marker of cerebrovascular injury in AD. Full article

Background: A range of cancer cells are significantly inhibited by FTY720. It is unknown, nevertheless, how FTY720 influences the onset of non-small cell lung cancer (NSCLC). Using bioinformatics techniques, we analyzed and the possible molecular mechanisms and targets of FTY720 for the treatment of NSCLC. Methods: DEGs (Differentially expressed genes) were acquired by differential analysis of the dataset GSE10072. Obtained FTY720 target genes and NSCLC disease genes from databases such as Swiss-TargetPrediction and GeneCard. Subsequently, target and disease genes, as well as DEGs, were merged for Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, gene ontology (GO), and protein interaction analysis. The overlapping genes of DEGs and target genes, and disease genes were also obtained separately and subjected to survival as well as expression analyses. We constructed the regulatory network of miRNAs and transcription factors (TFs) on hub genes. Finally, the immune cell association of hub genes was evaluated using the ssGSEA method, molecular docking of FTY720 to hub genes was carried out utilizing Autodock, and molecular dynamics simulations were conducted. Results: In this study, 444 DEGs, 232 target genes of FTY720, and 466 disease genes were obtained. Moreover, a total of 1062 genes were obtained by removing duplicate values after merging, among which PIK3R1, Akt1, and S1PR1 had the highest DEGREE values in the protein interactions network, and these genes were primarily enriched in MAPK, PI3K-Akt signaling pathways, with the PI3K-Akt signaling pathway being the most prominent. Among the overlapping genes, three potential targets of FTY720 for NSCLC treatment were found: S1PR1, ZEB2, and HBEGF. ZEB2 and S1PR1 were determined to be hub genes and to significantly affect NSCLC prognosis by survival analysis. Furthermore, hsa-miR-132-3p, hsa-miR-192-5p, and hsa-miR-6845-3p were strongly associated with FTY720 for the treatment of NSCLC; CTBP1 (carboxy-terminal binding protein 1), EZH2 (protein lysine N-methyltransferase), and ZNF610 (zinc-finger protein 610) may all influence the expression of ZEB2 and S1PR1. Hub genes had a substantial negative link with memory B cells and a significant positive correlation with memory CD8 T cells and Th17 helper T cells. The molecular docking and kinetic simulation results of FTY720 with the two hub genes indicate that the protein-ligand complex has good stability. Conclusion: Our research indicates that FTY720 may inhibit NSCLC via possible targets ZEB2 and S1PR1, further laying the theoretical foundation for the utilization of FTY720 in NSCLC treatment. Full article