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The association between dairy intake and dementia risk remains uncertain, especially for dairy products with varying fat contents. The aim of this study was to investigate the association between high-fat and low-fat dairy intake and dementia risk. This study used data from a prospective cohort in Sweden, the Malmö Diet and Cancer cohort, which consisted of community-based participants who underwent dietary assessment at baseline (1991-1996). Dietary intake was evaluated using a comprehensive diet history method that combined a 7-day food diary, a food frequency questionnaire, and a dietary interview. Dementia cases were identified through the Swedish National Patient Register until December 31, 2020, and cases diagnosed until 2014 were further validated. The primary outcome of the study was all-cause dementia, and the secondary outcomes were Alzheimer disease (AD) and vascular dementia (VaD). Cox proportional hazard regression models were used to estimate hazard ratio (HR) and 95% CI. This study included 27,670 participants (mean baseline age 58.1 years, SD 7.6; 61% female). During a median of 25 years of follow-up, 3,208 incident dementia cases were recorded. Consumption of ≥50 g/d of high-fat cheese (>20% fat) was associated with a reduced risk of all-cause dementia (HR 0.87; 95% CI, 0.78-0.97) and VaD (HR 0.71, 95% CI 0.52-0.96) compared with lower intake (<15 g/d). An inverse association between high-fat cheese and AD was found among Higher intake of high-fat cheese and high-fat cream was associated with a lower risk of all-cause dementia, whereas low-fat cheese, low-fat cream, and other dairy products showed no significant association. Show less

Extended periods of microgravity during orbital flights can impair astronauts' cognitive abilities, including learning and memory, posing a persistent health concern in the field of aerospace medicine. The study examined the pharmacological effects of agmatine and its influence on simulated neurobehavioral changes in rats under microgravity conditions. Rats were exposed to simulated microgravity (SMG) conditions using the hindlimb unloading (HU) model for 28 days and evaluated for behavioural alterations using the open field test, elevated plus maze, and forced swim test, and cognitive deficits using the novel object recognition test and Morris water maze. Further, brain agmatine levels, neurochemical and structural alterations in the hippocampus, and prefrontal cortex were examined. Chronic agmatine treatment dose-dependently (40 and 80mg/kg) and its endogenous modulation by l-arginine, and aminoguanidine prevented behavioral and cognitive deficits by improving exploratory behaviour, reducing anxiety-depressive-like symptoms, and enhancing cognitive performance. Our findings reported a significant reduction in agmatine levels in the hippocampus and prefrontal cortex in SMG conditions. Agmatine administration and its modulation normalized neurotransmitter imbalances, especially by restoring the reduced levels of gamma-aminobutyric acid, dopamine, and serotonin, along with a reduction of elevated levels of glutamate in SMG conditions. Moreover, agmatine decreased reactive oxygen species production, enhanced hippocampal antioxidant enzyme activities, suppressed pro-inflammatory cytokines (TNF-α, IL-6), and improved IL-10 and brain-derived neurotrophic factor levels in HU rats. Moreover, agmatine and its endogenous modulation preserved neuronal cells of the hippocampus and prefrontal cortex. In conclusion, the present study suggests that agmatine administration and modulation of endogenous agmatine levels effectively mitigate SMG-induced neurological dysregulation through neuroprotection and neuromodulation. Understanding the neurobiological mechanisms underlying these effects opens up new possibilities for creating novel interventions targeting agmatinergic signaling in spaceflight conditions and associated complications. Show less

Depression imposes significant social, economic, and health burdens worldwide. Although phlorotannin-rich extract from Ecklonia cava (PS) and its active compound dieckol (DK) exhibit various biological activities, their antidepressant- and anxiolytic-like effects and underlying mechanisms remain unclear. This study investigated the antidepressant- and anxiolytic-like potential of PS and DK in a corticosterone (CORT)-induced mouse model of depression and anxiety, focusing on glucocorticoid receptor (GR) signaling. CORT-treated mice were orally administered PS or DK, and behavioral tests were performed to assess depressive- and anxiety-like behaviors. PS composition was analyzed using LC-MS/MS. Molecular docking predicted the binding of PS components to GR. GR nuclear translocation, target gene expression, and downstream signaling were examined using behavioral, molecular, and computational approaches. PS alleviated CORT-induced depressive- and anxiety-like behaviors, accompanied by reduced GR nuclear translocation, suppression of Mkp-1, and restoration of ERK-CREB-BDNF signaling. Molecular docking analysis predicted strong binding of DK to the GR ligand-binding domain. Consistently, DK reduced GR nuclear translocation and GRE binding, downregulated GR target genes (Mkp-1, Sgk-1, Fkbp5, and Bdnf), and restored ERK-CREB-BDNF signaling. In vivo, DK also improved CORT-induced behavioral deficits and normalized HPA axis activity and neurotransmitter levels. Collectively, our results suggest that DK, a major bioactive phlorotannin from E. cava, exerts antidepressant- and anxiolytic-like effects in association with modulation antagonism of GR signaling, highlighting its therapeutic potential as a natural GR-modulating agent for stress-related mood disorders. Show less

Illness perceptions have been associated with outcomes in patients with atrial fibrillation (AF). This study aimed to identify distinct illness perception profiles in patients with AF and examine their associations with psychological and physical responses. A total of 150 patients with AF were enrolled in this study. Illness perception profiles were identified using latent profile analysis (LPA). Model fit indices were evaluated to determine the optimal class solution. Logistic regression analyses were conducted to examine the associations between illness perception profiles and psychological and physical outcomes, including Generalized anxiety disorder-7 (GAD-7), Patient Health Questionnaire-9 (PHQ-9), 12-Item Short Form Health Survey (SF-12) and University of Toronto atrial fibrillation severity scale (AFSS). A two-class model was identified as optimal, comprising a "Reactive-Minimizing" profile (Class 1, 49%) and a "Symptom-Helplessness" profile (Class 2, 51%). Univariate logistic analysis revealed significant differences between classes in age, AF type, work status, PHQ-9, AFSS-symptoms, and AFSS-burden. In the multivariable logistic regression adjusted for age and sex (logistic outcome: Class 2 vs. Class 1), higher AFSS-burden scores were independently associated with the "Symptom-Helplessness" profile (OR = 1.26, 95% CI: 1.09-1.45, p = 0.001). Conversely, higher PHQ-9 scores were associated with the "Reactive-Minimizing" profile (OR for Symptom-Helplessness = 0.92, 95% CI: 0.86-0.99, p = 0.018). Person-centered illness perception profiling revealed two distinct cognitive-emotional patterns in patients with AF that were associated with depressive symptoms and symptom burden, highlighting their potential value for individualized psychological and clinical management. Show less

Siponimod is an approved drug for secondary progressive multiple sclerosis (SPMS), and may exert neuroprotective effects beyond its established immunomodulatory properties. Brain-derived neurotrophic factor (BDNF) is a key molecule supporting neuronal survival and plasticity, and its secretion by immune cells may contribute to neuroregeneration in MS. We studied the impact of long-term siponimod therapy on the secretion of BDNF and other neurotrophic factors by immune cells in MS patients. Twenty patients diagnosed with relapsing-remitting MS (RRMS) or SPMS and receiving siponimod were assessed at baseline, 6 months, and 18 months. Peripheral blood mononuclear cells, CD3 A significant increase in BDNF secretion was observed in PBMCs and T cells after 18 months of siponimod treatment. The other neurotrophins remained below detectable thresholds. Correlation of RRMS vs. SPMS analyses (age, sex, disease duration, baseline Expanded Disability Status Scale, and disease course), and multivariable regression modelling revealed no significant associations between them and treatment-induced changes in BDNF. These findings suggest that prolonged siponimod therapy enhances BDNF secretion by immune cells, demonstrating a heretofore unreported neuroprotective mechanism contributing to siponimod's clinical efficacy in reducing disability progression in MS. Our study found that long-term treatment with siponimod, a drug for multiple sclerosis MS, led to a significant increase in the release of a BDNF by immune cells. This effect was seen after 18 months and was not influenced by patients' age, disease type, or disability level. The findings suggest that siponimod may support neuroprotection and repair in MS through a newly identified mechanism beyond its known immune effects. Show less

Late-life depression shows heterogeneous developmental trajectories. Prior studies in older Chinese populations have identified distinct depressive trajectories, yet the influence of family emotional support across the life course remains underexplored. We conceptualized intergenerational emotional interaction patterns as the combined configuration of early-life parental affection and later-life emotional support from adult children. This study identified late-life depressive trajectories and tested whether these patterns predict depressive trajectory among Chinese older adults. Using China Health and Retirement Longitudinal Study (CHARLS) data (2011-2020; n = 9888), this study identified depressive trajectories using Latent Class Growth Modeling (LCGM) and Latent Profile Analysis (LPA) was used to categorize participants into subgroups based on maternal/paternal affection and emotional support from adult children. Multinomial logistic regression and Chi-square tests assessed associations between profiles and trajectories. Four depressive trajectories emerged: "no depression" (56.3%), "deterioration" (22.4%), "alleviation" (12.3%), and "chronic depression" (9.1%). Three distinct intergenerational emotional interaction patterns were found: "emotional inheritance" (40.7%), "emotional compensatory" (17.4%), and "emotional mismatch" (41.9%). The "emotion inheritance" group was overrepresented in the "no depression" trajectory, whereas the "emotional compensatory" group faced elevated risks for being classified into "deterioration" and "chronic depression" trajectories. Intergenerational emotional interaction patterns are independently and jointly associated with depressive symptoms trajectories in later life. The strongest protective effects were observed for individuals with both high childhood parental affection and ongoing emotional support from children. Conversely, low parental affection-even when compensated by later-life support-was linked to worse mental health outcomes. Show less

Substance use disorder is characterized by compulsive seeking behavior that is associated with aberrant synaptic plasticity in mature neurons. Environmental enrichment (EE) has been shown to increase adult hippocampal neurogenesis and exert beneficial effects on addictive behaviors. However, the mechanisms of EE's effects on methamphetamine (METH)-induced synaptic plasticity in mature and newborn neurons remain unclear. We reported that EE decreased METH-induced seeking behavior with a decrease in the activity of mature granule cells and an increase in the number of newborn granule cells. Furthermore, the aberrant glutamatergic transmission in hippocampal mature and newborn granule cells was differentially regulated by EE. Moreover, EE restored the normal synaptic plasticity, accompanied by enhancement of brain derived neurotrophic factor (BDNF) expression. Importantly, the intervention of BDNF reversed the effects of EE on METH-induced reinstatement behavior and glutamatergic transmission in both mature and newborn cells. Finally, specifically knocking out the newborn neurons reversed the changes of EE in abnormal plasticity of mature neurons, as well as in seeking and cognitive behaviors. Taken together, regulating synaptic plasticity of mature and newborn neurons is involved in METH-induced seeking behavior and cognitive impairments, which highlights a critical role of adult neurogenesis in the treatment of METH addiction. Show less

To examine the association of types and intensities of physical activity (PA) and depression with all-cause mortality in a population-based cohort of older adults, where evidence is scarce or inconsistent. We analysed data from 2060 and 3263 older adults (70.5 ± 5.5 years; 2800 women) participating in the Seniors-ENRICA 1 and 2 cohorts, respectively. Time spent in walking, gardening, do-it-yourself (DIY) activities, housework, cycling, and sports was self-reported using the EPIC questionnaire. PA was categorized by intensity as follows: light (LPA; walking+housework), moderate (MPA; gardening+DIY), and vigorous PA (VPA; cycling+sports); in addition, moderate-to-vigorous (MVPA) and total PA were computed. Depression was measured using the Geriatric Depression Scale (GDS-10) score ≥ 3. All-cause mortality was ascertained up to January 31, 2024. Multivariable regression models were used to examine associations, adjusting for key confounders. Inverse associations were observed between all types and intensities of PA and both depression at baseline, except for cycling. In participants with depression, time spent in housework, sports, LPA, VPA, and total PA was similarly associated with reduced mortality risk. Meeting MVPA recommendations was associated with a 20 % and 32 % lower mortality in individuals without and with depression, respectively. In dose-response analyses, participants with depression who engaged in the same volume of PA as those without depression experienced a greater reduction in mortality risk. PA was associated with lower odds of prevalent depression in older adults. Notably, older adults with depression experienced greater mortality benefits from comparable levels of physical activity than those without depression. Show less

Air pollution exposure is associated with increased cardiovascular morbidity and mortality worldwide. Previous studies provide a causal relationship between exposure to particulate matter (PM) and atherosclerosis development. We have previously demonstrated increased aortic atherosclerosis and adverse metabolic effects in hyperlipidemic mice exposed to ambient ultrafine PM. However, the underlying mechanisms by which ambient PM promotes systemic effects leading to worsened atherosclerosis remain unknown. We have recently shown that the gut microbiota composition was altered in mice exposed to re-aerosolized PM in the ultrafine-size range for 10 weeks. We hypothesized that sub-chronic exposure to ultrafine PM induces gut dysbiosis in association with systemic prooxidative effects and atherosclerotic lesion development. Male apolipoprotein E knockout (ApoE Show less

Alcohol consumption during pregnancy is a major public health concern, as prenatal exposure to ethanol can disrupt embryonic development and lead to Fetal Alcohol Spectrum Disorders (FASD). These disorders are characterized by a wide range of morphological, behavioral, and cognitive impairments, which variability across individuals is strongly influenced by genetic background and environmental conditions. Animal models, particularly zebrafish, offer a powerful tool to investigate how such factors modulate susceptibility to alcohol. In this study, we examined the effects of embryonic alcohol exposure in three zebrafish populations (AB, TU, and OB), assessing developmental parameters, behavior, and gene expression. Results showed that the OB population exhibited higher mortality and pronounced alterations in genes related to metabolism and neurotransmission; AB displayed reduced body and eye growth, along with increased social cohesion under alcohol exposure; while TU was more vulnerable to behavioral effects despite showing morphological resilience. Furthermore, the expression of key genes such as sox2, th1, drd1b, gabra1, and bdnf varied according to both population and alcohol concentration. These findings emphasize the relevance of genetic differences in modulating alcohol's impact and reinforce zebrafish as a valuable translational model for FASD research, paving the way for more refined diagnostic and therapeutic approaches. Show less

Acrylamide (ACR), a potential neurotoxin prevalent in carbohydrate-rich foods, poses a significant public health concern. While ACR exposure is known to induce tau phosphorylation and synaptic impairment, the underlying mechanisms remain incompletely understood. The aberrant activation of the protein kinase RNA-like endoplasmic reticulum kinase (PERK)-eukaryotic initiation factor-2α (eIF2α) signaling pathway is emerging as a major common theme in neurodegenerative disorders. This study investigated the role of the PERK-eIF2α signaling pathway in ACR-induced neurotoxicity using human neuroblastoma SH-SY5Y cells. Our results showed that ACR exposure not only significantly increased tau phosphorylation at specific epitopes (Ser Show less

Depression induce by chronic neuroinflammation disrupts daily life and work, underscoring the importance of its treatment. It this study, depressive- and anxiety-like behaviors were induced in mice by injecting bacillus Calmette-Guérin (BCG), resulting from chronic neuroinflammation. Daily stimulation with specific acupuncture points (Baihui and Yintang, GV20 and GV29) with electroacupuncture (EA) for 14 days significantly alleviated depressive- and anxiety-like behaviors. Additionally, it also markedly reduced the levels of pro-inflammatory cytokines, including interleukin (IL)-6, IL-1β, and tumor necrosis factor-α, as well as inflammatory markers such as cyclooxygenase-2, in both the plasma and hippocampus. EA Stimulation significantly increased brain-derived neurotrophic factor (BDNF) mRNA expression in the hippocampus. Our results demonstrated that EA stimulation improved depression- and anxiety-like behaviors induced by chronic inflammation, an effect associated with the decreased expression of BDNF via regulation of NF-κB pathway. Show less

Bovine tuberculosis (bTB) is a chronic infectious disease caused by the Mycobacterium bovis (M. bovis). Rapid, cost-effective, and accurate diagnosis of bTB remains a significant clinical challenge globally. In this study, we performed a comprehensive proteomic analysis to evaluate the discriminatory power of plasma and plasma exosomes for bTB diagnosis. We compared protein expression profiles across three groups: M. bovis-negative controls (bTB_N, n = 10), M. bovis-positive cases (bTB_P, n = 10), and co-infected animals (Other_P, n = 10) with Brucella, infectious bovine rhinotracheitis virus (IBRV), and bovine viral diarrhea-mucosal disease virus (BVDV). Quantitative analysis identified 3820 exosomal proteins-2.27-fold more than the 1686 plasma proteins detected. Exosomal proteins exhibited superior sample clustering and discriminative capacity for infected groups. Notably, 227 plasma and 861 exosome-derived proteins were uniquely differentially expressed in bTB (bTB-specific DEPs). Pathway enrichment analysis revealed that exosome-specific DEPs were significantly enriched in TB-related pathways, including neutrophil extracellular trap (NET) formation, endocytosis, and tuberculosis, exhibiting greater biological relevance compared to plasma-specific DEPs. Furthermore, eight candidate proteins (APOE, FBLN5, VDAC1, ABCE1, LMAN1, PLG, SPP1, and SRP9) demonstrated high specificity for bTB discrimination, with two (FBLN5 and SPP1) displaying stage-specific expression patterns during M. bovis infection. This study underscore plasma exosome as a highly promising source of biomarkers for bTB diagnosis, offering enhanced sensitivity and deeper mechanistic insights over conventional plasma proteome. Show less

Our understanding of the genetic regulation of lipoprotein(a) [Lp(a)] is hindered by the complex structure of the LPA gene, limited non-European datasets and its elusive cellular receptor(s). This review summarizes recent efforts and advances providing new insights on its genetic architecture, variability across ancestries and regulators beyond the LPA gene. Impressive advances in DNA sequencing and bioinformatics now resolve LPA variants and kringle IV-type 2 copy number at scale. This provides new reference datasets and enables tools that unlock hidden variation also from already available sequencing datasets. In parallel, genetic studies broaden our understanding of the regulation of Lp(a) across ancestries and improve genetic risk scores. Finally, while recent studies implicate new mechanisms for Lp(a) uptake, upcoming genome-wide gene knockout screens allow comprehensive, agnostic scans for regulators and receptors. Puzzlingly, this still converges on the LDL receptor, whose exact role in Lp(a) uptake remains enigmatic. Technological advances establish a foundation for more accurate genetic risk assessment across ancestries. These advances are enhancing our understanding of Lp(a) regulation and build a framework for future integrative genetic studies, which may shed new light on the evolution of the Lp(a) trait, adding important context for its physiological and clinical relevance. Show less

The emergence of Alzheimer's disease (AD) pathology has been the focus of multiple hypotheses, with amyloid β (Aβ) playing a central role due to its presence in both familial and sporadic AD. Therefore, a crucial aspect of AD research is understanding the generation of different Aβ species. Aβ peptides result from the proteolytic processing of Amyloid Precursor Protein (APP) by β- and γ-secretases, with BACE1 being the most prominent β-secretase. However, BACE1-overexpressing mouse models exhibit disadvantages, making them limited for AD research. Importantly, N-terminally truncated Aβ species, which constitute up to 70 % of Aβ in AD brains, are not generated by BACE1. In recent years, alternative proteases capable of cleaving APP have been identified, bridging the gap between N-terminally truncated Aβ species and BACE1-derived Aβ. Among these novel players, the metalloprotease meprin β has emerged as a risk factor in AD pathology, generating both N-terminally truncated and full-length Aβ species. Our primary objective was to develop a mouse model that more accurately resembles the pathology of AD beyond BACE1-overexpressing models, while simultaneously confirming APP cleavage of meprin β in the hippocampus and cerebral cortex. Overexpression of meprin β led to a marked increase in soluble Aβ levels, particularly in the hippocampus, indicating a higher vulnerability or elevated meprin β activity in this region compared to the cerebral cortex. Notably, this biochemical change occurred without any observable behavioral deficits, suggesting a region-specific role of meprin β in AD pathology that may extend beyond immediate functional impairment. Show less

Abdominal aortic aneurysm (AAA) refers to a disease where the abdominal aorta progressively dilates to 3.0 cm or more, making it prone to rupture. The etiologic and pathophysiological mechanisms underlying the formation and development of AAA are not yet fully understood. A preliminary investigation was conducted into the effects of Kruppel-like factor 5 (KLF5) regulation of the nuclear factor erythroid-2-related factor 2/heme oxygenase 1 (NRF2/HO-1) signalling pathway on ferroptosis in AAA vascular smooth muscle cells (VSMCs). ApoE KLF5 expression was downregulated in abdominal aorta tissues from AAA mice. KLF5 overexpression ameliorated inflammatory response by reducing phenotypic switching in VSMCs and inhibited ferroptosis and vascular calcification by reducing oxidative stress. Induction of ferroptosis partially reversed the ameliorative effect of KLF5 on vascular calcification in VSMCs. KLF5 exerted antioxidant effects by increasing NRF2 nuclear translocation and upregulating HO-1. Inhibition of the NRF2/HO-1 pathway partially reversed KLF5 regulation of phenotypic switching and vascular calcification in VSMCs. KLF5 may exert a protective effect by inhibiting ferroptosis and calcium deposition in VSMCs in AAA through regulation of the NRF2/HO-1 signalling pathway. Show less

The causal links between gut microbiota, inflammatory cytokines, and chronic rhinosinusitis are unclear. A Mendelian randomization study used data from the MiBioGen consortium (211 microbiota taxa, n = 18,340), genome-wide association studies of 91 inflammatory cytokines, and chronic rhinosinusitis data from the FinnGen consortium. Five microbiota taxa were causally linked to chronic rhinosinusitis. The genera Ruminococcaceae NK4A214 group and Victivallis were risk factors, while Lachnospiraceae NC2004 group, Ruminococcus2, and Subdoligranulum were protective. Elevated levels of axin-1, C-X-C motif chemokine 10, interleukin-18 receptor 1, interleukin-1-alpha, and vascular endothelial growth factor A increased risk, whereas C-C motif chemokine 19, CD40L receptor, and Fractalkine were protective. The Ruminococcaceae NK4A214 group id.11358 increased risk through reduced Fractalkine and elevated vascular endothelial growth factor A levels. The study supports a causal link between Ruminococcaceae NK4A214 group id.11358 and chronic rhinosinusitis, mediated by Fractalkine and vascular endothelial growth factor A levels. Show less

Endothelial to mesenchymal transition (EndMT), the transformation of endothelial cells into a mesenchymal-like state, is regulated by various factors, including transcription factors such as activator protein 1 (AP-1). While recent studies have confirmed the role of EndMT in atherosclerosis, the involvement of AP-1 in EndMT, particularly in the context of human diabetes, remains unclear. This study aimed to elucidate the role of the AP-1 transcription factor complex in EndMT associated with atherosclerosis in diabetes, utilising both an in vivo preclinical model and an ex vivo model using patient-derived serum for translational relevance. Additionally, it sought to profile gene expression changes following AP-1 inhibition in an EndMT model under high glucose conditions. Serum from patients with and without type 2 diabetes mellitus (T2DM) was used to assess EndMT in primary human aortic endothelial cells (HAECs) in the presence and absence of the AP-1 inhibitor T-5224. EndMT was evaluated through immunofluorescent staining of these cells and of aortic sections from a murine model of diabetes-associated atherosclerosis in a preclinical early intervention study. Furthermore, HAECs were used to explore the effects of AP-1 inhibition on the transcriptional signature of EndMT. Patient-derived serum induced EndMT in HAECs, which T-5224 effectively prevented, as confirmed by immunofluorescent staining. Immunofluorescent analysis of the aortic sinus also revealed that T-5224 treatment inhibited EndMT, leading to reduced atherosclerosis in Apoe This study identifies AP-1 inhibition with T-5224 as a potential therapeutic approach for EndMT resulting in reduced atherosclerosis in diabetes. The use of human serum underscores the translational relevance of these findings. Show less

BackgroundPrevious whole exome and whole genome sequencing (WES/WGS) studies identified genome-wide significant associations for late-onset Alzheimer's disease (AD) with rare variants but highlighted the need for larger samples.ObjectiveIdentify associations of rare coding variants with AD risk in a large-scale, multi-ancestry exome-wide.MethodsWe combined non-overlapping portions of the Alzheimer's Disease Sequencing Project (ADSP) WES (n = 18 717) and WGS (n = 35 014) datasets obtaining a sample (n = 34 202) including participants ages ≥ 60 from four genomic similarity clusters consistent with European ancestry (EA, 9 744 AD cases and 9 095 controls), African American (AA, 1 944 AD cases and 4 215 controls), Caribbean Hispanic (CH 2 344 AD cases and 3 465 controls), and Native American Hispanic (NAH 743 AD cases and 2 652 AD controls) populations. Association of AD with 253,421 bi-allelic variants with minor allele count ≥ 20 in the total sample and each population group was evaluated using GENESIS. Gene-based tests comprising predicted moderate and high-impact variants were performed using SAIGE.ResultsNovel study-wide significant associations (p < 1.97 × 10 Show less

This study develops and tests an AI-empowerment Configural Model to explain how artificial intelligence (AI) empowers language learning engagement. Grounded in ecological systems theory (EST) and ecological affordance theory (EAT), the model theorizes AI as an interactive agent within the learning ecosystem. A mixed-methods study of 475 Chinese university language learners demonstrates that AI'S effect on engagement is significantly mediated by the perceived quality of its ecological coupling with teachers, peers, and the environment. Latent profile analysis (LPA) further identifies three distinct learner configurations: low coupling-low engagement, moderate coupling-moderate engagement and high coupling-high engagement, which systematically differ in their coupling of AI. The model ultimately shifts the paradigm from tool implementation to strategic ecological governance, providing a practical basis for designing learning environments that leverage synergistic human-AI coupling to foster deeper, sustained engagement. Show less

In the phase 3 CLEAR study, lenvatinib plus pembrolizumab showed improved efficacy versus sunitinib for patients with clear cell renal cell carcinoma (ccRCC). Previous preclinical studies demonstrated that lenvatinib attenuated tumor-associated macrophage (TAM) infiltration into tumor tissues by inhibiting fibroblast growth factor receptor (FGFR). However, the role of the FGFR pathway in ccRCC remains underexplored. This study aims to evaluate FGFR1-4 expression in ccRCC and investigate its relationship with the tumor microenvironment, particularly TAM. We primarily analyzed FGFR1-4 expression and CD163 positive cell count as estimation of TAM infiltration in 57 ccRCC specimens from patients undergoing nephrectomy using immunohistochemistry. Transcriptomic analysis was performed to assess immune-related gene signature and gene expressions. FGFR1 expression was elevated in over 80% of ccRCC samples and was significantly associated with increased CD163-positive TAM infiltration. FGFR1 expression was also negatively correlated with the IMmotion150 Teff gene signature and the expression of interferon-γ signaling targeted genes such as IFNG, GZMB, and CD274, suggesting an immunosuppressive phenotype. In contrast, FGFR2 and FGFR4 expression were less prevalent, and FGFR3 expression was not detected. This study provides the first comprehensive evaluation of FGFR1-4 expression in ccRCC and suggests that FGFR1 expression may contribute to the immunosuppressive tumor microenvironment by recruiting TAM. These findings indicate that FGFR1 could serve as a potential biomarker for therapeutic strategies and highlight the need for further research to explore FGFR-targeted therapies in ccRCC. Show less

To identify associations of polymorphic variants of the genes of Two hundred thirty-five patients with AfD and 62 patients with AR and comorbid AlD aged 18 to 65 years were examined. The severity of AfD was assessed using the Structured Interview Guide for the Hamilton Depression Rating Scale, Seasonal Affective Disorder Version (SIGH-SAD) and the Clinical Global Impression (CGI), and the level of anxiety was assessed using the Hamilton Anxiety Rating Scale (HARS) at baseline and on Day 28 of psychopharmacotherapy. Polymorphic variants rs6265, rs7124442, rs11030104, and rs7103411 of the In AfD patients, rs3924999* The polymorphic variants rs3924999 of the Show less

Cerebral amyloid angiopathy (CAA) is associated with age, apolipoprotein E (APOE) genotype, and a pathologic diagnosis of Alzheimer's disease (AD). Yet, the complete spectrum of CAA presence and severity across age, APOE genotype, AD and AD related disorders (ADRD) is incompletely reported. Additionally, recent experiments suggest associations of CAA with diffuse plaques. Here, we studied CAA in older adults who were followed in longitudinal studies of aging. Postmortem brains were evaluated for the presence and severity of CAA and co-pathologies. AD was defined as intermediate-to-high Alzheimer's disease neuropathologic change (ADNC). Regression models were used to analyze the association of AD-related (neuritic and diffuse plaques and neurofibrillary tangles) and ADRD-related counts with CAA, controlling for risk factors including demographics, AD, and APOE ε4. The 1938 participants with mean age-at-death of 89.8 years (SD=6.6) had no (415, 21.4%), mild (795, 41.0%), or moderate-to-severe (728, 37.6%) CAA. The odds of moderate-to-severe CAA was higher in persons who were older (odds ratio (OR) per 10 years older, 1.34, [95% CI, 1.22-1.63]), APOE ε4 allele carriers (OR, 3.62 [95% CI, 2.90-4.52]), or comorbid for AD (OR, 4.14 [95% CI, 3.28-5.23]). Despite strong association with AD, 117 of 1216 (9.62%) participants with AD had no CAA while 108 of 581 (18.59%) participants with moderate-to-severe CAA had no AD (i.e., none-to-low ADNC). However, moderate-to-severe CAA was associated with neuritic plaques (OR, 1.27 [95% CI, 1.09-1.48]) and neurofibrillary tangles (OR, 1.52 [95% CI, 1.32-1.76]). Among participants without AD, the odds of severe CAA was ∼28-fold higher in APOE Ɛ2 allele carriers when neuritic plaque and neurofibrillary tangle loads were higher. This unexpected association between CAA severity and combined neuritic plaque and neurofibrillary tangle load was not found in APOE Ɛ2 allele carriers when there was AD or in APOE Ɛ4 allele carriers with or without AD. ADRD were not related to CAA after controlling for AD and APOE Ɛ4. Logistic models using moderate-to-severe CAA as the outcome revealed an interaction between neurofibrillary tangles and neuritic plaques in the entire group (p=0.047) and in APOE Ɛ2 allele carriers (p=0.039). We conclude that CAA is associated with neuritic plaques and neurofibrillary tangles and this relationship is markedly enhanced in APOE ε2 allele carriers (exclude APOE Ɛ4) without AD. These findings indicate further work on the complex relationships between CAA and AD-related lesions must consider AD and APOE status for a more personalized approach to studying CAA. Show less

Hypertensive heart disease (HHD) and hypertrophic cardiomyopathy (HCM) are characterized by left ventricular hypertrophy and diastolic dysfunction. Despite overlapping remodeling features, their distinct mechanisms and therapeutic responses remain unclear. This study integrated genetic, imaging, and proteomic data to identify key mediators underlying β1-adrenergic receptor blockers (β1-blockers)-related therapeutic heterogeneity between HHD and HCM. Genetic instruments for β1-blockers were derived from two genome-wide association studies and integrated with cardiac magnetic resonance radiomic traits and plasma proteomic data from the UK Biobank, along with disease outcomes from FinnGen. A refined two-stage network Mendelian randomization framework with pleiotropy-robust estimators identified mediators of treatment response. To further elucidate their biological and clinical significance, additional analyses were performed, including drug-target profiling, molecular docking, adverse events (AEs) assessment, and drug prediction. We identified three types of imaging features and ten mediator proteins that contributed to therapeutic responses in HHD and HCM. These mediators were categorized as either mediating (aligned with therapeutic outcomes) or suppressing (opposing therapeutic outcomes). Left ventricular regional radial strain acted as a suppressing factor in HHD but a mediating factor in HCM, whereas end-diastolic and end-systolic volumes consistently showed suppressing effects in both. Regional myocardial wall thickness also exerted a suppressing role in HCM. Among protein mediators, APOE, CGREF1, ITGA5, LSP1, NOS3, and NPPB were linked to HHD, whereas DUSP13, ITGA11, NID1, and SERPINA4 were related to HCM. Specifically, APOE, ITGA5, NOS3, NPPB, DUSP13, and ITGA11 acted as mediating factors, while CGREF1, LSP1, NID1, and SERPINA4 served as suppressing ones. These findings remained robust after pleiotropy adjustment and other genetic analyses. Molecular docking revealed interactions between ADRB1, the β1-blockers target, and downstream proteins, while drug prediction identified eight potential compounds linked to these mediators. Additionally, AE analyses indicated that some targets, such as DUSP13, could both mitigate and aggravate common AEs while contributing to cardiac therapy. This integrative multi-omics analysis revealed distinct imaging and proteomic mechanisms of genetically proxied β1-blockers in HHD and HCM, providing genetic evidence for differential therapeutic responses and highlighting molecular targets for precision cardiovascular therapy. Show less

While a link between cardiovascular risk factors and increased Alzheimer's disease (AD) risk has been reported, it remains unclear whether AD pathology has a direct effect on cardiac function and myocardial innervation. AD and amyloidosis are known to impair neuronal function and affect brain neurotrophic factors (NGF and BDNF) expression. Amyloid aggregates and neuro-signaling impairments may also expose AD patients to peripheral nervous system deficits, promoting cardiac disorders. Here, we provide novel understanding of cardiac physiological impairment, amyloid pathology, neurotrophic factors loss, and impoverishment of cardiac neuronal fibers in Tg2576-AD mice hearts, human cardiomyocytes in culture, and human AD post-mortem left ventricular (LV) heart tissue. We reveal that Tg2576 animals exhibit increased myocardial fibrosis, amyloid β (Aβ) deposition, and brain/heart-axis neurotrophic deficiencies, resulting in myocardial denervation and cardiac dysfunction. Aβ oligomers challenge reduces BDNF expression in both human immortalized and iPSC-derived cardiomyocytes, by disrupting TrkB/CREB signaling. Analysis of human LV AD post-mortem tissue confirms cell and animal results. Our findings reveal potential pathways by which Aβ pathology may disrupt cardiac neurotrophic signaling and physiology, identifying a possible link between AD and heart degeneration. Show less

Inflammatory bowel disease (IBD) is a chronic gastrointestinal disorder with a high incidence of anxiety and depression. However, the underlying mechanisms of these symptoms remain to be fully elucidated. This study investigated the effects and mechanisms of a 20% ethanolic extract of Show less

Adolescent mental health issues have become a growing public health concern. This study seeks to identify potential profiles of mental health among Chinese adolescents and to detect high-risk groups for the formulation of targeted intervention strategies based on associated health risk behaviors (HRBs). A cross-sectional study. This study was based on the Monitoring and Intervention Project for Common Diseases and Health Influencing Factors among Secondary School Students in Nanjing, involving 9,865 secondary school students as participants. Latent profile analysis (LPA) was employed to identify mental health (symptoms of depression, anxiety, and stress, as well as sleep quality); categorical variables were analyzed by the chi-square test or Fisher's exact test, whereas multinomial logistic regression was used to examine associations between HRBs and distinct mental health profiles. Three profiles of mental health were identified among the adolescents, including "Low-risk Mental Health" (68.03 %), "Moderate-risk Mental Health" (26.19 %), and "High-risk Mental Health" (5.78 %). Compared with the "Low-risk Mental Health" profile, the "Moderate-risk Mental Health" profile was associated with behaviors such as drinking, injury, school bullying, unhealthy diet, internet addiction, physical activity, and outdoor activity time; and the "High-risk Mental Health" profile was associated with smoking, drinking, injury, school bullying, unhealthy diet, internet addiction, and outdoor activity time. Several HRBs are associated with mental health among Chinese adolescents. Healthcare professionals should target these HRBs and implement comprehensive measures to protect adolescent mental health. Show less

Endometriosis has been linked to cardiometabolic alterations, but whether these associations vary by disease severity or phenotype is unclear. We examined lipid profiles across endometriosis diagnosis, stage, and typology. Data came from 476 women in the NICHD ENDO cohort. Endometriosis was confirmed laparoscopically and staged using the rASRM criteria (I-IV). Typology was categorized as superficial endometriosis (SE), ovarian endometrioma (OE), deep infiltrating endometriosis (DE), and OE+DE. We compared endometriosis status, stage (I/II vs III/IV), and typology to no endometriosis using adverse lipid thresholds (total cholesterol ≥200 mg/dL, HDL <50 mg/dL, LDL ≥100 mg/dL, triglycerides ≥175 mg/dL, non-HDL ≥130 mg/dL, VLDL ≥30 mg/dL, ApoA1 <125 mg/dL, and ApoB ≥120 mg/dL). Adjusted prevalence ratios (aPR) and 95 % CIs were estimated via generalized linear models, controlling for age, race/ethnicity, BMI, income, marital status, and serum cotinine. Endometriosis diagnosis alone was not associated with adverse lipid profiles. In contrast, moderate/severe disease showed higher prevalence of elevated triglycerides (aPR= 2.27; 95 % CI: 1.18,4.35) and VLDL (aPR= 2.41; 95 % CI: 1.50, 3.85). Typology revealed stronger patterns: OE and OE+DE were associated with adverse profiles across multiple markers (aPRs 1.59-4.09), particularly ApoB and triglycerides. Minimal/mild disease and SE were not associated. The metabolic signal was phenotype-driven rather than diagnosis-driven, with severe stage and OE/OE+DE showing clear associations with adverse lipid profiles. These findings suggest lipid profiles may serve as markers of phenotype severity or shared biological milieu. Replication in larger cohorts is needed. Show less

Diet-based modulation of the gut microbiota has emerged as a promising strategy to alleviate obesity and its related complications. Our previous study demonstrated that polysaccharide derived from Cordyceps militaris (CMP) exerts anti-obesity effects, yet the specific mechanism linking gut microbiota to its metabolic impact remains unclear. Herein, we utilized murine models with distinct gut microbial profiles created via antibiotic cocktails to investigate these mechanisms. The protective effects of CMP against high-fat diet (HFD)-induced obesity and associated metabolic disturbances were substantially impaired in mice depleted of neomycin-sensitive gut bacteria. Metagenomic analyses further established that CMP required these bacteria to restore gut microbial homeostasis. Notably, we observed that CMP elevated hepatic levels of brassicasterol in a manner dependent on neomycin-sensitive gut bacteria. Brassicasterol treatment alone replicated the anti-obesity effects of CMP, as indicated by reduced body weight gain, improved lipid and glucose metabolism, and decreased inflammation. Through transcriptomic and functional analyses, we identified hepatic Apoa4 as a key downstream effector of brassicasterol. Our results indicated that brassicasterol upregulated Apoa4, facilitating lipid transport and suppressing inflammation both in vitro and in vivo. Collectively, our findings indicate that CMP exerts its anti-obesity effects through a neomycin-sensitive gut bacteria-brassicasterol-Apoa4 pathway. This work expands the mechanistic understanding of CMP and highlights a novel microbiota-metabolite-host regulatory axis for dietary intervention in metabolic disorders. Show less