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Cutaneous squamous cell carcinoma (cSCC) involves complex immune interactions. This study aimed to identify a T cell-related gene signature to characterize the immune landscape and aid in molecular diagnosis. We integrated single-cell RNA sequencing (scRNA-seq) and five bulk microarray datasets, utilizing an independent RNA-seq cohort for external validation. Feature genes were identified from the intersection of scRNA-seq-defined T cell-related genes (TRGs) and bulk differentially expressed genes using machine learning. A diagnostic nomogram was constructed, and its performance was assessed via ROC curves. In addition, immune infiltration, immunofluorescence staining, drug interactions, and clinical expression (qRT-PCR) were evaluated. Screening yielded 28 T cell-related DEGs enriched in extracellular matrix functions. machine learning selected a core signature: APOE, CYBA, and S100A2. The diagnostic model demonstrated high diagnostic performance in the studied cohorts (AUC > 0.9) across training and external validation cohorts. Clinically, qRT-PCR supported significant upregulation of CYBA and S100A2. APOE exhibited distinct immunomodulatory connectivity, correlating positively with Th17 cells and negatively with Tregs, whereas CYBA and S100A2 were associated with Treg infiltration. Immunofluorescence results revealed significantly elevated levels of S100A2 and Foxp3 in cSCC tissues compared to the control group. Pharmacogenetic analysis highlights the association of these genes, particularly the APOE gene, with drug response. This T cell-associated signature highlights the potential link between molecular diagnosis and immune characterization. Specifically, CYBA and S100A2 are identified as promising diagnostic candidate signatures, while APOE may reflect immunomodulatory heterogeneity. These findings offer insights for developing diagnostic strategies and targeted immunotherapies in cSCC. Show less

Alzheimer's disease (AD) is one of the most pressing public health challenges in an aging world. However, effective therapeutic strategies are still lacking. Imbalance in lipid homeostasis is a key driver of AD. Given the established link between dysregulated lipid metabolism and amyloid-beta (Aβ) aggregation, we investigated whether chicoric acid (CA), a dietary polyphenol with reported lipid-modulating properties, could mitigate Aβ pathology by modulating lipid metabolism in 5xFAD transgenic mice. In the brain, we found that CA upregulated the expression of liver X receptor Beta (LXR-β) and ATP-binding cassette transporter A1 (ABCA1) in 5xFAD mice. Through this pathway, it promoted apolipoprotein E (ApoE) lipidation and enhanced the expression of Aβ-clearance proteins (IDE and LRP1). Notably, in the periphery, CA reshaped the gut microbiota in 5xFAD mice, which reduced serum neurotoxic bile acid levels and preserved the integrity of the peripheral Aβ clearance system. Together, our study first demonstrated that CA globally regulated lipid homeostasis to alleviate Aβ pathology by coordinating cerebral cholesterol efflux with peripheral bile acid metabolism. The findings facilitated exploring active compounds from traditional Chinese medicine that may reduce Aβ deposition by targeting lipid metabolism pathways. Show less

Cardiovascular disease (CVD) is the leading cause of death among older adults, with sedentary behavior (SB) as a key modifiable risk factor. While physical activity (PA) is associated with cardiovascular health, evidence remains limited on the specific effects of replacing SB with PA of varying intensities. To systematically review evidence on the cardiovascular effects of substituting SB with PA in adults aged 65 and older using isotemporal substitution modeling (ISM). Following PRISMA guidelines, seven databases were searched up to April 2025. Risk of bias was assessed using the JBI tool, and a narrative synthesis was conducted. Eighteen observational studies (15 cross-sectional, 3 cohorts) using ISM were included. Replacing 10-60 min of SB with moderate-to-vigorous PA (MVPA) was associated with more favorable in blood pressure, triglycerides, waist circumference, inflammatory markers (CRP, IL-6, GDF-15), and insulin sensitivity (HOMA-IS, Matsuda-ISI). Light-intensity PA (LPA) showed modest associations, particularly among frail or mobility-limited individuals. A daily substitution of 30 min was identified as a feasible reference window, with ≥60 min linked to additional vascular and autonomic benefits. Replacing SB with PA, especially MVPA, was consistently associated with favorable cardiovascular profiles in older adults. Even brief substitutionsmay be beneficial, supporting intensity-stratified public health strategies and refinement of physical activity guidelines for aging populations.Because most included studies were cross-sectional, these findings should be interpreted as associations rather than definitive causal effects, and reverse causation remains a plausible concern. https://www.crd.york.ac.uk/prospero/view/CRD420251021829/1/0, PROSPERO CRD420251021829. Show less

Previous studies have reported that IGF-1 single nucleotide polymorphism is associated with milk fat traits, but they are limited to trait association analysis. We previously identified a synonymous mutation c.258 A > G (rs322131043) in IGF-1, which influenced IGF-1 expression and caused differences in metabolism. This study aims to reveal a new regulatory function of IGF-1 c.258 A > G on milk fat metabolism. Livers transcriptomics was used to identify differentially expressed genes between wild type mice (WT) and IGF-1 c.258 A > G mice (Homozygous mutation, Ho). Subsequently, lipid phenotyping, followed by metabolomics of mammary glands was conducted to verify transcriptomic findings. Finally, the potential mechanisms underlying IGF-1 c.258 A > G-induced changes in milk fat metabolism were explored though integrated transcriptomics-metabolomics analysis and Western blot validation. IGF-1 c.258 A > G changed the expression of genes related to lipid metabolism in livers of 8-week-old mice, including a 10-fold ‌lipoprotein lipase (LPL) expression (P < 0.01) and ‌80-90 % downregulation of acyl-CoA thioesterase 3 (Acot3), enoyl-Coenzyme A delta isomerase 3 (Eci3), fatty acid synthase (FASN), and sterol regulatory element binding protein1 (SREBP1) expression (P < 0.01). The milk fat content of Ho dams on the second day of lactation (L2D) was decreased 50 % than that of WT dams (P < 0.05), although there was no significant difference in adipose tissue of 8-week-old WT/Ho mice. The levels of triglycerides, sphingolipids and their related fatty acyl chains (10:0, 26:0, 14:2, 20:4, 11:3, 19:0) in mammary glands of L2D Ho dams were reduced 10-50 % observed by lipid metabolomics. And combined with transcriptomics and Western blot, the data suggested that a ‌2.5-fold upregulation of LPL expression‌ (P < 0.05) may contribute to the milk fat metabolism changes mediated by the ‌ IGF-1 c.258 A > G. This study revealed new function of IGF-1 c.258 A > G on milk fat metabolism, thereby informing the development of targeted genetic breeding on milk fat trait. Show less

Depression and anxiety are highly prevalent and often co-occurring mental health issues among adolescents, with comorbidity leading to poorer outcomes and additional challenges. Left-behind adolescents-a unique group experiencing disrupted parent-child relationships and limited social support-may face a higher risk of such comorbidity. Yet, few studies have examined the depression-anxiety network in this population. Latent profile analysis (LPA) identified subgroups with similar symptom patterns, and network analysis visualized the structure of comorbidities. Network comparison tests evaluated differences across subgroups. Based on the "Science Database of People Mental Health" managed by the National Population Health Data Center (China), a total of 3,205 left-behind adolescents (1,538 males; 1,667 females) were included. The Patient Health Questionnaire-9 and the Generalized Anxiety Disorder Scale-7 were used to assess depression and anxiety among left-behind adolescents. Three distinct profiles were identified: high-comorbidity (8.2%), moderate-comorbidity (28.7%), and low-comorbidity (63.1%). Network structures and global strength differed significantly between subgroups. "Restlessness" was the central bridge symptom in the high-comorbidity group, while "Nervousness" was central in the moderate- and low-comorbidity groups. These findings suggest tailored interventions targeting subgroup-specific bridge symptoms-such as restlessness or nervousness-may improve outcomes for left-behind adolescents with comorbid depression and anxiety. Show less

Chronic rhinosinusitis with nasal polyps (CRSwNP) is a prevalent inflammatory disorder characterized by nasal obstruction and polyp formation. Despite its prevalence, the complex pathogenesis of CRSwNP remains not fully understood, hindering the development of effective treatments. This study aims to delineate the immunological landscape of CRSwNP by integrating single-cell RNA sequencing (scRNA-seq) and Mendelian randomization (MR) approaches. We conducted a systematic MR analysis using summary statistics from genome-wide association studies (GWAS) and expression quantitative trait loci (eQTL) data. The identified genes were further scrutinized through scRNA-seq analysis of CRSwNP tissues to assess cell-specific expression patterns. Pathway enrichment and protein-protein interaction (PPI) network analyses were performed to explore the biological mechanisms underlying CRSwNP. The MR analysis identified several genes, including HLA-DRB1, HLA-DQA1, and HLA-DQB1, as significantly associated with CRSwNP. The scRNA-seq analysis validated these findings, revealing cell-specific enrichment in basal cells. Notably, these genes were found to be involved in immune cell recruitment and the reshaping of the immune microenvironment. Furthermore, the study highlighted the role of genes like TCF7L1, KANSL1-AS1, and POLR2J3, which showed contrasting expression patterns and potential regulatory roles in CRSwNP. This integrative study provides novel insights into the molecular and cellular underpinnings of CRSwNP. The identified genes and their role in immunopathogenesis offer potential therapeutic targets and highlight the importance of cell-specific gene expression in disease mechanisms. The combination of MR with scRNA-seq represents a powerful approach to elucidate complex traits and may pave the way for precision medicine in CRSwNP management. Show less

This study explored the potential mechanisms of action of Gualou-Xiebai-Baijiu Decoction (GXBD) in the treatment of atherosclerosis (AS) by integrating computational analyses with preliminary animal experiments. The putative targets of blood-absorbed components in GXBD were obtained and then intersected with AS-related targets, followed by protein-protein interaction network construction, core target identification, and GO and KEGG enrichment analyses. Targets presenting potential causal associations with AS were determined with Mendelian randomization (MR) analyses. Binding stability between candidate compounds and key targets was evaluated with molecular docking and molecular dynamics (MD) simulations. Finally, a mouse model of AS was established for in vivo validation. A total of 379 targets of six blood-absorbed components in GXBD and 1975 AS-related targets were identified, among which 154 were overlapping genes and 64 were further defined as core targets. Enrichment analysis results indicated the involvement of pathways including fluid shear stress, PI3K-Akt, and focal adhesion. Among the targets of GXBD, Show less

Alzheimer's disease (AD) is the most prevalent cause of dementia and can be conceptualized as a tauopathy initiated by the accumulation of amyloid-β (Aβ) in the brain. The clinical introduction of anti-Aβ antibody therapies has marked the beginning of a new era in disease-modifying treatment for dementia. While the deleterious effects of Aβ on postsynaptic spines and axonal microtubules have been increasingly clarified, recent studies have shifted attention beyond extracellular Aβ deposition as senile plaques to the pathogenic significance of intracellular Aβ. In particular, accumulating evidence highlights lysosomes as critical sites of intracellular Aβ toxicity. Interactions between Aβ and gangliosides, v-ATPase-dependent lysosomal acidification, and lysosomal membrane integrity are the key determinants of disease progression. In parallel, additional molecular players, including components of the complement cascade and asparaginyl endopeptidase, have been implicated in linking Aβ pathology to tau dysregulation and neurodegeneration. As therapeutic strategies targeting Aβ enter clinical practice, these emerging pathways represent promising targets for the next generation of AD treatment. Here, we summarize current insights and ongoing therapeutic developments centered on these mechanisms. Show less

A growing body of research highlights the crucial role of self-regulated learning (SRL) strategies in enhancing teaching effectiveness and promoting continuous professional growth. Teachers’ ability to plan, monitor, and evaluate their own learning processes has been linked to improved instructional quality and adaptability. While prior studies have explored the effects of accountability on teacher motivation and pedagogical practices, limited evidence exists regarding how teachers’ self-regulation patterns differ and how these variations relate to perceived accountability. This study aimed to identify distinct SRL profiles among teachers and examine their associations with internal and external accountability perceptions. A total of 339 primary and secondary school teachers in Türkiye participated in the study. Using latent profile analysis (LPA), teachers were classified based on their reported SRL strategies. Differences in accountability perceptions across the resulting profiles were examined through multivariate analyses. The LPA revealed three meaningful SRL profiles: Low Self-Regulators (Profile 1), High Self-Regulators (Profile 2), and Moderate Self-Regulators (Profile 3). Teachers in the High Self-Regulators profile reported significantly higher levels of both internal and external accountability than those in the other two groups, whereas the Low Self-Regulators profile was characterized by lower accountability across all measures. Moreover, internal accountability emerged as a stronger motivational factor than external mechanisms for teachers with well-developed SRL skills. These results indicate that SRL is a multidimensional construct closely linked to how teachers perceive and respond to accountability demands. The findings underscore the importance of fostering teachers’ self-regulatory capacities as part of professional development initiatives. Teacher education programs should adopt differentiated approaches that consider individual SRL profiles and accountability orientations to enhance reflective and autonomous teaching practices. Future research is encouraged to explore the longitudinal development of these profiles and evaluate the impact of accountability-driven interventions on sustained professional growth. Show less

Atherosclerosis (AS), a chronic cardiovascular disease, originates from endothelial dysfunction, a process closely linked to cellular energy metabolism. While rosmarinic acid (RA) exhibits protective cardiovascular effects, its precise mechanism against AS remains undefined. This study demonstrates that RA alleviates AS in ApoE Show less

24-h activity encompasses four categories: light-intensity physical activity (LPA), moderate-to-vigorous-intensity physical activity (MVPA), sedentary behavior (SB), and sleep (SP). This study aims to investigate the effects of different physical activity components on executive function in older adults with chronic diseases and to examine substitution effects among activity components. The findings provide scientific evidence to inform physical activity interventions for improving executive function in older adults with chronic diseases. A total of 105 older adults (72.64 ± 6.82 years) were recruited. Following questionnaire screening, 75 older adults with chronic diseases were ultimately included. Accelerometers objectively measured participants' daily SP, SB, LPA, and MVPA. Executive function was objectively assessed using the Stroop task, N-back task, and More-odd-shifting task. Component linear regression equation assessed the relationship between different activities and executive function in older adults with chronic diseases. The dose-response effects of "one-for-one" substitutions between different activity behaviors were explored. Component linear regression results showed that SB positively correlated with inhibitory control ( SP and MVPA significantly improve inhibitory control in older adults with chronic diseases, while LPA significantly enhances their working memory. It is recommended that older adults with chronic diseases adjust their daily time structure by increasing diverse physical activities, ensuring adequate sleep duration, and reducing sedentary behavior to improve executive function. Show less

Tumor-related metabolites in the tumor microenvironment may induce immune dysfunction, leading to malignant progression and metastasis of tumors. Here, it is demonstrated that tumoral PLA2G16, a phospholipase catalyzes phospholipids to generate free fatty acid (FFA) or lysophosphatidic acid (LPA), is an important contributor to triple-negative breast cancer (TNBC) lung metastasis in an immune-dependent pattern by improving tetracosatetraenoic acid (C24:4 (n-6)) accumulation in the early metastatic niche of lung and impairing immune function of pulmonary CD8 Show less

Gliomas comprise a heterogeneous group of central nervous system tumors in which gene fusions (GFs) are significant oncogenic drivers and emerging diagnostic and therapeutic biomarkers. In cancer diagnosis, GF detection largely relies on targeted short-read sequencing fusion panels, such as the Children's Hospital of Philadelphia (CHOP) Fusion Panel (FUSIP). While these panels are effective for detecting recurrent, well-characterized GFs, they are limited to predefined gene sets and cannot identify full-length transcripts. Here, we analyzed 49 high- and low-grade gliomas previously classified as fusion-negative by FUSIP using an untargeted whole-transcriptome RNA sequencing approach with Oxford Nanopore Technologies (ONT) long-read sequencing. This enabled transcriptome-wide fusion discovery of additional known and potentially novel oncogenic GFs beyond panel constraints. Long-read sequencing further allowed direct resolution of full-length fusion transcripts and their associated isoform structures. By integrating GF detection with isoform-level transcript analysis, we identified fusion-associated transcript isoforms with alternative splicing patterns that aligned near reported GF breakpoints, including Show less

Multiple studies show conflicting association between APOE polymorphisms and the risk of PDD, yielding inconsistent results. To elucidate, a meta-analysis was conducted using existing articles from Web of Science, PubMed, Cochrane, Google Scholar, Embase, WanFang, and CNKI databases, including case-control studies published up to January 31, 2025. A total of 27 studies (3,115 PD controls and 1,338 PDD cases) were included, with pooled Odds Ratio (ORs) and 95% confidence intervals (CIs) calculated using CMA, Biostat, United States. To assess APOE genotypes and PDD risk, three comparisons were examined: 5 genotypes vs. ε3/3, ε2+/ε4 + vs. ε3/3, and ε4 + vs. ε4-. The ε3/4 (OR = 1.56, 95% CI: 1.25-1.95); ε4 + vs. ε3/3 (OR = 1.52, 95% CI: 1.20-1.93) and ε4 + vs. ε4- (OR = 1.62, 95% CI: 1.39-1.90) genotypes were associated with an increased PDD risk, while ε2 + showed no significant effect (OR = 1.21, 95% CI: 0.88-1.65, Show less

Obesity and metabolic syndrome are associated with dysregulated hepatic lipid metabolism, contributing to metabolic dysfunction-associated steatotic liver disease (MASLD). Though lifestyle interventions such as a low-fat diet (LFD), treadmill (TM) exercise, and time-restricted feeding (TRF) reduce hepatic lipid accumulation, their combined effects on hepatic lipid composition and lipid metabolism-related gene regulation remain poorly understood. Here, we examined the individual and combined effects of LFD, TM, and/or TRF on liver function, comprehensive hepatic lipidomics, and lipid metabolism-related gene expression in diet-induced obese mice, thereby extending our previous work through detailed lipid class-specific analyses and assessment of interactive intervention effects. Among all interventions, LFD led to the greatest weight loss and normalized plasma aspartate aminotransferase (AST) as well as alanine aminotransferase (ALT) levels. Combined interventions, including TM and TRF, reduced markers of liver damage even under continued HFD conditions compared to HFD alone. LFD with TRF and/or TM decreased the expression of lipogenic genes (Srebf1, Lxrα, Apoe), while expression of genes further involved in lipid synthesis (Fasn and Hmgcr) tended to be increased when TM was combined with either LFD or HFD. β-oxidation-related genes (Ppara, Acox1, Cpt1a) were most downregulated in the LFD groups vs. the HFD + TM group, likely representing a metabolic adaptation to increased lipid mobilization. For the first time, lipidomics analysis demonstrated that in particular LFD alone or in combination with TM most effectively increased sphingomyelin (SM) and dihydrosphingomyelin (DHSM) as well as lysophosphatidylcholine (LPC) and phosphatidylcholine (PC), potentially reflecting compensatory lipid remodeling. Taken together, these findings highlight distinct and additive effects of combined lifestyle interventions on hepatic lipid composition and gene regulation, clearly delineating the novel contributions of the present study and supporting combined dietary and physical strategies as potential approaches to improve hepatic lipid homeostasis and mitigate MASLD development. Show less

Yiqi Huoxue Granule (YQHX), a traditional Chinese medicine (TCM) formulation, is extensively utilized for the treatment of atherosclerotic diseases. However, its active constituents and molecular mechanisms remain unclear. We utilized a systematic methodology to identify bioavailable compounds in vivo and predict and validate the principal targets and pathways responsible for their anti-atherosclerotic actions. Serum pharmacochemistry utilizing UPLC-Q-Exactive Orbitrap-MS was employed to identify the bioavailable compounds of YQHX. An integrated methodology combining network pharmacology and molecular docking was implemented to predict its potential targets and mechanisms against atherosclerosis, which were subsequently verified experimentally in apolipoprotein E-deficient (ApoE We identified 36 absorbable compounds in the serum of rats following YQHX administration, and 252 potential therapeutic targets were predicted. Protein-protein interaction analysis identified 10 hub targets, which are IL-6, TNF, EGFR, TP53, AKT, STAT3, SRC, CTNNB1, TLR4, and MMP-9. Enrichment analyses indicated that these targets are primarily involved in lipid metabolism and inflammatory responses, with significant enrichment in the PI3K-Akt and SRC signaling pathways. Molecular docking revealed strong binding affinities between the proteins EGFR, SRC, and AKT and their respective compounds. In ApoE This study systematically identified the bioactive compounds of YQHX and demonstrated its multi-target anti-atherosclerotic effect, which involved the enhancement of lipid metabolism and suppression of inflammation, mediated, at least in part, by the inhibition of the SRC/AKT signaling pathway. Show less

The angiopoietin-like protein (ANGPTL)3/8 complex regulates triglyceride partitioning, and its selective blockade lowers triglycerides while raising HDL-cholesterol (HDL-C). Clinical and genetic evidence support ANGPTL3/8 antagonism as a precision therapy for mixed dyslipidemia, monogenic hypertriglyceridemia (CREBH or APOA5 deficiency), and diabetic dyslipidemia by correcting a fundamental disturbance in lipid partitioning. Show less

G-protein-coupled receptors (GPCRs) are high-value therapeutic targets, yet antibody discovery remains limited by difficulties in preparing antigens that preserve native conformations. Here, we engineered a native-like, full-length human LPA2 antigen by combining N-terminal P9* fused with amphipathic poly-γ-glutamate (APG) stabilization, affording an antigen suitable for the selection of antibodies with therapeutic efficacy. By screening a large synthetic human scFv library, we isolated an antagonistic antibody against LPA2 that bound LPA2 selectively over LPA1 (EC Show less

Decline in pulmonary function (PF) and respiratory muscle strength (RMS) is influenced by environmental and genetic factors and is inconsistently linked to cognitive outcomes. This study explores the associations between PF, RMS, and cognitive function among community-dwelling older adults in China, analyzing interactions with APOE Ɛ4 and the mediating effect of serum total bilirubin. About 1,081 Hubei Memory and Aging Cohort (HMACS) participants underwent PF (PEF, FEV1 and FVC), RMS (MIP and MEP) assessment, cognitive tests, APOE genotyping, and bilirubin measurement. Multivariate logistic regression and general linear regression were used to analyze associations. Among 1,081 participants (mean age 70.52 ± 5.55 years), 26.1% had cognitive impairment. Lower PF and RMS scores were associated with cognitive impairment. Higher comprehensive PF (c-PF) and RMS indices protected against cognitive impairment (eg, c-PF: OR = 0.482-0.609, PF (especially PEF) and RMS (especially MEP) indices are significantly associated with cognitive function and impairment in older adults, independent of APOE Ɛ4 status. These findings provide biomarkers for assessing cognitive health risk and a basis for interventions targeting PF and RMS to preserve cognitive function. Show less

Diverse haematological neoplasms are driven by tyrosine kinase (TK) fusion genes formed by recurrent or non-recurrent genomic rearrangements. The resulting chimeric proteins often present excellent targets for treatment with kinase inhibitors, and the fusion transcripts or genomic junctions can be used as specific targets for molecular monitoring. Whilst the TK genes involved are generally well characterised (e.g. ABL1, PDGFRA, FGFR1), the fusion partners are very diverse, presenting a challenge for detection and characterisation of these structural variants (SV) using current diagnostic methods. We assessed the ability of targeted nanopore sequencing using adaptive sampling to detect fusion genes in myeloid neoplasms. We sequenced genomic DNA from patients (n = 20) with a known or suspected TK gene fusion and identified rearrangements in 18 cases, including all cases with a known TK fusion, typical and atypical BCR::ABL1 rearrangements, an 843Kb deletion causing a FIP1L1::PDGFRA fusion, novel AGAP2::PDGFRB and NFIA::PDGFRB fusions, and a complex CCDC88C::PDGFRB rearrangement with multiple translocation events. The approach was fast (<72 h/sample from DNA to result), flexible with minimal hands-on laboratory time, and provided accurate, patient-specific characterisation of genomic breakpoints. Show less

Alzheimer's disease widely affects millions of people worldwide, accounting for 60% of dementia cases. Clinically classified by the presence of cognition impairment, pathophysiological representation includes deposited senile plaques, neurofibrillary tangles, and neuroinflammation. The pathogenesis of Alzheimer's disease (AD) remains multifaceted and is governed by multiple hypotheses. However, it undeniably involves amyloid-β (Aβ) accumulation and hyperphosphorylated tau (p-tau) pathology as the crucial events in disease initiation. Substantial evidence has correlated Vitamin D Show less

Diabetes mellitus (DM) is hypothesized to increase the risk of Alzheimer's disease (AD). However, existing studies have yielded conflicting results, with some demonstrating a significant association between DM and AD risk while others have not. Therefore, this meta-analysis aimed to systematically evaluate the association between DM and AD risk. Comprehensive searches were conducted in PubMed, Web of Science, and Embase databases to identify cohort or case-control studies investigating the association between DM and AD risk. All eligible studies published before October 2025 were included. The Newcastle-Ottawa Scale (NOS) was used to assess the risk of bias. Hazard ratio (HR) and 95% confidence interval (CI) were pooled as the effect size for meta-analysis. Heterogeneity among studies was evaluated using Cochran's A total of 11 studies involving 3,393,545 participants were included. A meta-analysis revealed that DM was significantly associated with an increased risk of AD (HR = 1.36, 95% CI (1.19, 1.55), This meta-analysis provides compelling evidence that DM is an independent risk factor for AD, offering important implications for clinical practice and future research. However, due to the methodological limitations of this study, the results should be interpreted with caution. Large-scale, high-quality prospective cohort studies are needed to fully investigate the relationship between DM and AD risk. https://www.crd.york.ac.uk/prospero/, identifier CRD420251159844. Show less

Lysophosphatidic acid (LPA) is a cell-signaling lipid that has been proposed as an early-stage biomarker for ovarian cancer (OC). Diagnosing OC in Stage I is critical to improving patient outcomes, increasing the survival rate from 30% (when diagnosed in late stages of the disease) to over 90%. This significant improvement is due to the success of early interventions; however, current diagnostic methods are not as effective at early-stage detection, with only 15% of cases diagnosed in Stage I and over 70% diagnosed in Stage III or IV. There is a strong need for LPA detection that is sensitive, specific, rapid, low-cost, and automated to truly validate its effectiveness as a diagnostic characteristic for OC. We report the preliminary development and characterization of one such biosensor, which makes use of the advantages of magnetic particles and chemiluminescence for quick, sensitive detection of LPA. The sensor has proven to be viable, with a positive response to LPA concentration, a measurement time of 5 s after incubation, and an LOD of 3.5 nM. Show less

Apolipoprotein E4 (apoE4) is the strongest genetic risk factor for late-onset Alzheimer's disease (AD). Yet the molecular mechanisms underlying its contribution to AD remain to be fully elucidated. Here, we developed and characterized a set of apoE-specific single-domain antibodies (nanobodies) as a molecular toolbox to investigate intracellular apoE4. The nanobodies bind human apoE with nanomolar to sub-nanomolar affinity and recognize both apoE3 and apoE4. Domain-level epitope mapping revealed nanobodies that selectively bind either an N-terminal (residues 1-173) or C-terminal (residues 170-299) apoE4 fragment. Several nanobodies were validated as endoplasmic reticulum-targeted intrabodies that bind apoE4 intracellularly and promote its intracellular retention. These nanobodies constitute a versatile toolbox for probing and manipulating apoE4 in cellular models. As an exploratory application of this nanobody toolbox, we examined cytosolic apoE4, motivated by previous studies suggesting that cytosolic apoE4 fragments may influence AD-related cellular processes. Cytosolic expression of apoE4 resulted in perinuclear protein assemblies and the appearance of a ~25 kDa apoE4 fragment. Using a nanobody-based nuclear relocalization assay, we showed that cytosolic apoE4 remains accessible for nanobody binding but was not relocated to the nucleus by a nuclear localization signal-equipped nanobody. Altogether, this study introduces a nanobody-based toolbox to investigate apoE4 in distinct intracellular contexts, which can be relevant to AD. Show less

BackgroundAlzheimer's disease (AD) is the most common form of dementia, marked by progressive cognitive decline. Low-density lipoprotein cholesterol (LDL-C) has been implicated in AD pathology, but findings remain inconsistent. Apolipoprotein E4 (APOE4) status and sex may contribute to this variability.ObjectiveTo examine how LDL-C association with neurodegeneration in AD patients, differ according to APOE4 status and gender.MethodsWe stratified 106 AD patients by APOE4 status and sex into four subgroups: male APOE4+, female APOE4+, male APOE4-, and female APOE4-. Longitudinal cortical thickness changes were assessed using magnetic resonance imaging (MRI). We examined the association between LDL-C levels and cortical thinning within each subgroup.ResultsIn APOE4-positive females, higher LDL-C levels were significantly associated with accelerated cortical thinning in several regions, including the parahippocampal (β = -0.0075, p = 0.017), medial orbitofrontal (β = -0.0025, p = 0.028), fusiform (β = -0.0047, p = 0.034), posterior cingulate (β = -0.0097, p = 0.006), and inferior temporal cortices (β = -0.0085, p = 0.019). This subgroup also showed a significant association between LDL-C and MMSE decline (β = -1.409, p = 0.014) as well as longitudinal increases in cerebrospinal fluid phosphorylated tau181 (β = 0.014, p = 0.039). These effects were not observed in other subgroups.ConclusionsElevated LDL-C is associated with increased neurodegeneration and cognitive decline in female AD patients carrying the APOE4 allele. These exploratory findings highlight a subgroup-specific vulnerability to lipid-related neurodegeneration in AD and underscore the importance of considering both sex and genetic background in future studies. Show less

The SEMpsych project offered the "Blaufeuer" counselling service for people with psychological impairments and work-related stress. Firstly, this study investigated whether the recognisably high variability in the work-related problem areas can be explained by statistically and quantitatively determinable profile types. Secondly, it was investigated whether typical patterns of individual problem constellations in the course of life and habitual imprints (latent basic convictions) of Blaufeuer counselling participants, which are associated with psychological stress, can be reconstructed in their interaction.A convergent-parallel mixed methods approach was used. A latent profile analysis (LPA) was carried out statistically and quantitatively with 457 participants in the Blaufeuer programme. Qualitatively, 16 guided individual interviews were analysed using a combination of grounded theory and narrative analysis.The LPA revealed seven profiles of characteristic work and occupational problems. The qualitative analysis identified six latent basic beliefs and individual problem constellations that can contribute to the description of vulnerability risks.Both typifications provide guidance for the high variability of work-related stressors. Specifically, the qualitative findings show the necessity to consider latent basic beliefs as well as individual life events and everyday stresses in addition to the types of work-related stressors for counselling. Show less