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Natural killer (NK) cells are an integral component of the tumor microenvironment, and their role in immune checkpoint inhibitors (ICI) therapy has garnered increasing attention. However, comprehensive studies on NK cells across cancers, especially their impact on immunotherapy response, remain limited. We used machine learning algorithms to establish a pan-cancer natural killer cell immunotherapy predictive model (NKCIPM) by combining single-cell RNA sequencing data from 164 samples across 6 cancer types and bulk RNA-seq data from different tumor samples. Tumor immune cell infiltration analysis, drug sensitivity analysis, and cell-cell communication were also further conducted. An upregulation of NK cell proportions post-immunotherapy and the identification of 188 NK cell differentially expressed genes were observed through single-cell RNA sequencing analysis. By integrating bulk RNA-seq data and applying machine learning algorithms, 7 key hub genes were identified, ultimately leading to the construction of NKCIPM, with APOE emerging as the most influential hub gene. Further analysis using the CIBERSORT algorithm revealed that the signature genes within this model were significantly associated with immune cell infiltration and response to ICI. Additionally, therapeutic evaluation of CHEK1 and CHEK2 targets demonstrated potential significance in the communication between B cells, NK cells, and mast cells within the context of ICI therapy. In summary, the NKCIPM model offers a valuable tool for predicting immunotherapy outcomes and informing clinical decision-making, highlighting the potential of NK cell signature genes as therapeutic targets. Show less

Glaucoma is a neurodegenerative disease characterized by the progressive loss of retinal ganglion cell and optic nerve damage. Recent studies have highlighted the pivotal role of microglia in the onset and progression of glaucoma. This review aims to elucidate the key mechanisms of microglial activation in glaucoma and assess its potential as a therapeutic target for novel treatment strategies. Microglia activation in glaucoma is multifactorial, driven by biomechanical, metabolic, and inflammatory signals. Activated microglia contribute to both neuroinflammatory injury and neuroprotective responses. Their interaction with other kinds of cell establishes a dynamic inflammatory signaling network that exacerbates retinal ganglion cell loss. Furthermore, emerging evidence suggests that key targets in microglial activation, such as APOE, LGALS3, CX3CR1, etc. play critical roles in disease progression, revealing promising targets for therapeutic intervention. Microglia act as central regulators of the retinal immune microenvironment in glaucoma. Their dual role in neurotoxicity and neuroprotection is shaped by complex interactions with other kinds of cell. Targeting microglial activation state and restoring metabolic homeostasis represent promising strategies for the development of pressure-independent treatments for glaucoma. Show less

This study aims to compare the protein expression profiles of plasma-derived exosomes in patients with sudden sensorineural hearing loss (SSNHL) and normal hearing control groups to identify exosome proteins that may be associated with SSNHL or serve as biomarkers for SSNHL. Researchers collected peripheral venous blood from SSNHL patients and healthy controls for exosome isolation. The isolated exosomes were identified through nanoparticle tracking analysis, transmission electron microscopy observation, and Western blotting, followed by total protein extraction for proteomic sequencing. Differential expression proteins (DEPs) were screened using the threshold criteria of Researchers isolated exosomes from plasma and identified them through particle size analysis, morphological observation, and expression of exosome marker proteins. Comparative studies with healthy individuals revealed 363 DEPs in SSNHL. Additionally, 515 DEPs were identified in mild sudden deafness (MilSSNHL) and healthy controls, 982 in moderate cases (ModSSNHL) and healthy controls, and 1,161 in profound cases (ProSSNHL) and healthy controls. These proteins are involved in signaling pathways enriched by DEPs. Validation experiments demonstrated that the expression levels of these proteins consistently matched their sequencing results, ensuring high reliability. Furthermore, these candidate proteins show significant diagnostic potential for SSNHL. The four extracellular proteins identified in this study, including RPS2, RPL19, ACO2 and APOE, may be closely related to the occurrence and development of SSNHL or serve as biomarkers for the diagnosis and staging of SSNHL. Show less

Self-determination theory characterizes drinking motives according to level of autonomy and locus of control and aligns with harm reduction approaches to alcohol use. This study used latent profile analysis (LPA) to identify motivational profiles of self-determined behavioral regulations for drinking and to test their associations with sociodemographic variables and alcohol consumption and outcomes. Adults aged 18-57 (N = 630, M A four-profile model fit best. The "Aimless Drinkers" profile (n = 75, 11.9%) had low intrinsic regulation (e.g., enjoyment of drinking) and was disproportionately male (ORs = 2.35-2.65). The "Pleasure Drinker" profile (n = 114, 18.1%) had average intrinsic and low other regulations and was significantly older (OR = 1.07) than the "Externally Controlled Drinker" profile (n = 177, 28.1%), which had high external regulation (e.g., drinking due to social pressure). Externally controlled drinkers reported greater drinking intensity (M Older individuals were more likely to drink due to intrinsic enjoyment, which may reflect a shift toward greater autonomy over alcohol consumption with increasing age. Drinking primarily for enjoyment also facilitated more positive drinking outcomes. Future research should investigate whether motivational profiles of behavioral regulations for drinking predict long-term trajectories of alcohol consumption and alcohol-related risks. Show less

Disorders of pubertal onset and progression are a common cause for referral to paediatric endocrinologists, with delayed puberty in males being particularly frequent. Pubertal development depends on the hypothalamic-pituitary-testicular (HPT) axis, which is established during fetal life and undergoes distinct phases: fetal androgen production, postnatal "minipuberty", and reactivation during adolescence. Key regulators include GnRH neurons, Sertoli and Leydig cells, and biomarkers such as AMH, inhibin B, testosterone and INSL3. Puberty is marked clinically by testicular enlargement beyond 4 mL, usually at a median age of 11.5 years. Delayed puberty is defined as absence of testicular enlargement by age 14. The most common cause is self-limited delayed puberty (SLDP), often familial and benign. Functional hypogonadotropic hypogonadism due to chronic illness, and permanent central hypogonadism (congenital or acquired), account for additional cases. Congenital hypogonadotropic hypogonadism (CHH), including Kallmann syndrome, is frequently genetic, with variants in genes such as FGFR1, ANOS1 and GNRHR. Clinical assessment includes family history, growth patterns, and red flags such as micropenis, cryptorchidism or anosmia. Show less

ObjectiveTo describe characteristic CLEFT-Q response profiles and patterns in patients with cleft palate and/or lip (CP ± L).DesignRetrospective analysis using latent profile analysis (LPA) to categorize patient-reported outcome responses into distinct profiles.SettingTertiary care pediatric hospital with multidisciplinary cleft team.Patients, ParticipantsPatients aged 8-29 years with CP ± L completing CLEFT-Q questionnaires from September 2021 to June 2025 ( Show less

Abnormal glymphatic system may play a critical role in amyloid-β (Aβ) accumulation in mild cognitive impairment (MCI) and Alzheimer’s disease (AD) patients. This study aims to use diffusion tensor image analysis along the perivascular space (DTI-ALPS) and perivascular space volume fraction (PVSVF) to investigate the aberrant glymphatic functions and the association between Aβ deposition and clinical symptoms in AD spectrum. The ALPS index was significantly lower in AD patients compared to MCI and normal controls (NC) groups. Additionally, the AD group showed a significantly higher PVSVF in hippocampus (HP) compared to NC group. No notable variations were observed in the ALPS index or PVSVF across various regions when comparing the MCI group to the NC group. Apolloprotein E (APOE) ε4 + group showed significantly higher PVSVF-HP and PVSVF in basal ganglia compared to APOE ε4 − group. All participants’ HP volume, lower cognitive scores, and higher Our findings demonstrate that glymphatic dysfunction is associated with cognitive decline, underscoring the critical roles of Aβ pathology and the APOE genotype in mediating this relationship. Further exploration of glymphatic function holds significantly promise for advancing research on AD pathogenesis. The online version contains supplementary material available at 10.1186/s13550-025-01339-y. Show less

Lipoprotein(a) [Lp(a)] is an independent, inherited risk factor for atherosclerotic cardiovascular disease (ASCVD) and aortic stenosis. Lp(a) is an LDL-like particle containing apoB-100 and apo(a). Lifestyle changes and statin therapy lower LDL-cholesterol and apoB, but do not reduce Lp(a), whereas PCSK9 inhibitors exert a modest effect. There are currently no approved Lp(a)-lowering drugs, although several are at various phases of clinical development. We discuss the role of Lp(a) as a therapeutic target, describe the development, pharmacodynamics, pharmacokinetics, and metabolism of zerlasiran, a small interfering RNA (siRNA) targeting Lp(a), and report the findings of recent clinical trials. The GalNAc-conjugated siRNA zerlasiran reduces Lp(a) by targeting hepatic apo(a) synthesis and subsequent assembly of Lp(a), with comparable efficacy to other Lp(a)-lowering therapies in phase II development. Its long half-life, infrequent dosing, and potentially lower cost, together with its favorable safety and tolerability profile, make zerlasiran a promising candidate. However, long-term studies are needed to assess its impact on major adverse cardiovascular events and safety in diverse patient populations, and across different clinical settings. The phase III cardiovascular outcome study has not commenced. Show less

Pancreatic ductal adenocarcinoma (PAAD) metastasis is driven by complex tumor-microenvironment interactions. Here, we integrated single-cell and bulk transcriptomic analyses of 104,855 cells from 10 patients to delineate the cellular and molecular landscape of primary versus metastatic PAAD. We identified metastasis-associated epithelial (LMO7⁺, TOP2A⁺, PIGR⁺), fibroblast (IGKC⁺, RGS5⁺), and M2-like macrophage (APOE⁺, CD14⁺, FOLR2⁺, SPP1⁺) subpopulations, validated via bulk deconvolution. Functional analyses revealed upregulated Wnt signaling, epithelial-mesenchymal transition, and angiogenesis in metastatic epithelial and fibroblast compartments. Intercellular communication analysis highlighted SPP1-mediated macrophage-epithelial/fibroblast crosstalk involving key receptor-ligand pairs, contributing to immune suppression and metastatic niche formation. Integrating gene expression and cell proportions, we developed a prognostic model with high predictive accuracy (C-index > 0.85), stratifying patients into risk groups with distinct immune landscapes. Furthermore, PTK6 was identified as a driver of PAAD proliferation, migration, and invasion. Collectively, our study elucidates TME-driven mechanisms of PAAD metastasis, identifies prognostic and therapeutic targets, and provides a framework for precision intervention. Show less

Relying on a single biomarker in biomedical analysis is often insufficient for accurate disease or pathogen determination. A recent trend is using simultaneous multiplex detection of multiple biomarkers to improve diagnostic accuracy and throughput. To enable multiplex detection, we developed a series of surface-enhanced Raman scattering (SERS) nanoprobes, referred to as nanoaggregate-embedded beads (NAEBs). These NAEBs were synthesized using three distinct Raman reporter molecules: Safranin O, ethyl violet, and cresyl violet acetate. By integrating the NAEBs with magnetic nanoparticles and a simple capillary magnetofluidic device, we developed a rapid and simultaneous multiplex detection platform for genetic analysis of an aquacultural pathogen Vibrio parahaemolyticus (VP) for pirA, pirB, and ompA and genotyping of Alzheimer's disease's risk factor biomarker Apoliproprotein E (ApoE). For VP detection, a limit of detection (LOD) as low as ~ 10 Show less

The 808-nm wavelength laser has emerged as a promising non-invasive tool with significant therapeutic potential in various medical fields. This review highlights its biological mechanisms, including anti-inflammatory effects, tissue repair, and pain modulation. The laser inhibits the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway, reducing pro-inflammatory cytokines (e.g., tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6)) and increasing interleukin-10 (IL-10), an anti-inflammatory mediator that accelerates healing. The laser also activates the transforming growth factor-beta (TGF-β) pathway to stimulate collagen synthesis and fibroblast activity, enhancing tissue regeneration. Additionally, by promoting vascular endothelial growth factor (VEGF) expression, and improves neovascularization and tissue oxygenation as well. The modulation of transient receptor potential vanilloid 1 (TRPV1) channels, increased adenosine triphosphate (ATP) production, and activation of the phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) and the brain-derived neurotrophic factor (BDNF) pathways further support neuroprotection and cellular recovery. Importantly, recent insights suggest the laser's interaction with glial cells particularly astrocytes and microglia plays a critical role in managing neuro-inflammation and improving outcomes in neurological disorders such as hydrocephalus. The ability to influence cerebrospinal fluid regulation and enhance brain barrier permeability positions the 808-nm laser as a potential therapeutic option for improving life quality in affected individuals. Despite its potential, further clinical studies are required to validate and standardize its application across medical protocols. Show less

There is increasing interest in the importance of patterns of accumulation and overall daily time-use composition of physical activity (PA) and sedentary time (SED) for children's cardiometabolic health. This study examined cross-sectional associations between the time-use composition of PA and SED patterns with cardiometabolic risk factors in 4-year-olds. Data were drawn from the Barwon Infant Study 4-year review (n = 467). Accelerometer data were classified into short (≤ 1-minute) and long (> 1-min) SED, light-, moderate-, and vigorous-intensity PA (LPA, MPA, VPA) bouts. A waking time-use composition of eight distinct components (total volumes plus short and long bouts of SED, LPA MPA, VPA) was constructed using compositional data analysis. Linear mixed models examined associations between composition patterns and body mass index (BMI), percent body fat, triceps and subscapular skinfold thickness, blood pressure, heart rate, carotid-femoral pulse wave velocity, and aortic and carotid intima-media thickness. Adjusted models indicated a higher ratio of long versus short LPA bouts was associated with higher z-BMI (β = 1.69, SE = 0.83, p = 0.04), percent body fat (β = 10.72, SE = 3.71, p = 0.004), and z-triceps (β = 1.90, SE = 0.93, p = 0.04). A higher ratio of long versus short MPA bouts was associated with lower z-BMI (β = - 0.99, SE = 0.46, p = 0.03) and percent body fat (β = - 4.63, SE = 1.93, p = 0.02). A higher total volume of MPA versus VPA was associated with higher percent body fat (β = 4.07, SE = 1.63, p = 0.01) and z-triceps (β = 1.05, SE = 0.43, p = 0.01). Other outcomes showed no associations (p ≥   0.05). In preschoolers, accumulating LPA in shorter bursts, MPA in longer bursts, and maintaining a higher proportion of VPA may support healthier adiposity profiles. These findings underscore the importance of minimizing prolonged sedentary time and encouraging sustained, high-intensity PA from early childhood. Show less

Refugees and asylum seekers encounter numerous post-migration living difficulties (PMLDs) that can substantially affect their mental health. However, the role of PMLDs remains insufficiently explored, particularly in clinical refugee populations. This study aimed to identify subgroups based on patterns of PMLD by examining their relationship with depressive symptoms and determining which stressors function as key bridges. This study reports a secondary analysis of baseline data from the ReTreat trial. Data were collected from 141 refugees and asylum seekers enrolled in a multicentre randomized controlled trial of a culturally adapted CBT program in Germany. Participants completed measures of depressive symptoms (PHQ-9) and post-migration stressors (27-item checklist). Latent Profile Analysis (LPA) was used to identify distinct burden profiles. Exploratory Factor Analysis (EFA) examined the dimensionality of PMLDs. Network analysis was conducted to investigate symptom-stressor connectivity. Three latent profiles emerged: Class 1 showed elevated distress across all domains; Class 2 was characterized by family separation and homesickness; and Class 3 exhibited minimal post-migration stress. EFA of PMLDS supported a four-factor solution: institutional/legal stressors, structural hardship, health/service access, and emotional/family-related strain. Depressive symptoms differed significantly across profiles, with highest scores in the high burden group (Class 1). Network analysis identified institutional/legal and emotional/family-related stressors as central bridge nodes linking PMLDs to depressive symptoms. PMLDs are multidimensional and heterogeneously distributed among forcibly displaced individuals. Legal insecurity and emotional strain are particularly influential in connecting environmental hardship to depressive symptoms. This study uses baseline data from a registered randomized controlled trial (DRKS00021536). Show less

There were some evidences to suggest the correlation between circulating lipid levels and cholecystitis, but no evidence had been indicated the causal relationship between lipid-lowering drugs and cholecystitis. To investigate this, we employed drug target Mendelian randomization (MR), summary-data-based MR (SMR), and genetic colocalization analyses to assess the association between lipid-lowering drugs and cholecystitis. In this study, we used 2 sets of genetic tools to proxy lipid-lowering drugs: elevated high-density lipoprotein cholesterol (CETP), decreased low-density lipoprotein cholesterol (LDLR, HMGCR, NPC1L1, PCSK9, APOB, and ABCG5/ABCG8), and decreased triglycerides (LPL, PPARA, ANGPTL3, and APOC3); the expression quantitative trait locus of target genes from the eQTLGen consortium and Genotype-Tissue Expression project V8. Then, the causal effects of these lipid-lowering drugs genetic proxies on cholecystitis were estimated using a variety of MR, SMR, and colocalization as sensitivity analyses. Collectively, in the MR results, we found that the significant causal effects between genetically proxied ABCG5/ABCG8 enhancement and HMGCR inhibitors were associated with a reduced risk of cholecystitis. The results of SMR and heterogeneity in dependent instruments tests indicated that the expression of ABCG5/ABCG8 and HMGCR in multiple tissues were associated with cholecystitis. In conclusion, our study provides genetic evidence demonstrating a causal relationship between the enhancement of ABCG5/ABCG8 gene proxies and the use of HMGCR inhibitors with a reduced risk of cholecystitis. These findings support the potential reuse of lipid-lowering drugs in patients with cholecystitis and could inform the development of effective treatment strategies for this population in clinical practice. Show less

Lipoprotein (a) (Lp[a]) is an independent risk factor for cardiovascular disease (CVD). Structurally like low-density lipoprotein, Lp(a) is distinguished by the covalent attachment of apolipoprotein(a) to apolipoprotein B-100. Although its physiological role remains incompletely understood, evidence suggests that Lp(a) may facilitate wound healing and inhibit cancer growth and metastasis. In contrast, Lp(a) exhibits proatherogenic properties; it transports proinflammatory oxidized phospholipids, induces the secretion of proinflammatory cytokines, increases endothelial permeability, promotes smooth muscle cell migration and proliferation, and upregulates adhesion molecules that facilitate monocyte recruitment and retention. In addition, Lp(a) exerts prothrombotic activity by enhancing platelet aggregation, suppressing plasminogen activation, and inhibiting fibrinolysis. Although its clinical relevance in CVD is well established, the role of Lp(a) in peripheral arterial disease (PAD) remains unclear. This narrative review aimed to synthesize and critically examine the current evidence on the biological role of Lp(a) in PAD pathogenesis and identify knowledge gaps in PAD-specific outcomes. This review summarizes the epidemiology, pathophysiology, and management of elevated Lp(a) levels in patients with PAD and examines their association with post-treatment clinical outcomes. Elevated Lp(a) levels are associated with an increased PAD incidence and a higher risk of restenosis post-revascularization. Understanding the mechanisms by which Lp(a) contributes to PAD pathogenesis is essential for developing effective targeted therapeutic approaches and improving the identification and management of high-risk patients. Show less

Hypertrophic cardiomyopathy (HCM) is a prevalent cardiovascular disorder affecting populations worldwide, characterized by abnormal thickening of the heart muscle.(Supporting S1) The development of HCM is influenced by multiple factors, including genetic mutations, geographical conditions, lifestyle, and environmental exposures. The availability of extensive genomic datasets in public repositories provides an opportunity to identify potential genetic contributors and functional biomarkers associated with HCM. Previous studies have highlighted the pivotal role of the MYBPC3 gene in the pathogenesis of HCM. In this study, computational analyses were performed to predict gene mutations and functional biomarkers using RNA-sequencing and whole exome sequencing datasets. A total of 12 RNA-sequencing samples, comprising four healthy controls and eight HCM cases, along with 12 exome sequencing datasets, were retrieved from the Gene Expression Omnibus (GEO) database. RNA-sequencing analysis identified the top 20 differentially expressed genes associated with HCM, including MIB2, ZBTB48, MYBPC3, PRPF40B, CD27-AS1, MYH7, WDR90, KDM8, BCAM, ZSWIM9, KANK3, CCDC85A, ZNF512B, POLR3H, NUP210, PSMG4, GPLD1, GNL1, SH2D3C, and COL4A6. Among these, MYH7 exhibited the highest expression level, showing strong similarity to MYBPC3 in its association with HCM. Whole exome sequencing analysis further identified a panel of variant genes including MYBPC3, MYH6, MYH7, TNT, Titin, Desmin, ACE1, TGF-beta, Ang-2, SGCG, SGCA, DMD, and LaminA/C, all previously implicated in HCM pathophysiology. This integrative study underscores the correlation between differential gene expression patterns and clinical variants in HCM, providing valuable insights into the molecular mechanisms underlying the disease. Show less

This study aimed to perform a Meta-Analysis based on GWAS data and utilized them for multi-step analyses. Final data included 1,198,682 subjects (255,810 cases and 942,872 controls) in 26 studies among 11 ethnicities. R package utilized for GWAS Meta-Analysis, a Primary Gene List (PGL), and then a Secondary Gene List (SGL) were generated. All of the in-depth silico, systems biology, and Pharmacogenomics (PGx) analyses were performed by STRING-MODEL, miRTargetLink2, NetworkAnalyst, Enrichr, and PharmGKB. The cumulative effect size in a random effects model for the risk of AD was 1.55 [95% CI: 1.41-1.71]. APOE, APP, SPI1, hsa-miR-17-5p, hsa-miR-155-5p, hsa-miR-340, hsa-miR-125b, hsa-miR-199a-3p, hsa-miR-199a-5p, and hsa-miR-1908-5p, SP1, MYC, MAX, E2F1, Valproic acid, and Tretinoin were the most significant findings. According to the Enrichment Analysis, Immune System R-HSA-168,256 (q-value = 5.85E-07) and Amyloid Fiber Formation R-HSA-977,225 (q-value = 1.57E-05) were the most significant pathways. Amyloid-Beta Binding (GO:0001540) (q-value = 3.64E-04) in molecular function were among the most significant GOs. DDAs found Alzheimer Disease (q-value = 8.72E-45) with the highest incidence. PGx approaches, uncovered 40 potential annotations, among them, two annotations of rs429358 (APOE) were both directly associated with AD. Briefly, almost all of the findings presented in this study are supported by prior reports along with new findings. Show less

Lipoprotein(a) (Lp[a]) was discovered more than six decades ago. Since then, it has evolved from a subject of curious experiments performed by a few scientists to an extensively explored therapeutic target for prevention and management of cardiovascular disease (CVD). This has prompted an intense search for therapies and agents with potent Lp(a)-specific lowering effects on the horizon. Some of these agents are already in clinical trials to clarify whether lowering high Lp(a) levels would result in reductions in CVD events. The road to this point has been filled with many challenges, where landmark genetic discoveries opened new avenues and set the stage for interventions. Although there is no doubt that genetics play a key role in determining Lp(a) level, accumulating evidence also supports a role for some clinical conditions in influencing Lp(a) levels. CKD is a prevalent condition associated with elevated Lp(a) levels. Most available data show that elevated Lp(a) levels predict CVD risk in patients with CKD. Given the growing evidence for a relationship between Lp(a), CVD, and CKD as well as ongoing cardiovascular outcomes trials of Lp(a)-specific agents, we provide an overview of recent evidence on this topic. We focus on recent studies in patients with CKD on treatment modalities affecting Lp(a) level as well as on existing gaps in knowledge and future research directions related to clinical care and CVD risk reduction in patients with CKD. Show less

Engagement in physical and cognitive activities is associated with a decreased risk of mild cognitive impairment (MCI) and dementia, but the association with Alzheimer disease (AD) neuroimaging biomarkers is less clear. We thus examined associations of physical and cognitive activities with longitudinal trajectories of AD neuroimaging biomarkers among older adults free of dementia. We conducted a longitudinal study within the population-based Mayo Clinic Study of Aging (mean follow-up durations 1.3-3.4 years). Participants were aged 50 years or older and were cognitively unimpaired or had MCI at baseline. Engagement in physical and cognitive activities during 12 months before baseline was assessed through questionnaires. Participants underwent AD neuroimaging biomarker assessments at 1 or more time points. We ran linear mixed-effect models to examine associations between physical and cognitive activity composite scores and trajectories of individual yearly change in amyloid deposition (Pittsburgh compound B [PiB]-PET centiloid), tau burden (tau-PET standardized uptake value ratio [SUVR]), and regional glucose hypometabolism (fluorodeoxyglucose [FDG]-PET SUVR), adjusted for age, sex, We included 1,176 participants (47% female; mean [SD] age, 68.7 [9.6] years) for PiB-PET trajectories, 399 participants (49% female; mean [SD] age, 71.9 [11.0] years) for tau-PET trajectories, and 983 participants (46% female; mean [SD] age, 67.9 [9.2] years) for FDG-PET trajectories. PiB-PET and tau-PET measures increased during follow-up (3.4 [SD 4.0] and 1.3 [SD 2.1] years, respectively), whereas FDG-PET values decreased over 2.9 (SD 3.5) years of follow-up. Participants with higher total physical activity (interaction estimate 0.0017; 95% CI 0.0003-0.0031; Physical activity was associated with less synaptic dysfunction and cognitive activity with less synaptic dysfunction and lower amyloid burden over time, albeit effect sizes were small. Further research is needed to validate findings and clarify causal inference between physical and cognitive activities and AD neuroimaging biomarkers. Show less

The pathophysiology of tension-type headache (TTH) remains poorly understood, and current treatments are largely symptomatic. Identifying genetically supported, causally relevant proteins may provide insights into disease mechanisms and enable precision therapeutics. We conducted a proteome-wide Mendelian randomization (MR) analysis integrating large-scale plasma proteomic quantitative trait loci with genome-wide association study data for TTH. Phenome-wide MR, enrichment, protein-protein interaction (PPI), and mediation analyses were performed to identify druggable targets and clarify potential biological pathways. Thirteen plasma proteins exhibited significant causal associations with TTH (Bonferroni correction This integrative genetic analysis identified multiple plasma proteins with causal and pharmacologically relevant roles in NRXN3, CCL22, CLEC1B, and LRIG1 emerged as promising and potentially safe therapeutic targets. The online version contains supplementary material available at 10.1186/s10194-025-02235-5. Show less

Alzheimer's disease (AD) is one of the most prevalent neurodegenerative disorders characterized by β-amyloid (Aβ) deposition, neurofibrillary tangles, neuronal loss, and neuroinflammation. It represents a growing global health crisis. Although astrocytes contribute to neuroinflammatory cascades, their molecular regulators in AD progression remains elusive. Here, through single-cell transcriptomic analysis, we identified SerpinA3N as a disease-progressive modulator upregulated in AD astrocytes, with expression levels correlating with pathological severity. Astrocytic SerpinA3N knockdown in AD mice rescued cognitive deficits across multiple behavioral tests, and concurrently attenuated neuroinflammatory responses, as evidenced by decreased astrocytic/microglial activation and reduced cytotoxic substance release. Moreover, histopathological analyses demonstrated decreased neuronal loss and Aβ deposition following SerpinA3N knockdown. Mechanistically, we elucidated that SerpinA3N cooperated with APOE to exacerbate AD pathology through NFκB signaling activation. Our study uncovers a novel astrocyte-mediated pathogenic cascade driving AD progression and establishes SerpinA3N as a promising therapeutic target for neuroinflammation modulation in AD. Show less

Lipid-lowering therapy is typically initiated at high low-density lipoprotein(LDL) cholesterol marked by elevated apolipoprotein B(apoB). We tested the hypothesis that elevated apoB alternatively due to high remnant cholesterol confers equally high risk of atherosclerotic cardiovascular disease(ASCVD) but less initiation of lipid-lowering therapy, compared to elevated apoB due to high LDL cholesterol. From the Copenhagen General Population Study, 94 299 lipid-lowering therapy naïve adults without a history of ASCVD were included in 2003-2015. Discordance groups were formed by median levels of remnant cholesterol, LDL cholesterol and apoB. In the national Danish health registries, individuals were followed for a prescription of lipid-lowering therapy and for incident ASCVD until December 2021. During a median follow-up of 12 years, 9269 developed ASCVD. Compared to individuals with concordant low values of remnant cholesterol, apoB, and LDL cholesterol, those with high remnant cholesterol and high apoB but low LDL cholesterol had a hazard ratio(HR) of 1.45 (95% confidence interval: 1.34-1.56) for ASCVD and an odds ratio(OR) of 3.0 (2.5-3.6) for starting lipid-lowering therapy within one year. Correspondingly, those with low remnant cholesterol but high apoB and high LDL cholesterol had a HR of 1.20 (1.11-1.30) for ASCVD and an OR of 5.1 (4.3-5.9) for starting lipid-lowering therapy. In a primary prevention setting, elevated apoB due to high remnant cholesterol confers high risk of ASCVD but less initiation of lipid-lowering therapy compared to elevated apoB due to high LDL cholesterol, representing a guideline-based limitation and an unmet medical need. Show less

This study assessed the role of nucleotide-binding domain and leucine-rich repeat containing receptor, caspase recruitment domain containing 5 (NLRC5) in macrophages in atherosclerotic plaque formation in acute coronary syndromes (ACS) by modulating the nuclear factor-kappaB (NF-κB) cascade. Peripheral blood was obtained from ACS patients and matched controls, and NLRC5 expression and DNA methylation were analyzed. In vitro, peripheral blood mononuclear cells from donors were induced into macrophage-derived foam cells and transfected with small interfering RNA negative control (si-NC) or si-NLRC5 plasmids to assess foam cell formation and cytokine release. In vivo, ApoE Show less

Image-Based Sexual Abuse (IBSA) represents a significant and growing public health concern, yet individuals affected by IBSA exhibit diverse experiences of risk, victimization, and resilience. This study aimed to identify distinct profiles among individuals exposed to IBSA, childhood victimization and adversity, online risk behavior, and delinquency. Using Latent Profile Analysis (LPA), we analyzed data from 2,630 young adults (ages 18-28) recruited through an online survey, oversampling sexual and gender minorities and individuals with IBSA experiences prior to the age of 18. Seven distinct profiles emerged, reflecting varying levels of risk engagement. The largest group Show less

This study aimed to elucidate the molecular mechanisms by which celastrol (Cel) alleviates atherosclerosis (AS) through the regulation of macrophage autophagy. An AS model was established using ApoE Cel markedly reduced aortic plaque formation, ameliorated dyslipidemia, attenuated inflammatory responses, and enhanced plaque stability in ApoE Cel exerts anti-atherosclerotic effects by activating macrophage autophagy via the AMPK/ULK1 pathway, thereby improving lipid metabolism, reducing inflammation, and stabilizing plaques. These findings highlight the therapeutic potential of Cel and provide new insights into autophagy-targeted strategies against AS. Show less

Psoriasis is a chronic inflammatory condition related to an increased atherosclerotic cardiovascular disease (ASCVD) risk. To investigate whether lipoprotein (a) [Lp(a)] levels are increased in patients with psoriasis. A comprehensive literature search up to January 30, 2025 was conducted utilizing PubMed and Cochrane Library databases. A qualitative synthesis and a meta-analysis on Lp(a) mean differences (MD) between psoriasis cases and healthy controls (HC) was performed. The protocol of this meta-analysis has been registered to PROSPERO (No. CRD420250652465). Eighteen studies with 1650 psoriasis patients and 1621 HC were eligible for qualitative synthesis. Pooled analysis from 16 studies (1401 psoriasis patients and 1320 HC) demonstrated that psoriasis patients had significantly higher Lp(a) levels compared with the HC group (MD: 6.72 mg/dL, 95%CI: 4.32-9.12, Our findings suggest that Lp(a) levels are significantly elevated in psoriasis patients, further adding to their ASCVD risk. Show less

Alzheimer's Disease (AD) is a brain disorder with various neuropathological hallmarks and has become a major concern globally due to limited therapeutic options. Cholinergic dysfunction due to the depletion of acetylcholine (ACh) levels in the synapse caused by increased acetylcholinesterase (AChE) activity is one of the major factors that drives AD progression. AChE also accelerates amyloid beta (Aβ) formation and leads to amyloid plaque deposition in the brain. Production of Aβ from amyloid precursor protein (APP) with sequential cleavage by β-secretase (BACE1) and γ-secretase causes severe brain damage due to plaque toxicity. Neurofibrillary tangles (NFTs), a neuronal catastrophe resulting from hyperphosphorylation of tau protein due to upregulation of glycogen synthase kinase 3 beta (GSK3β) and downregulation of Wnt signaling because of Dickkopf-1 and low density lipoprotein receptor-related protein 6 (DKK1-LRP6) interaction, are a major pathogenic event in AD. Recent research has increasingly focused on targeting amyloidopathy, tauopathy, and cholinergic pathways as therapeutic strategies for mitigating AD pathology. Coptisine, a bioactive alkaloid having enormous pharmacological properties, including neuroprotective action, is considered in our in-silico investigation. Collective inhibition of key targets in AD pathogenesis, like AChE, β-secretase (BACE1), γ-secretase, GSK3β, and DKK1-LRP6 interaction, could be a positive approach in the arsenal of Alzheimer's treatment. In this article, we report that coptisine can inhibit these five major targets as evident from our molecular docking study, and propose it as a potential multi-target drug to play a key role in halting AD pathology. Further, comparative analysis based on predicted values of cheminformatics and pharmacokinetic profiling of coptisine and known inhibitors increases its possibility to ameliorate AD. However, robust research, including a preclinical and clinical study on coptisine for its safety and efficacy assessment against AD pathology, is warranted for its validation as an anti-AD drug. Show less

Genetic testing is valuable to confirm molecular diagnosis in nearly 60% of cases suspected of hypertrophic cardiomyopathy (HCM). However, the interpretation of variants, especially those of uncertain significance (VUSs), remains challenging for laboratories and clinicians. In April 2024, the ClinGen Cardiomyopathy Variant Curation Expert Panel (VCEP) adapted the ACMG/AMP criteria for eight of the sarcomeric genes ( Here, two groups of curators reinterpreted variants with the most recent data using the Cardiomyopathy VCEP specifications until a consensus was reached. To streamline the process, we created a semiautomated decision support tool based on these gene-specific rules. The application of the Cardiomyopathy VCEP specifications resulted in the reclassification of 17.4% ( Using gene-specific ACMG/AMP criteria reduces the rate of VUS, increasing diagnostic yield, and informing clinical management in the context of HCM. Nonetheless, ongoing efforts to generate evidence and promote standardization remain essential to improve variant interpretation. Show less

Dysbetalipoproteinemia (DBL) is a combined dyslipidemia associated with an increased risk of atherosclerotic cardiovascular diseases mostly occurring in ε2ε2 subjects and infrequently in subjects with rare Patients were divided into 3 groups according to their Total cholesterol (TC)/ApoB and NHDLC/ApoB are the best ratios to suspect DBL. In ε2ε2, according to their likelihood ratios (LR), the most clinically efficient algorithms were the HCL, Sniderman and De Graaf's. In APOEmut, Sniderman's algorithm exhibited the lowest negative LR (0.07) whereas the HCL's exhibited the highest positive LR (29). In both cohorts, the HCL algorithm had the best LR. We proposed a powerful algorithm based on ApoB concentration and the routine lipid profile, which performs remarkably well in detecting ε2ε2 or Show less

Atherosclerosis, a chronic inflammatory disease, presents significant "residual risk" even with effective lipid-lowering therapies, primarily due to persistent vascular inflammation. Apolipoprotein B100 (ApoB100) acquires pro-inflammatory properties upon modification and binds to cell-surface enolase 1 (ENO1), an immune modulator upregulated in inflammatory conditions. This interaction induces inflammatory responses via NF-κB activation. Targeting the ApoB100-ENO1 interaction may offer a novel strategy to reduce vascular inflammation and atherosclerosis progression. We developed PP3m, a stabilized ApoB100-derived peptide, to selectively inhibit the ApoB100-ENO1 interaction. Single-cell RNA sequencing (scRNA-seq) data from human atherosclerotic plaques were reanalyzed to characterize ENO1 expression in myeloid cells. In vitro, PP3m's anti-inflammatory effects were evaluated across various macrophage models stimulated by diverse inflammatory stimuli. Outcomes included cytokine secretion, inflammatory gene expression, foam cell formation, oxidized low-density lipoprotein (oxLDL) uptake, and signaling pathways activation. In vivo, Ldlr scRNA-seq analysis revealed that human atherosclerotic plaques harbor significantly more ENO1 macrophages, with ENO1 expression enriched in CD68 The ApoB100-ENO1 axis is a critical driver of macrophage-mediated inflammation in atherosclerosis. The novel peptide PP3m effectively inhibits this interaction, reducing vascular inflammation and plaque progression without altering lipid levels. PP3m represents a promising therapeutic candidate for cardiovascular disease by targeting residual inflammatory risk through a lipid-independent mechanism. Show less