📋 Browse Articles

Cirrhosis and hepatocellular carcinoma (HCC) are long-term complications of chronic liver disease (CLD). In this large multi-ancestry genome-wide association study of all-cause cirrhosis (35,481 cases, 2.36M controls) and HCC (6,680 cases, 1.76M controls), we identified 27 loci associated with cirrhosis (10 novel) and 11 with HCC (three novel). Three novel cirrhosis loci were replicated in independent cohorts (e.g. Show less

The maternal-to-zygotic transition (MZT) is a reprograming process encompassing zygotic genome activation (ZGA) and the clearance of maternally-provided mRNAs. While some factors regulating MZT have been identified, there are thousands of maternal RNAs whose function has not been ascribed yet. Here, we have performed a proof-of-principle CRISPR-RfxCas13d maternal screen, in which we targeted mRNAs encoding kinases and phosphatases or proteins regulating them in zebrafish. This screen identified branched-chain ketoacid dehydrogenase kinase, Bckdk, as a novel post-translational regulator of MZT. Bckdk mRNA knockdown caused epiboly defects, ZGA deregulation, H3K27ac reduction and a partial impairment of miR-430 processing. Phospho-proteomic analysis revealed that Phf10/Baf45a, a chromatin remodeling factor, is less phosphorylated upon Bckdk depletion. Further, phf10 mRNA knockdown also altered ZGA, and expression of a phospho-mimetic mutant of Phf10 rescued the developmental defects observed after bckdk mRNA depletion, as well as restored H3K27ac levels. Altogether, our results demonstrate the competence of CRISPR-RfxCas13d screenings to uncover new regulators of early vertebrate development and shed light on the post-translational control of MZT mediated by protein phosphorylation. Show less

Histone deacetylase 3 (HDAC3) is an epigenetic modifying enzyme closely linked to the development of atherosclerosis. Endothelial inflammation is a critical factor in atherosclerosis. However, the role of HDAC3 in mediating epigenetic modifications and regulating endothelial inflammation in atherosclerosis remains unclear. This study aims to investigate the impact of HDAC3 on endothelial inflammation and its contribution to atherosclerosis. Firstly, single-cell transcriptomic analysis identified elevated expression of HDAC3 and nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) in inflammatory endothelial cells of atherosclerotic plaques in symptomatic patients. Endothelial-specific knockout HDAC3 in an apolipoprotein E knockout (ApoE Show less

Atherosclerosis has an auto-immune component driven by self-reactive T and B cells. Identifying their antigenic drivers may lead to new diagnosis and treatment approaches. Here, we aim to identify immunogenic T cell epitopes derived from atherosclerosis-relevant proteins such as ApoB100 by studying the repertoire of peptides presented by HLA in human plaques. We used immunopeptidomics to identify peptides presented by HLA-DR molecules from plaques of patients that underwent endarterectomy surgery. We selected a set of 20 peptides derived from ApoB100 and studied the presence and cytokine profile of ApoB100-specific CD4 revealed significant CD4 We show that immunopeptidomics can be a valid approach to new discover antigens in atherosclerosis. Show less

To quantify international variations in lipid-lowering therapies (LLT) use among patients with coronary heart disease (CHD) and attainment of European guideline-recommended lipid goals. INTERASPIRE is an observational study (2020-23) covering 14 countries from all WHO regions. Patients (18-79 years) hospitalized in the preceding 6-36 months with CHD were invited for standardized interviews and examination, with central laboratory analyses for low-density lipoprotein cholesterol (LDL-C), non-HDL-C, and apolipoprotein B (apoB). Valid lipid data meeting quality control standards were available from 13 countries. Lipid goals followed the 2019 guidelines of the European Atherosclerosis Society and the European Society of Cardiology: LDL-C < 1.4 mmol/L, non-HDL-C < 2.2 mmol/L, and apoB <65 mg/dL.Among 4061 patients (78.8% male, mean age 60.3 years), between index event and interview, 66.3% had no change in treatment intensity. LLT use at interview was largely statin monotherapy: 49.6% high-intensity (inter-country range 5.3%-77.3%) and 24.1% low/moderate-intensity (inter-country range 5.1%-70.1%). Otherwise, 12.2% (inter-country range 0.2%-41.1%) were on combination therapy, and 12.7% on no LLT (inter-country range 3.5%-36.7%). Goal attainment for LDL-C was 17.5%. Corresponding non-HDL-C and apoB goals were achieved by 29.9% and 29.2%, respectively. Higher-income countries (defined by the World Bank's 2024-25 classification of income levels) did better in goal attainment than lower-middle-income countries. In this international study, contemporary lipid goals were not achieved in most CHD patients, with lower-middle-income countries having the worst goal attainment. Contributory factors include absence of any LLT use, low use of combinations and a failure to up-titrate LLT to achieve guideline targets. Show less

This review examines the existing literature on the structural and functional changes in the anatomy of the prefrontal cortex (PFC) associated with autism spectrum disorder (ASD), focusing on the roles of molecular signaling disruptions and trace element imbalances. A literature review was performed through a structured search of academic publications from 2010 to 2025. Anatomic variations and structural and functional abnormalities within the PFC, including disruptions in neural connectivity, synaptic plasticity, and neurochemical balance, significantly contribute to the cognitive, social, and emotional deficits observed in ASD. The interplay between brain-derived neurotrophic factor dysregulation, oxidative stress, and trace element imbalances further exacerbates these dysfunctions. According to our findings, the anatomy of the PFC appears to play a crucial role in the pathophysiology of ASD, given its involvement in executive function, emotional processing, and social cognition, suggesting a multifactorial pathophysiology that demands a multidimensional research approach. Show less

The onset of puberty is a critical developmental milestone regulated by complex neuroendocrine networks that integrate genetic, metabolic, and environmental cues. Among the molecular systems coordinating this transition, neurotrophins-including brain-derived neurotrophic factor (BDNF), nerve growth factor, neurotrophin-3, and neurotrophin-4/5-have emerged as important modulators of hypothalamic maturation and the activation of gonadotropin-releasing hormone (GnRH) neurons. Beyond their established roles in neuronal survival and differentiation, neurotrophins contribute to hypothalamic circuit plasticity, influence GnRH neuronal activity, and participate in the integration of metabolic and environmental signals relevant to reproductive maturation. Experimental studies, primarily based on animal and cellular models, demonstrate that BDNF and its receptor play a role in normal pubertal onset, whereas disruptions in neurotrophin signaling have been implicated in central precocious puberty, delayed puberty, and hypogonadotropic hypogonadism. In humans, available evidence is more limited and derives mainly from genetic studies, circulating neurotrophin measurements, and clinical observations. This review provides an integrative synthesis of current experimental and clinical data on neurotrophin-mediated regulation of pubertal timing, highlighting both physiological mechanisms and pathological conditions. While neurotrophins represent promising modulators at the intersection of neurodevelopment, metabolism, and reproduction, further longitudinal and translational human studies are required to define their diagnostic and therapeutic potential in pediatric endocrinology. Show less

Whether lipid-modifying drugs directly impact the outcome of sepsis remains uncertain. Therefore, systematic investigations are needed to explore the potential impact of lipid-related therapies on sepsis outcomes and to elucidate the underlying mechanisms involving circulating inflammatory cytokines, which may play critical roles in the pathogenesis of sepsis. This study aimed to utilize drug-target Mendelian randomization to assess the direct causal effects of genetically proxied lipid-modifying therapies on sepsis outcomes. First, a two-sample Mendelian randomization study was conducted to validate the causal associations among high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and sepsis. A subsequent drug-target Mendelian randomization study assessed the direct causal effects of genetically proxied lipid-modifying therapies on the risk of sepsis, sepsis-related critical care admission, and sepsis-related death. The identified lipid-modifying drug targets were subsequently explored for direct causal relationships with 36 circulating inflammatory cytokines. Finally, enrichment analyses of the identified cytokines were conducted to explore the potential relationships of lipid-modifying drugs with the inflammatory response. Genetically proxied cholesteryl ester transfer protein (CETP) inhibitors were significantly associated with sepsis-related critical care admission ( This study supports a causal effect of genetically proxied CETP inhibitors in reducing the risk of sepsis-related critical care admission and death. These findings suggest that the underlying mechanism may involve the modulation of some circulating inflammatory cytokines, influencing the inflammatory response pathway. Show less

Reducing LDL cholesterol prevents atherosclerotic cardiovascular disease (ASCVD) events. The aim of this study was to evaluate the LDL cholesterol-lowering efficacy of a fixed-dose combination (FDC) of obicetrapib, a CETP inhibitor, and ezetimibe. This randomised, double-blind trial across 48 US sites including hospitals, private and group practices, and independent research centres included participants at least 18 years old with pre-existing or high risk for ASVCD or heterozygous familial hypercholesterolaemia with LDL cholesterol concentrations of 1·8 mmol/L (70 mg/dL) or greater despite maximally tolerated lipid-lowering therapy excluding ezetimibe, or having statin intolerance. Participants were randomly assigned (1:1:1:1) to obicetrapib 10 mg plus ezetimibe 10 mg FDC, obicetrapib 10 mg monotherapy, ezetimibe 10 mg monotherapy, or placebo administered daily for 84 days. The co-primary endpoints in the intention-to-treat population were the percent LDL cholesterol changes in the FDC group compared with placebo, ezetimibe monotherapy, and obicetrapib monotherapy, and the placebo-adjusted change in the obicetrapib monotherapy group. The trial was prospectively registered (NCT06005597) and is completed. Between March 4 and July 3, 2024, 407 participants were randomly assigned. The median age was 68·0 years (IQR 62·0-73·0) and 177 (43%) were female. Mean baseline LDL cholesterol was 2·4 mmol/L, 2·5 mmol/L, 2·6 mmol/L, and 2·5 mmol/L in the placebo (n=102), ezetimibe monotherapy (n=101), obicetrapib monotherapy (n=102), and FDC groups (n=102), respectively. At day 84, percent differences in LDL cholesterol reduction with the FDC were -48·6% (95% CI -58·3 to -38·9) versus placebo, -27·9% (-37·5 to -18·4) versus ezetimibe, and -16·8% (-26·4 to -7·1) versus obicetrapib. Obicetrapib monotherapy decreased LDL cholesterol by 31·9% (22·1 to 41·6) versus placebo. Adverse event rates were similar in the FDC (52 [51%] of 102), obicetrapib (55 [54%] of 102), and ezetimibe (54 [53%] of 101) groups and lowest with placebo (38 [37%] of 102). Serious adverse event rates were generally similar across FDC (three [3%] of 102), obicetrapib (six [6%] of 102), ezetimibe (seven [7%] of 101), and placebo (four [4%] of 102) groups. Deaths occurred in one [1%] of 102 participants with FDC, one [1%] of 102 with obicetrapib, one [1%] of 101 with ezetimibe, and none with placebo. Combination therapy of obicetrapib and ezetimibe significantly reduced LDL cholesterol. This oral, single-pill therapy could improve LDL cholesterol management in patients with pre-existing or high risk for ASCVD. NewAmsterdam Pharma. Show less

The melanocortin-4 receptor (MC4R) agonists have emerged as potential treatments for obesity, particularly in patients with rare genetic syndromes. However, their overall effects on obesity and cardiometabolic risk factors remain uncertain. To systematically evaluate the efficacy of MC4R agonists on weight-related outcomes and cardiometabolic risk factors. We conducted this study following PRISMA 2020 guidelines. Eligible studies included clinical trials ((RCTs and single-arm trials) of the effects of MC4R agonist drugs on anthropometric factors and cardiovascular risk factors. Random model effects meta-analyses were performed for this meta-analysis, with heterogeneity and small-study effects explored through sensitivity and publication bias analyses. A total of 12 studies were included. Treatment with MC4R agonists significantly reduced body weight compared with placebo in RCTs (WMD − 5.07 kg; 95% CI − 8.13 to − 2.02), with even larger reductions in single-arm studies (–11.23%; 95% CI − 15.43 to − 7.04). MC4R agonists also lowered BMI by − 13.67% (95% CI − 17.21 to − 10.12), waist circumference by − 11.75 cm, BMI Z-score by − 0.98, and hunger scores by − 3.38. These agents reduced triglyceride levels by − 35.53 mg/dL and LDL-C levels by − 9.14 mg/dL, while HDL-C levels showed a nonsignificant increase of + 2.37 mg/dL. Systolic blood pressure declined by − 4.38 mmHg, while diastolic pressure showed no meaningful change. MC4R agonists produce clinically meaningful weight reduction and improvements in several cardiometabolic risk factors. These findings support MC4R agonists as a promising therapy for genetic forms of obesity, while their role in nonspecific obesity requires confirmation in large, long-term randomized trials. The online version contains supplementary material available at 10.1186/s13098-025-02071-2. Show less

Resistance and resilience are pathways through which modifiable behaviors may reduce Alzheimer's disease (AD) risk. Sleep - a known modifiable factor - is understudied in this context, especially among older women at elevated risk for AD. Forty-five functionally intact older women (≥65 years) at heightened risk for AD completed wrist actigraphy to capture average nocturnal sleep duration. Tau positron emission tomography imaging ( Shorter sleep duration amplified the association between APOE ε4 status and tau, while longer sleep mitigated it. Similarly, tau burden was related to worse memory performance only among those with short sleep duration. Longer sleep duration may promote resistance and resilience to AD in at-risk older women, highlighting sleep as a critical intervention target. Sleep was measured via wrist actigraphy, tau via PET imaging, and memory with a composite score. Longer sleep attenuated the link between APOE ε4 carriership and tau PET across Braak regions. Greater sleep duration weakened the negative impact of tau on memory performance. This is the first study to examine sleep in AD resistance and resilience among older women at heightened risk. Show less

Neurodevelopmental disorders (NDDs) exhibit complex genotype-phenotype associations that frequently result in inconclusive variant interpretations, contributing to suboptimal diagnostic yields (~ 40%). Koolen-de Vries syndrome (KdVS), an autosomal dominant NDD caused by KANSL1 haploinsufficiency, exemplifies this diagnostic challenge with its multisystem manifestations and lack of systematic genotype-phenotype associations. To address this gap, we constructed a comprehensive KdVS genotype-phenotype repository by systematically integrating all molecularly confirmed cases from global literature. Comprehensive phenotypic analysis revealed that core KdVS features include developmental delay/intellectual disability, characteristic craniofacial dysmorphism, hypotonia, and multisystem abnormalities. Phenotypic association analysis identified 249 significant correlations, demonstrating that KdVS clinical manifestations are highly interconnected rather than representing isolated features, such as the association between strabismus and hydrocephalus (OR = 14.26). Application of this repository to screen a Chinese rare disease cohort identified 53 KANSL1 variants. Among these, one de novo nonsense variant (NM₀₀₁₁₉₃₄₆₆.2: c.902T > G, p.Leu301Ter) was classified as pathogenic in a Chinese boy with classic KdVS features. The remaining 52 variants were categorized as variants of uncertain significance (VUS), approximately half of which were absent from gnomAD databases. Each VUS was comprehensively annotated with detailed clinical profiles to facilitate phenotype-driven reinterpretation. In conclusion, this study establishes KdVS as a highly interconnected multisystem disorder and demonstrates that deep phenotypic association analysis enhanced genetic diagnosis. This disease-specific repository approach provides a scalable framework for improving molecular diagnostics across rare NDDs. Show less

Atherosclerosis (AS) is a serious threat to human health. Although glucose balance, lipid metabolism, inflammation and hypertension are closely related to AS, whether methyltransferase-like (METTL) family members are involved in the occurrence and development of AS remains elusive. Differentially expressed genes of METTLs in AS and normal blood vessels in GSE43292 and GSE100927 databases were analyzed. Random forest screening was used to screen marker genes, and the intersection genes in the two databases were selected. GSE28829/GSE41571 and clinical tissue samples were used for verification. The databases were further used to analyze marker genes' tissue and cellular localization and their correlation with lipid metabolism and efferocytosis. 7 and 17 differentially expressed METTL genes were obtained from GSE43292 and GSE100927 databases, respectively. METTL7B and METTL5 were verified as the intersection marker genes. Compared with the control group, the expression of METTL7B was significantly increased in advanced AS, AS ruptured plaque and clinical heavy-load plaque tissues. ROC curve analysis showed that the AUC of METTL7B in GSE28829 and GSE41571 was greater than 0.9. In addition, it was found that METTL7B was significantly correlated with lipid metabolism-related genes and promoted the formation of lipid droplets. METTL7B was positively correlated with atherosclerosis and macrophage-mediated efferocytosis. RNA-seq and targeted lipidomics results also confirmed that METTL7B is closely related to lipid metabolism and atherosclerosis. And further analysis also indicated that METTL7B could regulate 104 kinds of lipids, such as Lipid-n-0041, Lipid-n-0056, Lipid-n-0057, Lipid-n-0098, Lipid-n-0099 and Lipid-n-0169, mediated by AKR1C1, CETP and RORA. This study reveals a new mechanism for the occurrence and development of AS, thereby providing a potential target for the treatment of AS. In conclusion, METTL7B can be used as a predictor and therapeutic target for AS. Show less

Acute coronary syndrome (ACS) survivors have heightened risk for subsequent cardiovascular events. All baseline characteristics collected in both the Dal-Outcomes and Dal-GenE trials were considered as potential risk markers. A prediction index for subsequent fatal and non-fatal myocardial infarction (MI) following ACS was developed using Cox proportional hazards modeling on data from Dal-Outcomes placebo patients (n=7086). This prediction index was then applied in all Dal-GenE participants (n=5989) to determine whether the reduction in MI observed with dalcetrapib (versus placebo) in patients with the AA genotype at rs1967309 in the ADCY9 gene remained significant, independent of the other markers integrated into the prediction index. Of the 36 baseline variables considered as potential risk markers, 18 contributed to the prediction index with a Harrell's C-index of 0.72 (95% CI, 0.69-0.75) in Dal-Outcomes placebo patients. Prior history of coronary events, LDL-C, blood pressure, A1c, hs-CRP, smoking and age were contributors. The prediction index was strongly predictive when applied to the 5989 AA genotype patients from Dal-GenE, with a HR for MI of 1.92 (95%CI: 1.78-2.08) for each SD increase in score. When adjusting for the prediction index, the HR for dalcetrapib versus placebo was 0.77 (95% CI, 0.63-0.94) in Dal-GenE. Despite guideline directed therapy following ACS, history of prior coronary events and on-treatment LDL-C, A1c, hs-CRP and blood pressure remain determinants of future MI. In the Dal-GenE AA genotype patients, dalcetrapib reduced the rate of MI, independently of those variables. The Dal-GenE 2 trial is designed to confirm this pharmacogenetic hypothesis. Show less

Convergence of amyloid precursor protein (APP) and β-site APP cleaving enzyme 1 (BACE1) in endosomes initiates the production of amyloid-β (Aβ) peptides that accumulate in brains of Alzheimer's disease patients. APP and BACE1 are segregated in neurons, and mechanisms triggering their convergence have remained poorly understood, limiting therapeutic attempts to reduce Aβ production. Neural cell adhesion molecule 2 (NCAM2) is a cell surface localized protein, which increases Aβ levels via mechanisms that are not known. We show that APP binds to the extracellular domain of NCAM2. The intracellular domain of NCAM2 binds to the Rab11 adaptor protein Rab11-FIP5. The NCAM2/APP complex is endocytosed from the cell surface and targeted to BACE1-containing Rab11-positive recycling endosomes where it is processed. Convergence of APP with BACE1 is increased in transfected CHO cells and neurons expressing NCAM2. Consequently, the levels of amyloidogenic APP cleavage products are increased in cells expressing NCAM2. In NCAM2-deficient neurons, APP accumulates at the cell surface and in early endosomes, and APP levels in recycling endosomes are reduced. Aβ production is increased by Aβ oligomers and neuronal activity, and we show that the binding of NCAM2 to APP is increased in neurons treated with Aβ oligomers or after activation of synaptic NMDA receptors. Together, our data indicate that NCAM2 binds to APP and promotes APP targeting from the neuronal cell surface to recycling endosomes where APP is cleaved by BACE1. This novel mechanism regulating the convergence of APP and BACE1 in neurons can contribute to Aβ accumulation in Alzheimer's disease. Show less

While the β-secretase BACE1 is responsible for the rate-limiting initial step to generate amyloid-β (Aβ) peptides, BACE1 inhibitor clinical trials have been halted due to a lack of efficacy and/or safety concerns at symptomatic/prodromal stages of Alzheimer's disease (AD). These trials were often targeted at high levels of BACE1 inhibition (>70 %) and ended up with signs of mild cognitive worsening instead of expected improvement. BACE1 concentration and activity are elevated in the cerebrospinal fluid and plasma/serum as well as brains of patients with mild cognitive impairment and AD dementia. Interestingly, recent evidence suggests that these fluid-based biomarkers reflective of BACE1 elevation may be associated with yet asymptomatic pathological changes in preclinical AD populations who are at high-risk for developing AD. Consistent with these findings, it has been demonstrated that exposures to major environmental and genetic risks such as diabetes, sleep disturbances, seizure, vascular disorders, stress, apolipoprotein E4, etc. converge on BACE1 elevation in humans and animal models, which may contribute to triggering sporadic AD. Moreover, vicious cycles exist between BACE1/Aβ elevations and certain prognostic conditions, further accelerating disease progression. Conversely, protective factors for AD are associated with reduced BACE1 level/activity. This review provides an overview of BACE1 alterations as common responses to a broad battery of AD risk and protective factors. The findings validate BACE1 as a biomarker for preclinical AD status that may be useful for earlier diagnosis and identifying subpopulations of individuals under AD risks who would benefit from preventive low-dose BACE1 inhibitor treatment with a higher probability. Show less

Aluminum oxide nanoparticles (Al₂O₃NPs) are used across industrial and consumer sectors, raising concerns about their potential neurotoxic effects. Despite growing application, the mechanisms underlying Al₂O₃NP-induced neurodegeneration remain poorly understood. This study investigated the mechanistic pathways of Al₂O₃NP neurotoxicity in adult male Sprague-Dawley rats exposed intraperitoneally to 15, 30, or 60 mg/kg Al₂O₃NPs for 60 days. Comprehensive analyses included hematological profiling, serum biochemistry, oxidative stress markers (MDA, Nrf2/Keap1), neurotransmitter assays (dopamine, acetylcholine, AChE), quantitative PCR of APP, BACE1, and BDNF, inductively coupled plasma spectroscopy for brain aluminum levels, histopathology, immunohistochemistry (caspase-3, BCL2), and ultrastructural examination by transmission electron microscopy. Al₂O₃NP exposure induced dose-dependent anemia, disrupted iron and calcium homeostasis, and triggered oxidative stress, evidenced by elevated MDA and suppressed Nrf2/Keap1 signaling. Neurochemical analyses revealed marked dopamine and acetylcholine depletion alongside diminished AChE activity. Molecular assays showed significant upregulation of amyloidogenic markers (APP, BACE1) and severe BDNF suppression, indicating impaired neurotrophic support. Brain histopathology revealed progressive neuronal shrinkage, Purkinje cell loss, astrogliosis, and perivascular edema, while immunohistochemistry demonstrated heightened caspase-3 activation and reduced BCL2 expression. TEM confirmed ultrastructural axonal degeneration, demyelination, and necrotic neuronal profiles. Notably, aluminum bioaccumulation increased 116-fold at the highest dose, tightly correlating with neurodegeneration severity. These findings demonstrate that subchronic Al₂O₃NP exposure promotes neurodegeneration via a multifaceted oxidative stress mechanism, activating the amyloidogenic pathway, synaptic dysfunction, neurotrophic impairment, and apoptosis. This work underscores the urgent need for rigorous safety assessments of nanoparticle exposure in biomedical and environmental settings. Show less

People with mild cognitive impairment (MCI) are candidates for early intervention, but not all progress to Alzheimer's disease (AD) dementia. Identifying a subgroup at highest risk may improve treatment targeting. We analyzed data from participants with MCI enrolled in the Alzheimer's Disease Neuroimaging Initiative (ADNI). Cognitive domains included memory, executive functioning, language, and visuospatial abilities. We evaluated baseline performance and 6-month change scores, using proportional hazards models to estimate associations with time to conversion to AD dementia. The strength of association varied by domain, but in general both baseline performance and 6-month change were associated with conversion. The strongest effects observed for memory and language. Observed associations were largely independent of established risk biomarkers, including APOE genotype, structural MRI measures, and CSF biomarkers. 6-month change scores on cognitive tests may help identify a high-risk subgroup of persons with MCI likely to progress to AD dementia. Systematic review. The authors reviewed the literature using traditional (e.g. PubMed) sources. There is a modest literature on change scores in the context of the AD clinical spectrum, but few investigations have evaluated whether short-term changes may be able to identify a high-risk subgroup of people with MCI. The authors have published a systematic review of this literature (Jutten et al. 2020) and appropriately refer to relevant citations here.Interpretation: Our findings suggest that short-term changes in cognition may be useful as part of a strategy to identify subsets of people with MCI who are at highest risk of conversion. Findings were clearest for memory and language. Domain-specific changes appeared to be independent from other biomarkers used to identify people at highest risk. Domain-specific changes did not appear to be better than changes in global cognition as measured by the MMSE or the CDR-sum of boxes.Future directions: Short-term changes in cognition may be useful to help identify a subgroup of people with MCI at highest risk of conversion to AD dementia. Future work could consider time frames shorter than the 6-month data we had available, better characterizing changes with more than 2 time points, or developing strategies that combine changes in cognition with other biomarkers to identify a subgroup of people with MCI to target for treatment. Show less

Alzheimer's disease and related dementias (ADRD) are major public health concerns. DNA methylation (DNAm)-based biomarkers such as GrimAge and PhenoAge predict aging and health risk, but were not designed to optimize prediction of cognitive decline. We used data from the 2016 Venous Blood Study of the Health and Retirement Study (HRS), a nationally representative cohort of U.S. adults aged ≥51 years (N = 3575 with high-quality DNAm). Epigenetic g scores were computed using CpG weights from a BayesR+ model of general cognitive ability developed in Generation Scotland. Cognitive function was measured with a modified version of the Telephone Interview for Cognitive Status (TICS) at each interview wave; 6-year incident dementia was defined using the validated Langa-Weir algorithm. Linear regression estimated associations with cognitive scores; logistic regression estimated 4-year dementia risk. Models were adjusted sequentially for demographics, education, parental education, APOE ε4 status, and blood-based neurodegeneration markers (NfL, GFAP, Aβ42/40, pTau181). Higher epigenetic g was associated with better baseline cognition (β=2.55, 95% CI 1.92-3.17) and cognition at the time DNAm was measured (β=2.30, 95% CI 1.62-2.99) after demographic adjustment. Associations attenuated but remained significant with education and parental education (β=1.23-1.89). Each unit increase in epigenetic g predicted 29% lower 6-year risk of dementia (fully adjusted HR=0.71). Results were robust to adjustment for APOE ε4 and neurodegeneration biomarkers. Epigenetic g is a scalable, blood-based marker of cognitive function and dementia risk that adds predictive value beyond demographics, socioeconomic indicators, APOE, and neuropathology. Its validation in a diverse, nationally representative U.S. cohort underscores its potential for early risk profiling and for research on social determinants of cognitive aging in cross-national samples. Show less

Long noncoding RNAs (lncRNAs) are involved in various biological events. Previously we reported that lncRNA CCDC26 controls myeloid leukemia cell proliferation and mortality by regulating the proto-oncogene KIT. However, the mechanism of lncRNA CCDC26 effects on carcinogenesis and cell differentiation remains unclarified. To investigate the mechanism of lncRNA CCDC26 activity, we analyzed its protein partners using the S1 aptamer/cross-linking-immunoprecipitation (S1-CLIP) experiment. We identified a cytoskeleton protein (vimentin), chromatin proteins (chromobox 1/5 transcription factors [CBX1 and CBX5]) and a nuclear splicing-related protein heterogeneous nuclear ribonucleoprotein C (HNRNPC) as its interaction partners. As lncRNA CCDC26 is ubiquitously present in the cell (in cytoplasm, nucleoplasm, and chromatin cellular fractions); these results evidence that lncRNA CCDC26 is a unique multifunctional lncRNA that functions by interacting with several proteins in multiple intracellular compartments. We further identified the sequence through which it interacts with proteins by using a series of truncated-lncRNA CCDC26 fragments and RNA immunoprecipitation (RIP) experiments. Furthermore, using RIP, we identified the vimentin domain required for the lncRNA CCDC26 binding. Notably, CCDC26 knockdown reduced CBX1/CBX5 binding at certain gene promoters, correlating with increased gene expression. These findings suggest that CCDC26 may regulate transcription by interacting with CBX1 and CBX5. Show less

Ochratoxin A (OTA) is a core environmental toxin that induces kidney injury by interfering with glomerular filtration, antioxidant defense, and tubular transport functions. Alginate oligosaccharides (AOS), as active substances from marine, carry natural antioxidant, anti-inflammatory and other biological activities. The purpose of this study is to explore the molecular network of AOS against nephrotoxicity caused by OTA. A total of 36 5-week male mice were randomly divided into three groups: the CON group, the OTA group (250 μg/kg B.W. OTA) and the AOS + OTA group (400 mg/kg B.W. AOS +250 μg/kg B.W. OTA). The treatment was continued for 21 d. OTA induced renal injury in mice, manifested by glomerular capsule blurring, lymphocytic infiltration, and mitochondrial damage in tubular epithelial cells. Treatment with AOS significantly alleviated these pathological changes. Multi‑omics analysis revealed that AOS activated the PPAR signaling pathway, upregulating key genes (Aldehyde Dehydrogenase 1 Family Member A3 ( This study reveal that AOS antagonizes OTA-induced nephrotoxicity in mice through PPAR signaling axis, thus providing new insight into the renal protection mechanism of marine active substances. Show less

With the aging population in China, research on preventing frailty is crucial. This study aims to investigate the independent and combined associations of the Dietary inflammatory index (DII) and physical activity (PA) with frailty among Chinese older adults. A total of 285 participants aged ≥60 years with 87 males and 186 females were recruited from Hunan Province. Daily moderate physical activity (MPA), vigorous physical activity (VPA) and light physical activity (LPA) were objectively measured using a triaxial accelerometer. A Food Frequency Questionnaire 25 (FFQ25) was used to assess the participants' dietary patterns, and DII was calculated. Six combined exposure groups were formed based on PA and DII: pro-inflammatory diet and insufficient PA group, neutral diet and insufficient PA group, anti-inflammatory diet and insufficient PA group, pro-inflammatory diet and sufficient PA group, neutral diet and sufficient PA group, and anti-inflammatory diet and sufficient PA group. Frailty was assessed using the Frailty Phenotype (FP), logistic regression analyzed the associations between dietary patterns, PA, and frailty. A total of 285 older adults participants were initially recruited, but 12 were excluded due to missing data. Consequently, 273 participants were included in the final analysis. Compared to individuals with insufficient PA, those with sufficient PA were associated with significantly lower odds of frailty (OR = 0.468, 95%CI = 0.242-0.907). Participants following an anti-inflammatory diet had significantly lower odds of frailty compared with those following a pro-inflammatory diet (OR = 0.467, 95%CI = 0.221-0.988). In the combined groups, frailty prevalence was significantly lower the group with anti-inflammatory diet and sufficient PA group (OR = 0.204, 95%CI = 0.072-0.583), compared with pro-inflammatory diet and insufficient PA group. The sensitivity analysis showed that the associations between anti-inflammatory diet and sufficient PA with frailty remained statistically significant, with the direction of the associations unchanged. These findings suggest that the results are robust. Our study indicates that adhering to an anti-inflammatory diet and maintaining sufficient PA may be associated with a lower likelihood of frailty. Achieving an adequate amount of PA and following a healthy dietary pattern may serve as potential preventive measures against frailty. Show less

Memory function is susceptible to decline with age, stress, and neurological diseases, highlighting the importance of exploring effective and sustainable strategies to enhance memory consolidation. Epinephrine plays a key role in memory consolidation; acute, moderate elevations enhance memory, while chronic high levels are inhibitory. Given the limitations of pharmacological interventions, this study aims to investigate exercise as a non-pharmacological means to promote post-learning memory consolidation by inducing acute epinephrine release, focusing on its mechanisms and optimized implementation strategies. This narrative review systematically reviews evidence from neurophysiology, molecular biology, and behavioral experiments and finds that exercise can safely and controllably activate the sympathetic-adrenal system, leading to a rapid rise in epinephrine. The release kinetics align highly with the critical time window for memory consolidation. Moderate-intensity aerobic exercise implemented within 30 min post-learning can significantly improve memory retention. The mechanisms involve not only epinephrine enhancing synaptic plasticity and LTP by activating hippocampal β-adrenergic receptors, but also synergistic effects across multiple systems, such as promoting osteocalcin signaling, upregulating BDNF expression, inducing neurogenesis, and optimizing cerebral metabolism and blood flow. Evidence suggests that exercise, as a non-pharmacological intervention, significantly enhances post-learning memory consolidation through the precise modulation of epinephrine release and multi-system synergy, offering both high efficacy and safety. Future research should focus on developing precise exercise prescriptions based on individual characteristics and leveraging wearable devices and digital technologies to improve intervention adherence and applicability, promoting its widespread use in educational and clinical settings. Show less

Alzheimer's disease (AD) is the most common type of dementia with a complex pathobiology. The clinically approved treatments against AD attempt to provide only symptomatic relief. Therefore, the current findings highlighted the neuroprotective effect and the potential signaling mechanism of quinic acid (1) and its amide derivatives (2-4) against phytohaemagglutinin (PHA)-induced neurotoxicity. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay was conducted to assess the proliferative potential of 1-4 which were observed to increase the viability of SH-SY5Y cells. Microscopic examination of the cells induced with PHA and post treated with the respective test compound showed that 1 as well as its derivatives (2-4) improved morphology of the cells and subside the toxic effects of PHA. Evaluation of reactive oxygen species (ROS) production demonstrated that the test compounds except 4 decreased PHA-induced ROS in SH-SY5Y cells. The mRNA expression analysis of IL-1β, TNF-α, p38-α, p38-β and the disease associated ADAM10 and BACE1 genes revealed that 1 and its derivatives (2-4) reduced the PHA-induced elevated levels of inflammatory molecules whereas the compounds did not positively modulate the expression of proteolytic secretases. Moreover, the compounds reduced the disease specific increased expression of amyloid beta (Aβ), phosphorylated tau and activated p38 MAPK observed through fluorescence microscopy. Show less

This study evaluated the neuroprotective potential of a combination therapy using liraglutide (LIRA), an antidiabetic agent, and rivastigmine (RIVA), a standard treatment for Alzheimer's disease (AD), in a rat model of aluminum chloride (AlCl₃)-induced AD. Male rats were divided into five groups: control, AD (AlCl₃,75 mg/kg for 60 days), RIVA-treated (1 mg/kg daily for 6 weeks), LIRA-treated (300 µg/kg daily for 6 weeks), and combination-treated (LIRA + RIVA). Cognitive function was assessed behaviorally, and hippocampal biomarkers related to AD-such as microtubule-associated protein Tau (MAPt), Beta-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1), Sequestosome 1 (SQSTM1/p62), and acetylcholinesterase (AChE) activity-were evaluated. Histopathological changes, immunohistochemistry, and transmission electron microscopy were also assessed. The levels of MAPt, BACE1, SQSTM1/p62, and AChE in the LIRA + RIVA group were 11.32 ± 0.467 ng/mL, 1069 ± 80.1 pg/mL, 408.7 ± 19.41 pg/mL, and 0.805 ± 0.342 µmol of acetylthiocholine iodide hydrolyzed/min/g of tissue, respectively. These levels were significant (p < 0.01) when compared with the AlCl Show less