Cerebrospinal fluid amyloid beta 42, total tau, and phosphorylated tau 181 are well accepted markers of Alzheimer's disease. These biomarkers better reflect disease pathogenesis compared to clinical d Show more
Cerebrospinal fluid amyloid beta 42, total tau, and phosphorylated tau 181 are well accepted markers of Alzheimer's disease. These biomarkers better reflect disease pathogenesis compared to clinical diagnosis. Here, we perform a genome wide association study meta-analysis including 18,948 individuals of European ancestry and identify 12 genome-wide significant loci across all three biomarkers, eight of them novel. We replicate the association of biomarkers with APOE, CR1, GMNC/CCDC50 and C16orf95/MAP1LC3B. Novel loci include BIN1 for amyloid beta and GNA12, MS4A6A, SLCO1A2 with both total tau and phosphorylated tau 181, as well as additional loci on chr. 8, near ANGPT1 and chr. 9 near SMARCA2. We also demonstrate that these variants have significant association with Alzheimer's disease risk, disease progression and/or brain amyloidosis. The associated genes are implicated in lipid metabolism independent of APOE, coupled with autophagy and brain volume regulation driven by total tau and phosphorylated tau 181 dysregulation. Show less
Effective real-time monitoring and tracking of lipid droplets (LDs) are essential for the precise diagnosis of atherosclerotic plaques and the assessment of pathological progression. However, viable s Show more
Effective real-time monitoring and tracking of lipid droplets (LDs) are essential for the precise diagnosis of atherosclerotic plaques and the assessment of pathological progression. However, viable strategies for Show less
The Lipoprotein(a) (LPA) rs3798220 and rs10455872 polymorphisms have been indicated to be involved with the coronary heart disease (CHD) susceptibility. However, there are still differences between th Show more
The Lipoprotein(a) (LPA) rs3798220 and rs10455872 polymorphisms have been indicated to be involved with the coronary heart disease (CHD) susceptibility. However, there are still differences between the individual studies. To explore the correlation of LPA gene rs3798220 and rs10455872 polymorphisms and CHD, the current meta-analysis was performed. The random or fixed effect genetic models were used to calculate the pooled odds ratios (ORs) and their corresponding 95 % confidence intervals (CI). A significant association was found between LPA rs3798220 polymorphism and CHD under allelic (OR: 1.488), recessive (OR: 1.543), dominant (OR: 1.534), homozygous (OR: 1.544), heterozygous (OR: 1.498) and additive genetic models (OR: 1.531). There was also a significant association between LPA rs10455872 polymorphism and CHD under allelic (OR: 1.607), dominant (OR: 1.751), heterozygous (OR: 1.723) and additive genetic models (OR: 1.686). LPA rs3798220 and rs10455872 polymorphisms were significantly associated with increased CAD risk. The persons carrying C allele of LPA rs3798220 and G allele of LPA rs10455872 polymorphisms might have higher CHD risk than the T allele of rs3798220 or A allele of rs10455872 carriers. Show less
We aim to examine prospective associations of longitudinal adherence to antihypertensive medication, A longitudinal cohort using 12-year survey data from wave 8 (2006) to wave 14 (2018) in the Health Show more
We aim to examine prospective associations of longitudinal adherence to antihypertensive medication, A longitudinal cohort using 12-year survey data from wave 8 (2006) to wave 14 (2018) in the Health and Retirement Study, an ongoing national survey recruiting community-dwelling adults aged ≥50 years in the United States. Longitudinal adherence to antihypertensive medication was evaluated during wave 8 (2006) to wave 10 (2010), based on self-reported antihypertensive medication use at each wave. Incident dementia cases were ascertained during wave 10 (2010) to wave 14 (2018) by combining self-reported diagnosis and standardized cognitive batteries, excluding prevalent cases during the medication adherence evaluation period. Cox proportional hazard regression was utilized to assess dementia risk, with adjusted hazard ratios (HR) and 95% CIs calculated, controlling for sociodemographic characteristics, socioeconomic status indicators, lifestyle factors, and clinical conditions, as well as blood pressure measurements. A total of 18 469 participants were screened, after which 11 835 participants (mean [SD] age: 66.2 [10.1] years; men: 40.6%) were included, with 1136 incident dementia cases. After controlling blood pressure and other known risk factors, hypertension participants who persistently adhered to antihypertensive medication during follow-up had a 27% lower dementia risk (HR, 0.73 [95% CI, 0.61-0.87]) than the low adherence group, which was more evident than the associations between baseline antihypertensive medication use and dementia. The difference in dementia risk was insignificant when comparing the high adherence group with the normotension group (HR, 1.03 [95% CI, 0.88-1.21]). The results were consistent in non- Persistently adhering to antihypertensive medication was consistently associated with a lower subsequent dementia risk in community-dwelling middle-aged and older adults. Show less
Tripartite motif-containing protein 21 (TRIM21), an E3 ubiquitin ligase of the TRIM superfamily, modulates critical cellular processes including ubiquitination, autophagy, and oxidative stress respons Show more
Tripartite motif-containing protein 21 (TRIM21), an E3 ubiquitin ligase of the TRIM superfamily, modulates critical cellular processes including ubiquitination, autophagy, and oxidative stress response. Accumulating evidence highlights its context-dependent regulatory roles in hepatocellular carcinoma (HCC)-the most prevalent primary liver malignancy with high mortality and limited therapeutic efficacy. This review systematically summarizes the core mechanisms by which TRIM21 orchestrates HCC progression: ① Autophagy regulation: TRIM21 modulates HCC autophagy via multiple axes, including CCR4-NOT complex (TNKS1BP1/CNOT4)-mediated substrate ubiquitination, ATG14-dependent autophagosome initiation, and RETREG1-driven reticulophagy, with context-dependent effects on tumor proliferation. ② Drug resistance: TRIM21 enhances oxaliplatin sensitivity by ubiquitinating and degrading G6PD (the rate-limiting enzyme of the pentose phosphate pathway), while its role in sorafenib resistance involves dual pathways-the MST1/YAP axis and the ApoE/cholesterol/PI3K-AKT cascade. ③ Metastasis suppression: TRIM21 restricts HCC invasion and metastasis by ubiquitinating key oncoproteins, preserving epithelial integrity and inhibiting mesenchymal transition. ④ Reactive oxygen species (ROS) balance: TRIM21 regulates oxidative stress in HCC via the SQSTM1/p62-Keap1-NRF2 axis, coordinating with HIF1α to modulate antioxidant responses and tumor cell survival. Additionally, we discuss the regulatory significance of TRIM21 in HCC associated with hepatitis B virus (HBV) infection (via HBx/DNA polymerase ubiquitination) and nonalcoholic steatohepatitis (NASH) (via suppressing lipogenic enzymes to reduce steatosis-driven carcinogenesis). This review provides a theoretical basis for TRIM21 as a potential diagnostic marker and therapeutic target for HCC. Show less
The paraventricular hypothalamus (PVH) controls behavioral and physiologic processes, including appetite, social behavior, autonomic outflow, and pituitary hormone secretion. However, molecular marker Show more
The paraventricular hypothalamus (PVH) controls behavioral and physiologic processes, including appetite, social behavior, autonomic outflow, and pituitary hormone secretion. However, molecular markers for centrally projecting PVH neuron populations remain largely undefined, and a complete census of PVH cell types has not been established. Therefore, we performed extensive single-cell/nucleus RNA sequencing to catalog PVH neuron subtypes and multiplexed error-robust fluorescence in situ hybridization (MERFISH) to map them spatially. Our spatial transcriptomic atlas resolves 26 Sim1 Show less
Brain-derived neurotrophic factor (BDNF) plays an important role in the survival of dopaminergic neurons. Clinical studies have suggested that serum BDNF levels are reduced in patients with Parkinson' Show more
Brain-derived neurotrophic factor (BDNF) plays an important role in the survival of dopaminergic neurons. Clinical studies have suggested that serum BDNF levels are reduced in patients with Parkinson's disease (PD). However, no study has investigated peripheral BDNF levels and BDNF Val66Met polymorphism in the prodromal stage of PD and their relationship with disease conversion. In total, 120 patients with video-polysomnography confirmed isolated REM sleep behavior disorder (iRBD) and 120 healthy controls (HCs) were enrolled. Genetic analyses were performed, and plasma levels of BDNF were measured. All patients with iRBD underwent comprehensive clinical testing, and 107 iRBD patients were prospectively followed up. Plasma BDNF levels were significantly lower in the iRBD group than in HCs (18,878.85 pg/mL vs. 24,649.85 pg/mL, p = 0.002), but no differences were observed in BDNF Val66Met carrier rates between the two groups. Plasma BDNF levels did not differ significantly between BDNF Val66Met carriers and noncarriers. Notably, higher plasma BDNF levels were associated with an increased risk of short-term disease conversion (hazard ratio = 3.418, 95% CI: 1.520-7.684, p = 0.003), whereas BDNF Val66Met carrier rates showed no such association. Our findings suggest that plasma BDNF is significantly associated with iRBD and may likely serve as a prognostic biomarker for the development of neurodegenerative disease. However, the BDNF Val66Met polymorphism may not be involved in the pathogenesis of iRBD as well as phenoconversion in the studied population. Show less
Depression is a debilitating psychiatric disorder with high prevalence and suicide risk, imposing significant burdens on global health. Against this global health burden, the active ingredients of Gek Show more
Depression is a debilitating psychiatric disorder with high prevalence and suicide risk, imposing significant burdens on global health. Against this global health burden, the active ingredients of Gekko gecko Linnaeus (AIGG), a traditional Chinese medicine (TCM), have shown empirical antidepressant effects. However, their specific pharmacological mechanisms remain unclear. This study systematically elucidated the antidepressant mechanisms of AIGG by integrating GC-MS-based component analysis, network pharmacology, molecular docking, and a corticosterone (CORT)-induced depressive mouse model. GC-MS identified 10 bioactive compounds (including fatty acids) in AIGG. Network pharmacology screening of 51 potential targets revealed significant enrichment in synaptic transmission and cAMP pathways. Molecular docking confirmed strong binding affinities between AIGG-derived compounds and key targets. In vivo experiments demonstrated that AIGG significantly reversed depression-like behaviors in both forced swim and tail suspension tests, suppressed Interleukin-6 (IL-6), tumor necrosis factor α (TNF-α), and elevated β-nerve growth factor (β-NGF) levels, attenuated neuroinflammatory infiltration and neuronal apoptosis in brain tissue, and upregulated protein expression of protein kinase cAMP-activated catalytic subunit alpha (PRKACA), brain-derived neurotrophic factor (BDNF), and postsynaptic density protein 95 (PSD95). The study confirmed that AIGG alleviates depression by activating the cAMP-PRKACA-BDNF axis to restore synaptic plasticity, providing a novel natural product-based strategy for treatment of the resistant depression. Show less
Apolipoprotein E (APOE) ε4 is the strongest genetic risk factor for Alzheimer's disease (AD). However, it is known that other pathways independent of APOE also play a role in AD. Disentangling APOE-de Show more
Apolipoprotein E (APOE) ε4 is the strongest genetic risk factor for Alzheimer's disease (AD). However, it is known that other pathways independent of APOE also play a role in AD. Disentangling APOE-dependent and independent effects is instrumental for understanding the biology of AD. We conducted an APOE-stratified multi-omic analysis in multiple large datasets to identify AD-associated plasma proteins and metabolites. More than 64% of the identified proteins were not found in non-APOE stratified studies, and 17% of the proteins showed APOE-specific trends. Mitochondrial dysfunction was associated in AD independently of APOE and was accompanied by disruptions in glucose and lipid metabolism and cell death and increased in inflammatory signaling activation. Lipid upregulation was found in AD cases when compared with controls with the same APOE genotype, indicating that additional factors beyond APOE affect lipid regulation and AD risk. These findings may be informative in guiding the development of effective medications for AD. Show less
Gene fusions are common primary drivers of pediatric leukemias and are the result of underlying structural variants (SVs). Current clinical workflows to detect such alterations rely on a multimodal ap Show more
Gene fusions are common primary drivers of pediatric leukemias and are the result of underlying structural variants (SVs). Current clinical workflows to detect such alterations rely on a multimodal approach, which often increases analysis time and overall cost of testing. In this study, we used long-read sequencing (lrSeq) as a proof-of-concept to determine whether clinically relevant (cr) SVs could be detected within a small (n = 17) pediatric leukemia cohort. We show that this methodology successfully determined all known crSVs (n = 5/5) detected through routine clinical testing. This approach also identified crSVs that resulted in the classification of a leukemia genetic subtype for four additional patients (n = 4/12), such as an ins(11;10)(q23.3;p12p12) forming a KMT2A::MLLT10 fusion, that were missed by routine clinical approaches. This study demonstrates the diagnostic potential of lrSeq as an assay for SV detection in pediatric leukemia and supports lrSeq as a valuable tool for the accurate detection of crSVs. Show less
Disruption of circadian rhythms is increasingly recognized as a contributor to cognitive dysfunction, but its role in gestation-associated cognitive changes remains unexplored. Here we combine human c Show more
Disruption of circadian rhythms is increasingly recognized as a contributor to cognitive dysfunction, but its role in gestation-associated cognitive changes remains unexplored. Here we combine human cognitive screening with a comprehensive longitudinal mouse model to investigate whether gestational cognitive impairment and postpartum recovery are coupled with disruption and restoration of hippocampal circadian rhythms. Cognitive function was assessed in pregnant and postpartum women using the Montreal Cognitive Assessment (MoCA) and Mini-Mental State Examination (MMSE). In mice, four reproductive stages were compared: control, gestation, 1 month postpartum, and 3 months postpartum. Serum gonadotropins and sex hormones levels were quantified using ELISA. Home-cage locomotor activity was recorded over 48 h under a 12 h:12 h light-dark cycle. Hippocampal-dependent memory was evaluated using the novel object recognition test and Barnes maze at Zeitgeber times ZT6 (day) and ZT18 (night). Hippocampal amyloid β (Aβ) deposition was visualized via immunofluorescence; protein expression of amyloid precursor protein (APP), β-site amyloid precursor protein cleaving enzyme-1 (BACE1), and phosphorylated tau was measured by Western blots. Hippocampal clock gene expression was quantified by RT-qPCR at six time points; circadian parameters (mesor, amplitude, acrophase) were derived by cosinor analysis and compared between groups. Human cognitive screening confirmed modest gestational decline with postpartum recovery. In mice, gestation disrupted daily locomotor activity rhythms and reduced nocturnal preference; both partially recovered by 1 month and fully by 3 months postpartum. Behaviourally, pregnancy impaired the normal day-night difference and performance in novel object exploration and Barnes maze, which recovered progressively. At the molecular level, gestation increased hippocampal APP and BACE1 expression, elevated Aβ42 deposition, and induced tau hyperphosphorylation at multiple sites-hallmarks of Alzheimer's disease-related pathology. These alterations partially reversed by 1 month postpartum and normalized by 3 months. Hippocampal clock genes maintained 24 h rhythmicity, but gestation induced gene-specific phase shifts, amplitude reductions, and mesor alterations. These parameters showed gradual, gene-dependent normalization postpartum. Gestational cognitive impairment and postpartum recovery are associated with reversible disruption and restoration of both hippocampal circadian rhythms and Alzheimer's disease-related molecular pathology. These findings are correlational in nature and provide a foundation for future causal investigations. Show less
Chronic pain, marked by nociceptive sensitization and maladaptive neuroplasticity, affects 30% of the global population with escalating socioeconomic burdens. Epidemiological data show a 2-3-fold incr Show more
Chronic pain, marked by nociceptive sensitization and maladaptive neuroplasticity, affects 30% of the global population with escalating socioeconomic burdens. Epidemiological data show a 2-3-fold increase in neuropsychiatric co-morbidities among individuals with chronic pain, where epigenetic dysregulation serves as a key mechanism linking ongoing pain to emotional disorders. This review systematically explores epigenetic signatures in supraspinal integration hubs, notably the limbic-paralimbic networks and prefrontal regulatory circuits. The identified epigenetic signatures encompass dysregulation of DNA methyltransferases (DNMTs), RNA modifications, histone post-translational modifications and locus-specific alterations, including aberrant methylation at the brain-derived neurotrophic factor (BDNF), opioid μ receptor and transient receptor potential ankyrin 1 (TRPA1) gene loci. Additionally, they involve dysfunction of the glucocorticoid receptor (GR)/corticotropin-releasing factor (CRF) axis via epigenetic modulation. Building on these findings, we evaluate therapeutic strategies addressing epigenetic dysregulation. While preclinical data demonstrate the efficacy of histone deacetylase (HDAC) and DNMT inhibitors, clinical translation faces significant barriers, including limited blood-brain barrier permeability. Notably, our analysis highlights the benefits of combining pharmacological interventions with non-invasive neuromodulation for enhanced co-morbidity management. Looking forward, this review proposes innovative approaches that leverage CRISPR-based chromatin editing platforms, biomimetic nanocarriers for neuron-specific delivery and closed-loop neuromodulation integrating real-time biomarker feedback, collectively establishing a precision medicine framework for pain or neuropsychiatric co-morbidities. Show less
Hypertensive heart disease (HHD) and hypertrophic cardiomyopathy (HCM) are characterized by left ventricular hypertrophy and diastolic dysfunction. Despite overlapping remodeling features, their disti Show more
Hypertensive heart disease (HHD) and hypertrophic cardiomyopathy (HCM) are characterized by left ventricular hypertrophy and diastolic dysfunction. Despite overlapping remodeling features, their distinct mechanisms and therapeutic responses remain unclear. This study integrated genetic, imaging, and proteomic data to identify key mediators underlying β1-adrenergic receptor blockers (β1-blockers)-related therapeutic heterogeneity between HHD and HCM. Genetic instruments for β1-blockers were derived from two genome-wide association studies and integrated with cardiac magnetic resonance radiomic traits and plasma proteomic data from the UK Biobank, along with disease outcomes from FinnGen. A refined two-stage network Mendelian randomization framework with pleiotropy-robust estimators identified mediators of treatment response. To further elucidate their biological and clinical significance, additional analyses were performed, including drug-target profiling, molecular docking, adverse events (AEs) assessment, and drug prediction. We identified three types of imaging features and ten mediator proteins that contributed to therapeutic responses in HHD and HCM. These mediators were categorized as either mediating (aligned with therapeutic outcomes) or suppressing (opposing therapeutic outcomes). Left ventricular regional radial strain acted as a suppressing factor in HHD but a mediating factor in HCM, whereas end-diastolic and end-systolic volumes consistently showed suppressing effects in both. Regional myocardial wall thickness also exerted a suppressing role in HCM. Among protein mediators, APOE, CGREF1, ITGA5, LSP1, NOS3, and NPPB were linked to HHD, whereas DUSP13, ITGA11, NID1, and SERPINA4 were related to HCM. Specifically, APOE, ITGA5, NOS3, NPPB, DUSP13, and ITGA11 acted as mediating factors, while CGREF1, LSP1, NID1, and SERPINA4 served as suppressing ones. These findings remained robust after pleiotropy adjustment and other genetic analyses. Molecular docking revealed interactions between ADRB1, the β1-blockers target, and downstream proteins, while drug prediction identified eight potential compounds linked to these mediators. Additionally, AE analyses indicated that some targets, such as DUSP13, could both mitigate and aggravate common AEs while contributing to cardiac therapy. This integrative multi-omics analysis revealed distinct imaging and proteomic mechanisms of genetically proxied β1-blockers in HHD and HCM, providing genetic evidence for differential therapeutic responses and highlighting molecular targets for precision cardiovascular therapy. Show less
Major depressive disorder (MDD) in adolescents is a critical public health concern, yet objective diagnostic biomarkers remain lacking. We conducted an integrative lipidomics study across human cohort Show more
Major depressive disorder (MDD) in adolescents is a critical public health concern, yet objective diagnostic biomarkers remain lacking. We conducted an integrative lipidomics study across human cohorts and a chronic unpredictable mild stress (CUMS) rat model. Targeted UPLC-MS/MS profiling was applied to a training cohort (95 MDD, 40 controls), and untargeted UPLC-HRMS profiling to an independent cohort (56 MDD, 37 controls). Candidate biomarkers were identified using univariate tests, partial least squares discriminant analysis, and three feature-selection methods (Boruta, LASSO, RFE), with predictive performance evaluated by cross-validation and external replication. Translational relevance was examined in CUMS rats through behavioral assays and lipidomic profiling of serum and brain tissues. Pathway enrichment and regression models explored metabolic context and clinical associations. In the training cohort, we found that 244 lipids were significantly altered, highlighting altered glycerophospholipid, glycerolipid, and sphingolipid metabolism. A 29-lipid panel achieved 90.4% cross-validation accuracy, while a reduced 7-lipid subset reached 94.8%. In the validation cohort, an 8-lipid panel achieved 71.2% accuracy, and a minimal 2-lipid set-LPA(18:2) and SPH(d16:1)-reached 72.1%. Cross-species analysis confirmed consistent downregulation of SPH(d16:1) in serum of both humans and rats, and of LPC(0:0/16:0) specifically in the rat prefrontal cortex. Regression analyses linked sex, age, and anxiety severity to lipid alterations. This cross-platform, cross-species study identifies reproducible lipid signatures of adolescent MDD, highlights SPH(d16:1) and LPC(0:0/16:0) as translational biomarkers, and implicates glycerophospholipid metabolism in MDD pathophysiology, providing a foundation for biomarker-guided diagnostics and therapeutics. Show less
To investigate the therapeutic mechanisms of miR-9-5p-overexpressing human umbilical cord mesenchymal stromal cells (hUC-MSCs) in neonatal rat models of hypoxic-ischemic brain damage (HIBD). Fresh neo Show more
To investigate the therapeutic mechanisms of miR-9-5p-overexpressing human umbilical cord mesenchymal stromal cells (hUC-MSCs) in neonatal rat models of hypoxic-ischemic brain damage (HIBD). Fresh neonatal umbilical cords were collected to isolate and culture human umbilical cord mesenchymal stromal cells (hUC-MSCs). Recombinant adenovirus was used to amplify miR-9-5p and transduce hUC-MSCs, generating miR-9-5p-overexpressing cells. Functional assessments included: ELISA to evaluate secretory function (e.g., neurotrophic and anti-inflammatory factors), real-time cell analysis to measure proliferation capacity, Transwell and Dunn chamber assays to assess chemotactic migration ability. Healthy 7-day-old Sprague-Dawley (SD) rats of both sexes were randomly allocated into four groups (n = 12/group, with 4 rats per group assigned to TTC staining, Western blot, or Morris water maze assay, respectively): Sham-operated control group (mock surgery), Hypoxic-ischemic brain damage (HIBD) model group, miR-9-5p-hUC-MSCs treatment group, and Adenovirus-transduced hUC-MSCs (Ad-hUC-MSCs) treatment group. The HIBD model was induced in groups 2-4. At 24 h post-modeling, 1×10 Spindle-shaped and polygonal adherent cells emerged within 3-5 days following umbilical cord tissue block inoculation, with flow cytometric analysis confirming their identity as mesenchymal stromal cells (MSCs). Compared to the Ad-hUC-MSCs treatment group, miR-9-5p enhanced the secretion of neuroreparative and anti-inflammatory factors (e.g., NGF, BDNF, IL-6) in hUC-MSCs while suppressing pro-inflammatory cytokines (e.g., IL-1, IL-2) (p < 0.05). Furthermore, miR-9-5p significantly promoted hUC-MSCs proliferation and augmented the chemotactic migratory capacity of miR-9-5p-hUC-MSCs. At 48 h post-transplantation in the miR-9-5p-hUC-MSCs group, the sham-operated controls showed no detectable cerebral infarction, whereas the model group exhibited distinct pale infarct foci occupying 33.15% ± 4.38% of total brain volume (vs. controls, p < 0.05), indicating severe cerebral injury. Both miR-9-5p-hUC-MSCs and Ad-hUC-MSCs treatments markedly reduced infarct volumes to 14.85% ± 2.79% and 19.11% ± 4.57%, respectively, with the miR-9-5p-hUC-MSCs group demonstrating a statistically superior therapeutic effect compared to Ad-hUC-MSCs (p < 0.05). Transplantation of either Ad-hUC-MSCs or miR-9-5p-hUC-MSCs significantly improved short- and long-term neurobehavioral outcomes in hypoxic-ischemic brain damage (HIBD) rats. At 48 h post-HIBD induction, upregulated expression of Beclin-2 and Caspase-3 proteins was observed in brain tissue. Notably, these elevated protein levels were attenuated following treatment with miR-9-5p-hUC-MSCs or Ad-hUC-MSCs. MiR-9-5p enhances the secretion of immunomodulatory factors and improves the migratory and proliferative capacities of hUC-MSCs. Overexpression of miR-9-5p promotes in vivo homing of hUC-MSCs, which mitigate cerebral injury and exert neuroprotective and reparative effects through dual mechanisms: modulating immune responses and providing neurotrophic support. Furthermore, hUC-MSCs significantly reduce cerebral infarct volume in hypoxic-ischemic brain damage (HIBD) rats and downregulate levels of apoptotic proteins (Beclin-2 and Caspase-3) in brain tissue, demonstrating potent cerebroprotective effects. Show less
Sepsis is a syndrome caused by the host's inflammatory response to an infection with an unknown mechanism. This study aimed to identify differentially expressed genes (DEGs) potentially involved in th Show more
Sepsis is a syndrome caused by the host's inflammatory response to an infection with an unknown mechanism. This study aimed to identify differentially expressed genes (DEGs) potentially involved in the development and recovery of tracheal injury from septic shock. Nine New Zealand white rabbits were randomized to control (CON), septic shock model (SS), and septic shock norepinephrine treatment (SSNE) groups (each group n = 3). The SS and SSNE groups were injected with lipopolysaccharide to induce septic shock. The SSNE group was administered Ringer lactate with norepinephrine to maintain normal blood pressure. All animals underwent cuffed endotracheal intubation for 2 h. The injured tracheal segment was harvested. RNA sequencing was performed to identify the DEGs, followed by bioinformatics analysis, and pathological staining (both HE and Masson) was performed for pathological evaluation. Bioinformatics analysis included principal component analysis (PCA), gene set enrichment analysis (GSEA), and protein-protein interaction (PPI) network construction. Key findings were validated by qRT-PCR and immunohistochemistry. We obtained 124 upregulated and 28 downregulated DEGs in SS vs. CON groups, along with 60 upregulated and 178 downregulated DEGs in SSNE vs. SS groups. The pathological score showed that trachea tissue in the SS group had the highest score. The protein-protein interaction (PPI) prediction identified APOB and CD36 as the hub genes. The molecular experiments further confirmed that at mRNA and protein levels, APOB was significantly upregulated, while CD36 was significantly downregulated. Subsequent qRT-PCR and immunohistochemical analyses confirmed that APOB expression was significantly upregulated while CD36 was downregulated in the septic shock group, a trend partially reversed by norepinephrine treatment. Our study results suggest that APOB and CD36 may be involved in the pathogenesis of tracheal injury recovery in septic shock patients treated with NE. Not applicable. Show less
Hypertrophic cardiomyopathy (HCM) arises from genetic mutations in sarcomere proteins, resulting in major structural abnormalities and limited treatment options. Patients with HCM had reduced expressi Show more
Hypertrophic cardiomyopathy (HCM) arises from genetic mutations in sarcomere proteins, resulting in major structural abnormalities and limited treatment options. Patients with HCM had reduced expression of the FGF12 (fibroblast growth factor 12), but its precise functional role remains unclear. To explore FGF12's function and interactions, we utilized clustered regularly interspaced short palindromic repeats-Cas9 technology in cardiomyocytes derived from human induced pluripotent stem cells-induced cardiomyocytes, as well as in other cell lines and mouse models (MYH7 First, we observed a decrease in FGF12 expression and a difference in its subcellular localization in patients with HCM compared with healthy volunteers. In hypertrophic mouse models, injecting adeno-associated virus 9 reduced myocardial hypertrophy. FGF12 binds to calmodulin and inhibits its phosphorylation. This interaction also suppresses the expression and phosphorylation of downstream proteins, including CaMKII, ERK1/2, CREB1, and MCU. The nuclear-localization FGF12 binds to the promoter region of CREB1. FGF12 inhibits the expression of the CREB1-MCU axis expression, leading to reductions in both mitochondrial Ca This study reveals a pathological mechanism associated with HCM linked to FGF12. FGF12, located outside the nucleus, suppresses the expression of metabolism-related genes by reducing the phosphorylation levels within the calmodulin-ERK1/2-CREB1-MCU axis. In contrast, the nuclear localization of FGF12 facilitates its binding to the promoter regions of CREB1, inhibiting CREB1 expression. This dual action maintains cardiomyocyte function and mitochondrial homeostasis. Our findings position FGF12 as a promising therapeutic target for HCM. Show less
This study investigated the impact of This retrospective case-control study involved 628 CAD patients and 628 matched controls without CAD. ApoE genotyping was conducted using PCR-chip technology, and Show more
This study investigated the impact of This retrospective case-control study involved 628 CAD patients and 628 matched controls without CAD. ApoE genotyping was conducted using PCR-chip technology, and genotype and allele frequencies were compared between groups. Multivariate logistic regression analyzed the link between ApoE polymorphisms and CAD risk in populations at middle and high altitudes. The data revealed significant differences in These findings validated that the 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 diag Show more
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
Adolescence is a critical period for rapid emotional and cognitive development. Depression and cognitive impairment frequently co-occur in this population, yet their comorbidity patterns and symptom-l Show more
Adolescence is a critical period for rapid emotional and cognitive development. Depression and cognitive impairment frequently co-occur in this population, yet their comorbidity patterns and symptom-level interactions remain insufficiently explored. A total of 2,244 students (mean age = 16.8 ± 0.84 years; 1,218 males, 1,026 females) from a high school in Heilongjiang Province, China, were recruited. Depressive symptoms and cognitive impairment were assessed using the Center for Epidemiologic Studies Depression Scale (CES-D) and the Perceived Deficits Questionnaire–Depression (PDQ-D). Latent profile analysis (LPA) was applied to identify subgroups, followed by network analysis to examine central symptoms (expected influence, EI), bridge symptoms (bridge expected influence, BEI), and network differences (NCT). The optimal LPA model identified three comorbidity subgroups: low, moderate, and high. NCT revealed significant differences in network structure and global strength between the low–moderate (S = 1.514, Adolescent Depression and Cognitive Impairment can be classified into low, moderate, and high comorbidity subgroups. Somatic symptoms emerged as the central symptom, while prospective memory impairment and interpersonal problems were identified as key bridge symptoms, suggesting potential intervention targets for early screening and stratified treatment. Not applicable. The online version contains supplementary material available at 10.1186/s12888-026-07946-w. Show less
Endothelial cells under oxidative stress and inflammation are vital contributors to the progression of atherosclerosis. Although Orientin possesses antioxidant and anti-inflammatory activities, the ef Show more
Endothelial cells under oxidative stress and inflammation are vital contributors to the progression of atherosclerosis. Although Orientin possesses antioxidant and anti-inflammatory activities, the effects of Orientin on oxidized low-density lipoprotein and high glucose (ox-LDL/HG)-triggered endothelial cell injury and diabetes-accelerated atherosclerosis remain unclear. ApoE Show less
AllergoOncology has emerged as an interdisciplinary field exploring the interaction between allergic diseases and cancer; however, the lack of stable in vivo models has limited mechanistic investigati Show more
AllergoOncology has emerged as an interdisciplinary field exploring the interaction between allergic diseases and cancer; however, the lack of stable in vivo models has limited mechanistic investigations. This study aimed to establish an experimental animal model to explore the impact of systemic allergic responses on tumor progression and to provide preliminary insights into the regulatory role of allergy in cancer development. An ovalbumin (OVA)-induced systemic allergy tumor-bearing mouse model (OVA-TM) was established by OVA sensitization followed by subcutaneous implantation of CT26 colon cancer cells. Tumor growth, immune responses, and behavioral changes were systematically evaluated. Tumor immune microenvironment alterations were assessed using immunological and histological analyses. Transcriptomic profiling and mass spectrometry imaging (MSI) were integrated to investigate immune-related metabolic alterations. Human tumor survival datasets were used to validate the prognostic relevance of differentially expressed genes (DEGs), and enrichment analyses of allergy- and cancer-associated genes were performed using humanized databases. OVA-induced systemic allergy significantly suppressed tumor growth and promoted immune cell infiltration, particularly CD3 This study establishes a practical in vivo model for AllergoOncology and demonstrates that systemic allergic responses can modulate tumor progression through immune activation, apoptosis, and inflammation-metabolism axis reprogramming, providing a foundation for future mechanistic and therapeutic studies. Show less
Brain metastasis significantly worsens prognosis in late-stage cancer., with Its treatment hindered by the blood-brain barrier (BBB) and an immunosuppressive tumor microenvironment. Within this enviro Show more
Brain metastasis significantly worsens prognosis in late-stage cancer., with Its treatment hindered by the blood-brain barrier (BBB) and an immunosuppressive tumor microenvironment. Within this environment, tumor-associated macrophages (TAMs) represent the predominant immune population. Through their roles in immune modulation, angiogenesis, and tumor invasion, TAMs are critical drivers of disease progression. TAMs are highly heterogeneous. While traditionally categorized into M1 (anti-tumor) or M2 (pro-tumor) phenotypes, this dichotomy is an oversimplification. Recent single-cell studies have revealed a spectrum of functional subpopulations, such as lipid-associated, interferon-responsive, and pro-angiogenic TAMs, with M2-like states typically prevailing to mediate immunosuppression. This review explores the diversity and functions of TAMs in brain metastasis. We first detail their biological characteristics, including origins, heterogeneous subtype classifications (e.g., lipid-associated macrophages that extend beyond the simple M1/M2 dichotomy), and polarization states. We further discuss how polarization is regulated by signaling pathways (e.g., STAT, NF-κB) and microenvironmental factors (e.g., hypoxia, metabolic reprogramming). We examine TAM roles from pre-metastatic niche formation to tumor colonization, using breast and lung cancer brain metastases to illustrate how TAMs disrupt the BBB and facilitate immune evasion through molecules like ANGPTL4 (angiopoietin-like 4) and MMP9. Key pathways of TAM-tumor cell interactions, including neuro-cancer interactions, immune-metabolic regulation, and exosome-mediated communication, are also discussed. Targeting TAMs offers promising therapeutic avenues. These strategies include reprogramming TAMs (e.g., using CSF1R inhibitors), combining TAM-targeted therapy with immune checkpoint inhibitors, and developing novel approaches such as nanotechnology and CAR-macrophages. However, several challenges remain, including TAM heterogeneity, lack of targeting specificity, and the obstacle of BBB delivery. Future research should leverage technologies like single-cell sequencing and spatial transcriptomics to decode TAM heterogeneity, and develop personalized treatments based on biomarkers such as GPNMB and TRAIL, aiming to improve patient outcomes in brain metastasis. Show less
Lecanemab, an anti-amyloid beta (Aβ) protofibril antibody, was introduced in China in 2024, but its real-world performance remains unknown. In this prospective, multicenter study across 21 sites, 261 Show more
Lecanemab, an anti-amyloid beta (Aβ) protofibril antibody, was introduced in China in 2024, but its real-world performance remains unknown. In this prospective, multicenter study across 21 sites, 261 Alzheimer's disease patients (mild cognitive impairment to moderate dementia) received biweekly lecanemab (10 mg/kg). A matched Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort served as comparator. Cognitive tests, plasma biomarkers, and optional amyloid/tau positron emission tomography (PET) were assessed over 6 months. Lecanemab significantly attenuated cognitive decline versus ADNI. Plasma Aβ42, Aβ40, phosphorylated tau 217 (p‑tau217), glial fibrillary acidic protein (GFAP), and ratios showed robust changes; a p‑tau217 reduction correlated with amyloid PET clearance (mean -22.1 Centiloid; 29.2% turned amyloid-negative). Apolipoprotein E (APOE) ε4 non-carriers showed greater improvements. Infusion reactions occurred in 11.1% and amyloid-related imaging abnormalities in 9.2% (1.6% symptomatic), with no stage-related safety differences. Lecanemab was effective and well tolerated in real-world Chinese patients. Plasma p‑tau217 may serve as a sensitive, minimally invasive treatment-response biomarker. Show less
To characterize ultra-processed food (UPF) circulating metabolic signatures associated with Crohn's disease (CD) and to localize key metabolic mediators linking UPF intake to CD risk. Prospective coho Show more
To characterize ultra-processed food (UPF) circulating metabolic signatures associated with Crohn's disease (CD) and to localize key metabolic mediators linking UPF intake to CD risk. Prospective cohort study. Two large multi-center cohorts (UK Biobank [UKB] and Whitehall II [WHII] study) across the UK and an Eastern multi-center cohort ONE-IBD Study from China. UK Biobank discovery cohort (n=10,229) for signature derivation, internal validation cohort (n=91,306), external validation cohort Whitehall-II (n=7,893), and three additional cohorts (two Western and ONE-IBD) for validation of key metabolic drivers. Primary outcomes were UPF-related circulating metabolic signatures and their associations with CD risk; secondary outcomes included evidence supporting causal roles of candidate metabolites and genetic pathways assessed by Mendelian randomization, colocalization, and gene-environment analysis. A UPF metabolic signature of 73 metabolites was constructed and validated across cohorts (Spearman ρ: 0.20-0.25). More pronounced UPF metabolic signature was associated with increased CD risk (HR The adverse effects of UPF on CD risk may be driven by a relative deficiency of protective metabolites such as DHA, apart from additive harm to metabolic depletion. This reframes UPF-related risk and highlighting potential targets for precision nutrition in CD prevention. 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 Show more
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
The brain is vulnerable to DNA damage and cardiometabolic risk. Yet, whether genetic variation in DNA repair interacts with cardiometabolic factors to explain cognitive variability remains unclear. Pa Show more
The brain is vulnerable to DNA damage and cardiometabolic risk. Yet, whether genetic variation in DNA repair interacts with cardiometabolic factors to explain cognitive variability remains unclear. Participants (n = 376,533) of white-British ancestry from the UK biobank with cognitive, neuroimaging, and whole-exome sequencing data were included. Six cognitive outcomes were assessed: fluid intelligence (FIQ), symbol-digit matching task (SDMT), visual matching (MATCH), trail making (TRAIL1 and TRAIL2), and prospective memory (PMEM). Seven brain regions of interest were assessed: total brain (TBV), grey matter (GMV), left and right white matter (LWM/RWM), left and right hippocampi (LHC/RHC), and white matter hyperintensities (WMH) volumes. A total of 3487 genetic variants across 39 DNA repair genes were tested. SNP and gene/gene-set level associations were tested using regression models adjusted for age, sex, APOE ε4, ancestry, and outcome-specific covariates. Genetic interactions with a multidimensional cardiometabolic risk index (CMRI), encompassing established risk factors, were assessed. We detected 107 genetic variants (mostly extremely rare) across 36 DNA repair genes associated at Bonferroni-significance (p ≤ 1.4 × 10 Show less
Convergent evolution offers a unique lens through which to explore the molecular underpinnings of significant phenotypic transformations. Similar selective pressures likely drove the evolution of anal Show more
Convergent evolution offers a unique lens through which to explore the molecular underpinnings of significant phenotypic transformations. Similar selective pressures likely drove the evolution of analogous milk traits in sheep and goats. Consequently, the current study aimed to identify common selection signals for milk traits across dairy and non-dairy breeds of sheep and goats worldwide. In this study, a total of 308 whole-genome sequences from diverse sheep (n = 108) and goat (n = 200) breeds, including both dairy and non-dairy types, across the world were utilized. The population structure and genetic diversity of dairy and non-dairy sheep and goat breeds were characterized. Species-specific genes associated with milk traits, such as POU2F1, ABCD2, TRNAC-GCA in sheep and PRPF6, VPS13C, TPD52L2, NFX1 and B4GALT1 in goats, were identified. Further gene annotation and bioinformatics analyses indicated that different biological pathways are important for milk traits in each species: fatty acid oxidation and AMP metabolic process in sheep, the U2-type spliceosomal complex and propanoate metabolism in goats. Additionally, common signatures of selection such as CLASP1, PDS5B, ZNF831, CCDC73 were found in sheep and goats. Haplotype and transcriptional analyses further confirmed the role of these genes in milk production and provided evidence for their analogous evolution in sheep and goats. The CLASP1 gene was identified as a target of convergent selection, representing a promising candidate for genetic improvement programs in dairy species. These results provide insights into the genetic basis of convergent dairy traits, offering valuable targets for improving milk production and advancing dairy sheep and goat breeding programs. Show less
Zhongxiao Lin, Jianyu Xiong, Fuyuan Zhang+15 more · 2026 · Molecular therapy : the journal of the American Society of Gene Therapy · Elsevier · added 2026-04-24
Vascular senescence is a fundamental driver of age-related cardiovascular diseases, yet the epigenetic mechanisms controlling this process remain poorly understood. This study investigated the role an Show more
Vascular senescence is a fundamental driver of age-related cardiovascular diseases, yet the epigenetic mechanisms controlling this process remain poorly understood. This study investigated the role and underlying mechanisms of lysine acetyltransferase 8 (KAT8), a key histone acetyltransferase, in maintaining endothelial cell homeostasis and preventing vascular senescence. We found that KAT8 expression is consistently downregulated in human aged vessels, senescent rats and mice, and cellular models of aging. Using CRISPR-Cas9-based loss-of-function and gain-of-function approaches in endothelial cells, C57BL/6J mice, and ApoE Show less