Alcohol use disorder (AUD) is a chronic condition marked by compulsive drinking and withdrawal-related negative affect. Histamine (HA) signaling, particularly via the histamine H3 receptor (H3R), may Show more
Alcohol use disorder (AUD) is a chronic condition marked by compulsive drinking and withdrawal-related negative affect. Histamine (HA) signaling, particularly via the histamine H3 receptor (H3R), may modulate alcohol-related behaviors. We investigated the effects of pitolisant, an FDA-approved H3R antagonist, on ethanol (EtOH)-related behaviors in mice. Adult male C57BL/6J mice underwent acute or chronic (2 or > 8 weeks) intermittent alcohol exposure. Pitolisant pretreatment was administered, and then pharmacological behavior, histologic, and molecular assays were conducted. Pitolisant administration reduced acute EtOH-induced locomotor activation, conditioned place preference, and sedative effects, and also curtailed EtOH intake. It alleviated anxiety and depression-like behavior during 24-h withdrawal (Post-EtOH). Mechanistically, the Post-EtOH condition was featured by complicated brain cFos expression mapping, including elevated cFos, [HA] and [glutamine]/[glutamate] ratio in the lateral habenula (LHb). However, systemic pitolisant treatment significantly increased [norepinephrine]/[normetanephrine] ratio, and restored the diminished phosphorylated CREB and BDNF levels in the LHb. Intra-LHb H2R antagonist cimetidine infusion partly blocked the pitolisant therapeutic effect on alcohol-related behavior. These findings highlight the HAergic system as a critical regulator of alcohol-related behaviors. The LHb HA signaling and norepinephrine neurotransmission might underlie pitolisant's potential novel therapeutic strategy for AUD. Show less
Apigenin is a bioactive flavonoid and widely found in herbs, fruits, and vegetables. Accumulated evidences have demonstrated the protective potential of apigenin on cardiovascular diseases, but its ro Show more
Apigenin is a bioactive flavonoid and widely found in herbs, fruits, and vegetables. Accumulated evidences have demonstrated the protective potential of apigenin on cardiovascular diseases, but its role in atherosclerosis remains unclear. Here, we aim to investigate the therapeutic effects of apigenin on atherosclerosis in vivo and explore the potential mechanism. ApoE Apigenin obviously reduced lesion areas in both en-face aortas and aortic root in HFD fed ApoE Apigenin alleviated atherosclerosis development by inhibiting macrophage foam cell formation via PPARγ-LXRα-ABCA1/ABCG1 pathway. Show less
Diabetic foot ulcers (DFU) are a severe complication of diabetes. Although dysregulated M2 macrophage polarization is recognized as a key driver of chronic inflammation in DFU, the molecular checkpoin Show more
Diabetic foot ulcers (DFU) are a severe complication of diabetes. Although dysregulated M2 macrophage polarization is recognized as a key driver of chronic inflammation in DFU, the molecular checkpoints that can be therapeutically targeted to restore M2 bias remain poorly defined. Here, we aimed to determine whether the RNA-binding protein TAF15 acts as a post-transcriptional stabilizer of the M2-promoting CEBPB/APOE/PTX3 axis, thereby accelerating DFU healing. First, we confirmed that APOE positively regulates PTX3, which supports M2 polarization and the proliferation and migration of HDF. CEBPB transcriptionally activated APOE and promoted M2 macrophage polarization. TAF15 stabilized CEBPB mRNA and affected HDF cell proliferation and migration by promoting M2 macrophage polarization. Additionally, TAF15 overexpression partially counteracted the disruption of M2 macrophage polarization caused by APOE silencing and facilitated DFU wound healing. Collectively, our findings establish TAF15-driven stabilization of CEBPB mRNA as a target point that sequentially activates APOE/PTX3 signaling to enforce M2 polarization and accelerate DFU closure. This study provides a preclinical rationale for the development of TAF15-targeted oligonucleotides or small-molecule strategies to reprogram wound macrophages and improve DFU outcomes in patients with diabetes. Show less
Atherosclerosis (AS) is a central pathological driver underlying most cardiovascular diseases. Gut microbiota and related metabolites participate in regulating atherosclerosis. Fifty C57BL/6J ApoE Ath Show more
Atherosclerosis (AS) is a central pathological driver underlying most cardiovascular diseases. Gut microbiota and related metabolites participate in regulating atherosclerosis. Fifty C57BL/6J ApoE Atherosclerotic plaques accumulated in the aorta and aortic sinus after HFD, while statin and high-dose GP alleviated this burden. TC, TG, LDL-C, MCP-1, MCP-3 and IL-2 showed significant increase after HFD, while statin and GP decreased LDL-C, MCP-1 and MCP-3. The goblet cells, ZO-1 and Occludin decreased after HFD, while statin and GP increased them, indicating that the intestinal barrier integrity was improved. Additionally, the composition of gut microbiota was modulated by GP. Some candidate taxa were identified, such as This study suggests that GP is beneficial for alleviating atherosclerosis in HFD-induced ApoE Show less
To evaluate the current status and latent profiles of caregiver self-care contributions for patients with chronic obstructive pulmonary disease (COPD) and examine the associations between demographic Show more
To evaluate the current status and latent profiles of caregiver self-care contributions for patients with chronic obstructive pulmonary disease (COPD) and examine the associations between demographic characteristics, health literacy, confidence in self-care contributions, family intimacy, and profile membership. We recruited 275 dyads of patients with COPD and their family caregivers from five tertiary hospitals between May and November 2022 using convenience sampling. Latent profile analysis (LPA) was used to identify distinct profiles of caregiver self-care contributions. Univariate analysis and multinomial logistic regression were subsequently conducted to examine associations between participant characteristics and profile membership. LPA identified four distinct profiles of caregiver self-care contributions: low-contributing, under-monitored, maintenance-prioritized, and high-contributing. Significant differences were observed across these profiles in terms of patients' symptom severity, exacerbation frequency, number of hospitalizations, caregivers' education levels, caregiving duration, health literacy, confidence in self-management contributions, and family intimacy using univariate analysis. Multinomial logistic regression analysis revealed that caregivers' education levels, caregiving duration, confidence in self-management contributions, and health literacy were significant predictors of profile membership. Caregiver self-care contributions for patients with COPD can be characterized by four distinct profiles, with caregivers' educational level, health literacy, and confidence in self-management identified as key factors associated with profile membership. Show less
Atherosclerotic plaque instability is a direct cause of cardiovascular and cerebrovascular events. In this study, a mitochondria-targeted liposome (LIP), modified with triphenylphosphonium (TPP) to en Show more
Atherosclerotic plaque instability is a direct cause of cardiovascular and cerebrovascular events. In this study, a mitochondria-targeted liposome (LIP), modified with triphenylphosphonium (TPP) to enable specific mitochondrial delivery, was innovatively constructed to encapsulate a PCSK9 inhibitor (TPP-LIP@PCSK9). The aim was to explore a novel strategy for stabilizing plaques by restoring mitochondrial function in endothelial cells. Characterization results showed that TPP-LIP@PCSK9 possesses favorable nano-characteristics, and its targeting capability was confirmed through mitochondrial co-localization experiments. In an Apoe Show less
Atherosclerotic plaque destabilization during acute infections such as pneumonia represents a critical clinical challenge, yet the underlying molecular dynamics remain poorly characterized. This study Show more
Atherosclerotic plaque destabilization during acute infections such as pneumonia represents a critical clinical challenge, yet the underlying molecular dynamics remain poorly characterized. This study introduces a furin-responsive photoacoustic/fluorescence dual-modal probe (FRP) to investigate intraplaque furin activity in ApoE Show less
The fat mass and obesity-associated (FTO) gene, though widely studied in human obesity and livestock lipid accumulation, remains poorly understood in bovine adipogenesis. This study investigated its r Show more
The fat mass and obesity-associated (FTO) gene, though widely studied in human obesity and livestock lipid accumulation, remains poorly understood in bovine adipogenesis. This study investigated its role in bovine adipocytes via overexpression, given its high expression in Guanling cattle adipose tissue. Results demonstrated that FTO significantly increased triglyceride content, adiponectin secretion, and lipid droplet accumulation (P < 0.01). It also upregulated key adipogenic markers (PPARγ, C/EBPβ, FABP4, LPL; P < 0.05). Transcriptomic analysis revealed that FTO promotes adipocyte differentiation and lipogenesis through regulating multiple lipid metabolic pathways. These findings reveal that FTO positively regulates bovine adipocyte differentiation by modulating lipid metabolic networks, thereby filling a critical gap in the understanding of FTO-mediated lipid metabolism in ruminants. Show less
Given the heterogeneous nature of Alzheimer's disease (AD) and its higher prevalence in females, it is crucial to understand sex-related differences in AD presentation and changes in the brain. This s Show more
Given the heterogeneous nature of Alzheimer's disease (AD) and its higher prevalence in females, it is crucial to understand sex-related differences in AD presentation and changes in the brain. This systematic review investigates sex differences in AD and summarizes key findings from neuroimaging studies over the past two decades to examine how genetics, hormones, and lifestyle factors influence neuroimaging biomarkers and their correlation with cognitive decline and AD progression. A comprehensive literature search was conducted across several databases for human studies from 2004 to 2024 related to AD, biological sex differences, and neuroimaging. After a 3-step review process, the final extraction included 120 peer-reviewed studies using various neuroimaging modalities, such as MRI, amyloid-beta PET, tau-PET, and fluorodeoxyglucose (FDG) PET, to investigate sex as a biological predictor variable in adults with or at risk for AD. Over 90% of the reviewed studies identified clear sex-specific patterns of imaging biomarkers related to cognitive reserve, hormonal changes, APOE-ɛ4 genotype, inflammation, vascular health, and lifestyle factors. Machine learning studies increasingly incorporate sex as a key variable, revealing sex-specific biomarkers and improving model performance in predicting disease status and progression. Considering biological sex in AD research is essential for improving diagnostic accuracy, tailoring interventions, and health outcomes. This systematic review identifies sex-specific patterns in neuroimaging biomarkers of AD, influenced by cognitive reserve, hormones, APOE-ɛ4 genotype, inflammation, vascular health, and lifestyle. Recognizing these differences is crucial for understanding, diagnosis, and treatment efficacy. Show less
Neuropathic pain (NP), a chronic disorder caused by somatosensory nervous system lesions, severely impairs the quality of life. Microglial metabolic reprogramming and neuroinflammation drive NP progre Show more
Neuropathic pain (NP), a chronic disorder caused by somatosensory nervous system lesions, severely impairs the quality of life. Microglial metabolic reprogramming and neuroinflammation drive NP progression. Although ChREBP (key metabolic regulator) protects against NP, its specific mechanisms remain unclear. NP rat model was established via spared nerve injury (SNI) surgery, and mechanical allodynia was evaluated using Von Frey tests. ChREBP expression in microglia was detected through immunofluorescence, RT-qPCR, and western blot. Functional studies involved ChREBP knockdown/overexpression to assess effects on microglial polarization, neuroinflammation, neuronal excitability, pain behaviors, and fatty acid metabolism. Mechanisms were explored via dual-luciferase reporter and chromatin immunoprecipitation assays. Mechanical pain thresholds were significantly decreased on the ipsilateral side after SNI. ChREBP was upregulated in SDH microglia after SNI and in LPS-stimulated microglia in vitro. ChREBP knockdown inhibited anti-inflammatory microglial polarization, exacerbated neuroinflammation, and aggravated pain. Conversely, ChREBP overexpression promoted the anti-inflammatory phenotype, suppressed neuroinflammation, and alleviated pain. ChREBP enhanced microglial fatty acid oxidation and energy metabolism. Mechanistically, ChREBP bound to the TFBS1 site on the PGC-1α promoter to activate its transcription. PGC-1α overexpression rescued the impairments caused by ChREBP knockdown, including reduced fatty acid oxidation, suppressed anti-inflammatory polarization, elevated inflammatory factors, and increased neuronal excitability. The protective effects of ChREBP were attenuated by the fatty acid oxidation inhibitor Etomoxir. ChREBP alleviates NP by enhancing microglial fatty acid oxidation and anti-inflammatory phenotype via PGC-1α transcriptional activation, revealing a novel metabolic-immune axis for potential NP therapy. Show less
Anxiety and depression are highly comorbid mental health disorders with heterogeneous symptom patterns and poorly understood transdiagnostic mechanisms. This study aims to characterize latent subgroup Show more
Anxiety and depression are highly comorbid mental health disorders with heterogeneous symptom patterns and poorly understood transdiagnostic mechanisms. This study aims to characterize latent subgroups, risk factors, and symptom-level interactions underlying depression-anxiety comorbidity across adolescents and adults in multi-ethnic Southwest China. The study included a total of 41,394 adolescents (aged 9-19) and 17,345 adults (aged 18-80). Adolescents were recruited using multistage stratified cluster sampling, whereas adults were recruited by convenience sampling. All participants completed a self-designed sociodemographic questionnaire, the Patient Health Questionnaire-9 (PHQ-9), and the Generalized Anxiety Disorder-7 (GAD-7). Latent profile analysis identified subgroups, logistic regression analyzed risk/protective factors, and network analysis mapped symptom interactions and bridge nodes. This study found that three adolescent profiles emerged: high (11.66 %), moderate (31.95 %), and low/no depression-anxiety (56.39 %). Adults were classified into low/no comorbidity (90.63 %) and comorbid depression-anxiety (9.37 %). Risk factors for adolescents included female gender (OR = 2.77, 95 %CI: 2.55-3.00; OR = 1.59, 95 %CI: 1.52-1.67), higher grade levels (OR = 3.45, 95 %CI: 3.10-3.84; OR = 3.56, 95 %CI: 3.33-3.80), smoking (OR = 1.72, 95 %CI: 1.51-1.96; OR = 1.28, 95 %CI: 1.17-1.41),drinking (OR = 2.45, 95 %CI: 2.23-2.70; OR = 1.66, 95 %CI: 1.55-1.77), family instability (OR = 1.16, 95 %CI: 1.02-1.31; OR = 1.33, 95 %CI: 1.14-1.56) and "other" ethnic minority (OR = 1.15, 95 %CI: 1.04-1.26). For adults, female gender(OR = 1.68; 95 %CI: 1.44-1.97), living alone(OR = 1.37; 95 %CI: 1.14-1.65), poor self-rated health (OR = 0.13, 95 %CI: 0.11-0.15), and Dai ethnicity (OR = 0.70, 95 %CI: 0.49-0.96) predicted comorbidity. Network analysis revealed distinct bridge symptoms: adolescents in the high depression-anxiety group had five symptoms: depressed or sad mood (phq2), psychomotor agitation/retardation (phq8), nervousness or anxiety (gad1), restlessness (gad5), and irritable (gad6); however, adults with comorbidity had one symptom: afraid something will happen (gad7). This study identified three patterns of depression-anxiety comorbidity in adolescents and two in adults. Efforts should prioritize adolescents from "other" ethnic minorities, strengthening family and peer support, as well as smoking and drinking interventions for adolescents, and addressing social isolation, physical health, and catastrophizing cognition in adults may mitigate the comorbidity burden. Show less
Atherosclerosis is a chronic and progressive inflammatory disease that can lead to adverse cardiovascular and cerebrovascular events. Phenotypic switching of vascular smooth muscle cells (VSMCs) plays Show more
Atherosclerosis is a chronic and progressive inflammatory disease that can lead to adverse cardiovascular and cerebrovascular events. Phenotypic switching of vascular smooth muscle cells (VSMCs) plays a pivotal role in its development and progression, but the upstream regulatory mechanisms remain incompletely defined. Here, we identify ubiquitin-fold modifier 1 (UFM1), a ubiquitin-like protein, as a critical regulator of VSMCs plasticity and atherogenesis. In VSMCs stimulated with oxidized low-density lipoprotein (ox-LDL), UFM1 overexpression markedly attenuated phenotypic switching, restoring contractile features and suppressing synthetic activation, accompanied by reduced proliferation and migration. In contrast, UFM1 knockdown further exacerbated these phenotypic alterations. In ApoE Show less
This study explores the influence of congruence and incongruence in father-mother co-parenting on adolescent depression, as well as the mediating effect of self-esteem. A total of 1389 adolescents com Show more
This study explores the influence of congruence and incongruence in father-mother co-parenting on adolescent depression, as well as the mediating effect of self-esteem. A total of 1389 adolescents completed questionnaires assessing their levels of depression and self-esteem, while their fathers and mothers correspondingly reported on their own co-parenting behaviors using the Parental Co-parenting Scale in this cross-sectional study. Dates were analyzed using LPA, RSA, and mediation consecutively. The results show that: (1) We identified three distinct co-parenting profiles: positive parental co-parenting, negative parental co-parenting, and mixed parental co-parenting. (2) In cases of congruent parental co-parenting, high positive parental co-parenting was associated with lower adolescent depression, whereas high negative parental co-parenting was linked to higher depression, and the difference manifests in different forms among boys and girls. Girls showed nonlinear changes in depression while boys exhibited linear trends. (3) In cases of incongruence in parental co-parenting, mothers' co-parenting exerted a stronger influence on boys' depression, while girls were not affected by mothers' and fathers' discrepancies. (4) Self-esteem mediated the relationship between parental co-parenting (in)congruence and depression across both genders. This study provides evidence for the mechanism through which parental coparenting influences adolescent depression and offers a basis for future interventions targeting adolescent depression. 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
Xinyi Ma, Yang Xu, Yeqi Nian+9 more · 2026 · American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons · Elsevier · added 2026-04-24
Carboxymethylcellulose (CMC), a common food emulsifier, induces microbiota dysbiosis and systemic inflammation; however, its impact on transplant immunity remains unclear. Allogenic heart rejection wa Show more
Carboxymethylcellulose (CMC), a common food emulsifier, induces microbiota dysbiosis and systemic inflammation; however, its impact on transplant immunity remains unclear. Allogenic heart rejection was observed in CMC-fed recipient mice, with increased abundance of lysophosphatidic acid (LPA)-producing bacteria and increased serum LPA concentration. CMC-induced transplant rejection was caused by the gut microbiota, as confirmed by fecal microbiota transplantation and gut microbiota depletion. Furthermore, LPA-treated macrophages demonstrated a proinflammatory ability to accelerate allograft rejection in cytotoxic T lymphocyte-associated protein 4 immunoglobulin-induced allograft survival by upregulating glycolysis. Conversely, the administration of a glycolysis inhibitor resulted in allograft survival and abrogated the detrimental effect of LPA. Mass spectrometry and single-cell RNA sequencing confirmed that transplant patients with rejection showed significantly elevated serum LPA levels and LPA receptor 6 (LPAR6) expression in graft-infiltrate macrophages. Mechanistically, LPA preferentially promoted LPAR6 expression, which interacted with Rho-associated protein kinase 2 to activate the mammalian target of rapamycin/hypoxia-inducible factor 1-alpha pathway, thereby enhancing glycolysis and inducing proinflammatory macrophage polarization. Treatment with Ki16425, an LPAR antagonist, prolonged allograft survival in CMC-fed recipients. Our findings reveal a major detrimental effect of CMC on macrophage physiology and suggest that controlling LPAR6 expression or glycolysis in macrophages may improve allograft survival in transplant recipients. Show less
Alterations in the FGFR family act as oncogenic drivers for multiple pediatric and adult tumors, leading to the development and approval of several FGFR inhibitors. However, the on-target gatekeeper a Show more
Alterations in the FGFR family act as oncogenic drivers for multiple pediatric and adult tumors, leading to the development and approval of several FGFR inhibitors. However, the on-target gatekeeper and "molecular brake" mutations confer clinically acquired resistance to the FDA-approved FGFR inhibitors, which presents a significant unmet medical need. Herein, we report the first novel macrocycle-based FGFR inhibitors targeting both wild-type and clinically acquired variants of the FGFR family. The representative compound Show less
Gary Chen, Adrienne Sexton · 2026 · Patient education and counseling · Elsevier · added 2026-04-24
This scoping review aims to map the experiences and outcomes of patients and their families undergoing genetic testing and counseling regarding dementia to inform future research directions and clinic Show more
This scoping review aims to map the experiences and outcomes of patients and their families undergoing genetic testing and counseling regarding dementia to inform future research directions and clinical practice. Rigorous scoping review methodology was followed. Ovid Medline, Embase, PsycINFO, and CINAHL were searched with keywords and MeSH terms related to "genetic testing", "genetic counseling", "dementia", "decision making", and "patient outcomes" for peer-reviewed studies with adult participants published over the last ten years. Thirty-six articles met inclusion criteria. Narrative synthesis organized findings into temporal categories including motivations for genetic testing, experiences during the testing/counseling process, and outcomes after testing. Common motivators included reducing uncertainty, reproductive planning, life planning, and the prospect of a treatment becoming available in the future. A lack of current treatments and fear that knowledge of genetic risk would be difficult to cope with were common barriers to testing. Patient-centered communication improved satisfaction. Genetic testing was generally psychologically well tolerated, and a wide range of practical responses were reported including changes to lifestyle, diet, advanced care and financial planning, and engaging in clinical trials. This review maps the experiences and outcomes of genetic testing or counseling for people with or at potentially increased genetic risk of dementia. Genetic testing and counseling for directly causal dementia genes and APOE genotype appears well tolerated but long-term outcome data is lacking. Motivations, concerns and perceived benefits of knowing genetic results vary depending on personal, familial and cultural viewpoints. Genetic counseling can help patients and families prepare, reduce decisional regret, and adapt to results. Motivations varied, and a patient-centered approach addressing both information and psychological aspects improves satisfaction. Future longitudinal research should ascertain ways to support individuals from a wide range of demographics with understanding and adjusting to genetic risk information regarding dementia. Show less
Despite therapeutic advances, atherosclerosis remains a major global health challenge. Most current treatments target systemic risk factors rather than the diseased vascular wall. Our previous work id Show more
Despite therapeutic advances, atherosclerosis remains a major global health challenge. Most current treatments target systemic risk factors rather than the diseased vascular wall. Our previous work identified genistein, a soy isoflavone, as a cannabinoid receptor 1 (CB1) antagonist capable of suppressing CB1-mediated vascular inflammation and atherosclerosis. However, its poor water solubility and low oral bioavailability limit clinical application. We aimed to develop water-soluble, orally bioavailable CB1 antagonists for atherosclerosis and to investigate the role of endothelial CB1 in hemodynamic regulation. RNA-sequencing datasets from the NCBI GEO repository were analyzed to assess CB1 expression in atherosclerotic patients. Apolipoprotein E-deficient (Apoe We found CB1 was upregulated in atherosclerotic lesions from patients and mice, and in endothelial cells exposed to disturbed flow. Mechanistically, this was driven by ZNF610 and Spi1 binding and KLF4 dissociation at the CB1 promoter. Daidzein, a soy isoflavone structurally similar to genistein, was identified as a novel CB1 antagonist. To enhance solubility and bioavailability, we developed genistein 7-O-phosphate (G7P) and daidzein 7-O-phosphate (D7P). Pharmacological treatment with these isoflavone monophosphates or genetic CB1 ablation reversed disturbed flow-induced endothelial dysfunction and endothelial-to-mesenchymal transition (EndMT). Oral administration of G7P and D7P significantly reduced atherosclerotic plaque formation in mice. This is the first study to identify transcriptional regulators that drive endothelial CB1 upregulation in response to disturbed flow. We further demonstrated that isoflavone monophosphates ameliorate disturbed flow-induced endothelial dysfunction and EndMT via CB1 inhibition, offering promising oral therapeutics for atherosclerosis. Show less
The international consensus classification or the World Health Organization classifications underrepresented driver alterations enriched in pediatric acute myeloid leukemia (AML). To address this, we Show more
The international consensus classification or the World Health Organization classifications underrepresented driver alterations enriched in pediatric acute myeloid leukemia (AML). To address this, we retrospectively characterized the genomic landscape of 105 pediatric patients with AML of East Asian ancestry using transcriptome and whole-exome sequencing (WES). In addition to the common recurrent fusions such as RUNX1::RUNX1T1 and CBFB::MYH11, we identified rearrangements involving KMT2A, NUP98, GLIS, as well as FLT3 and UBTF tandem duplications. The median somatic mutation rate in AML was 0.97 per megabase, as estimated by WES. Frequently mutated pathways included signaling: 68.6% (72/105), transcription: 37.1% (39/105), epigenetic regulation: 26.7% (28/105), cohesin: 7.6% (8/105), RNA binding: 3.8% (4/105), and protein modification: 5.7% (6/105). When analyzed together, high-risk genetic subtypes including GLISr, UBTF tandem duplications, PICALM::MLLT10, and HOXr were significantly associated with poorer 5 year overall survival (OS) in multivariable analysis (p-value = 0.037). Although FLT3 internal tandem duplications were significantly associated with inferior 5 year OS in univariable analysis, this effect was not significant in multivariable analysis (p-value = 0.382). Patients with RUNX1 mutations had inferior 5 year OS in multivariable analysis (p-value = 0.009). These findings suggest specific genomic alterations that may refine risk stratification and guide future therapeutic protocols in Taiwanese pediatric patients with AML. Show less
The clinical interpretation of Alzheimer's disease (AD) is frequently complicated by the prevalence of missense variants designated as being of uncertain significance within associated genes. Conventi Show more
The clinical interpretation of Alzheimer's disease (AD) is frequently complicated by the prevalence of missense variants designated as being of uncertain significance within associated genes. Conventional computational prediction tools often overlook disease-specific pathophysiological contexts and lack pertinence and interpretability. Therefore, the present study aimed to develop a novel, interpretable framework for predicting the pathogenicity of AD missense variants by integrating transcriptomic and proteomic data enrichment patterns with machine learning methods. A cross-sectional variant-level analysis was performed using publicly available databases. Missense variants in APOE, APP, PSEN1, PSEN2, SORL1, and TREM2 reported in AD patients were retrieved from Alzforum and compared with missense variants from individuals without neurological diseases, as cataloged in the gnomAD v2.1.1 non-neuro subset. Variants were annotated with tissue-specific expression, secondary structure, relative solvent accessibility, and other functional features using tools like AlphaFold. Enrichment of specific features was assessed with Fisher's exact tests with Bonferroni correction for multiple comparisons. Given that PSEN1 showed the strongest enrichment signals, six machine-learning algorithms were trained on PSEN1 variants to distinguish AD-associated variants from gnomAD variants, using a 10 × 5 nested cross-validation scheme. External validation was conducted using PSEN1 missense variants from ClinVar annotated as pathogenic/likely pathogenic or benign/likely benign. Model performance was compared with SIFT and PolyPhen-2, and interpretability was evaluated by feature ablation and SHapley Additive exPlanations analyses. AD-associated variants exhibited statistically significant enrichment within some transcriptomic or proteomic features, with PSEN1 contributing significantly to the enrichment observed across these features. Random forest and gradient boosting models achieved high performance in the internal training dataset and maintained high recall in the external validation dataset, outperforming SIFT and approaching the performance of PolyPhen-2. Relative solvent accessibility was the most discriminative individual feature, while regional and topological features provided complementary discriminative power. This integrative, multi-omics framework links disease-specific enrichment patterns with interpretable gene-level machine learning for AD missense variants. The results highlight the importance of expression level, structural context, etc. for PSEN1 variant pathogenicity and may help prioritize variants for functional studies. Further validation in additional genes and independent cohorts is warranted prior to any clinical application. Show less
The mammalian class III phosphatidylinositol-3-kinase complex (PtdIns3K) forms two biochemically and functionally distinct subcomplexes including the ATG14-containing complex I (PtdIns3K-C1) and the U Show more
The mammalian class III phosphatidylinositol-3-kinase complex (PtdIns3K) forms two biochemically and functionally distinct subcomplexes including the ATG14-containing complex I (PtdIns3K-C1) and the UVRAG-containing complex II (PtdIns3K-C2). Both subcomplexes adopt a V-shaped architecture with a BECN1-ATG14 or UVRAG adaptor arm and a PIK3R4/VPS15-PIK3C3/VPS34 catalytic arm. NRBF2 is a pro-autophagic modulator that specifically associates with PtdIns3K-C1 to enhance its kinase activity and promotes macroautophagy/autophagy. How NRBF2 exerts such a positive effect is not fully understood. Here we report that NRBF2 binds to PIK3R4/VPS15 with moderate affinity through a conserved site on its N-terminal MIT domain. The NRBF2-PIK3R4/VPS15 interaction is incompatible with the UVRAG-containing PtdIns3K-C2 because the C2 domain of UVRAG outcompetes NRBF2 for PIK3R4/VPS15 binding. Our crystal structure of the NRBF2 coiled-coil (CC) domain reveals a symmetric homodimer with multiple hydrophobic pairings at the CC interface, which is in distinct contrast to the asymmetric dimer observed in the yeast ortholog Atg38. Mutations in the CC domain that rendered NRBF2 monomeric led to weakened binding to PIK3R4/VPS15 and only partial rescue of autophagy deficiency in Show less
Rodents are widely used in immunology but do not always recapitulate human immune functions. The tree shrew (Tupaia belangeri) is phylogenetically closer to primates than rodents and may help bridge t Show more
Rodents are widely used in immunology but do not always recapitulate human immune functions. The tree shrew (Tupaia belangeri) is phylogenetically closer to primates than rodents and may help bridge this gap, yet its immune system has not been comprehensively characterised at single-cell resolution. Here, we present a single-cell transcriptomic atlas of the tree shrew immune system, profiling 39 cell types across 12 tissues. We uncover human-like tonsillar structures and two transcriptionally distinct splenic macrophage subsets: an NR1H3 Show less
Hypertrophic scar (HS) is a fibroproliferative disorder characterized by fibroblast hyperactivation and aberrant extracellular matrix deposition. This study identifies macrophage-derived lactate as a Show more
Hypertrophic scar (HS) is a fibroproliferative disorder characterized by fibroblast hyperactivation and aberrant extracellular matrix deposition. This study identifies macrophage-derived lactate as a key mediator of fibroblast phenotypic remodeling via monocarboxylate transporter 1 (MCT1)-mediated histone H3 lysine 23 lactylation (H3K23la) in HS. Elevated lactate levels and MCT1 expression were observed in HS tissues, with macrophages in stiff mechanical microenvironments identified as the primary lactate source. Lactate influx through MCT1 upregulated H3K23la, thereby promoting transcriptional activation of profibrotic genes HEY2 and COL11A1. Mechanistically, HEY2 activated YAP1/SMAD2 signaling, while COL11A1 stabilized MCT1 to enhance lactate transport, forming a positive loop that amplified fibrosis. Fibroblast-specific Mct1 deletion or pharmacological inhibition of Mct1 in male mice reduced collagen deposition, accelerated wound healing, and attenuated scar formation. Our findings redefine the macrophage-fibroblast crosstalk in HS and establish the MCT1-H3K23la-HEY2/COL11A1 axis, particularly its self-reinforcing loop, as a novel therapeutic target. Show less
Lipoprotein(a) [Lp(a)] is a genetically determined lipoprotein that has been established as an independent and causal risk factor for atherosclerotic cardiovascular disease (ASCVD) and calcific aortic Show more
Lipoprotein(a) [Lp(a)] is a genetically determined lipoprotein that has been established as an independent and causal risk factor for atherosclerotic cardiovascular disease (ASCVD) and calcific aortic valve disease (CAVD). Structurally composed of a low-density lipoprotein (LDL)-like particle covalently linked to apolipoprotein(a) [apo(a)], Lp(a) exhibits unique atherogenic, thrombogenic, and inflammatory properties, largely due to its role as a carrier of oxidized phospholipids (OxPL). Plasma Lp(a) concentrations are predominantly determined by the number of kringle IV type 2 (KIV-2) repeats in the LPA gene, with minimal influence from lifestyle or environmental factors. Despite substantial evidence linking elevated Lp(a) to cardiovascular risk, clinical testing remains underutilized, especially in East Asian countries. In Taiwan, although population-level Lp(a) concentrations are comparatively low, a significant subset exceeds risk thresholds, with local studies confirming its prognostic value in coronary artery disease and ischemic stroke. Barriers, including limited physician awareness, implementation barriers, and therapeutic nihilism, contribute to its under-recognition. This review highlights the molecular features of Lp(a), its pathogenesis of cardiovascular disorders, epidemiology, and current barriers and future advances in diagnostic testing, with a particular focus on implications for cardiovascular risk management in Taiwan. Show less
Alzheimer's disease (AD), the most prevalent form of dementia, is characterized as a slowly progressing neurodegenerative disease marked by senile plaques and neurofibrillary tangles due to the buildu Show more
Alzheimer's disease (AD), the most prevalent form of dementia, is characterized as a slowly progressing neurodegenerative disease marked by senile plaques and neurofibrillary tangles due to the buildup of amyloid-beta peptide (Aβ) and phosphorylated tau in the brain. It is reported that arctigenin (ATG) reduces the level of the enzyme 1 that cleaves β-site amyloid precursor protein and increases Aβ clearance by enhancing autophagy. Compound ARC-18 is a derivative of ATG. The main objective of this study is to investigate whether ARC-18 could improve cognitive function and disease progression by promoting autophagy in Alzheimer-like animal models. Three-month-old 5 × FAD mice were orally treated with the drug for three consecutive months. Water maze and novel object recognition were used to assess cognitive abilities of 5 × FAD mice. In the hippocampus of the mice' brain, APP processing-related proteins (sAPP Show less
Ye Yang, Anne P Beigneux, Troy L Lowe+21 more · 2026 · Proceedings of the National Academy of Sciences of the United States of America · National Academy of Sciences · added 2026-04-24
Apolipoprotein AV (APOA5) regulates intravascular triglyceride metabolism by binding to the angiopoietin-like protein 3/8 complex (ANGPTL3/8) and suppressing its ability to unfold the native conformat Show more
Apolipoprotein AV (APOA5) regulates intravascular triglyceride metabolism by binding to the angiopoietin-like protein 3/8 complex (ANGPTL3/8) and suppressing its ability to unfold the native conformation of lipoprotein lipase (LPL). LPL unfolding results in loss of catalytic activity and the detachment of LPL from the surface of cells. An Show less
To examine the causal association between obesity and osteoarthritis (OA) using an improved definition of obesity, and to identify mediating genes that may link obesity to OA pathogenesis. We analyzed Show more
To examine the causal association between obesity and osteoarthritis (OA) using an improved definition of obesity, and to identify mediating genes that may link obesity to OA pathogenesis. We analyzed data from the U.S. National Health and Nutrition Examination Survey (NHANES, 2011-2018; n = 8981). Obesity was defined using body mass index (BMI ≥ 30 kg/m²) combined with body fat percentage (BFP ≥ 25 % in men and ≥ 32 % in women). Logistic regression and subgroup analyses were conducted to evaluate associations with OA. Genetic correlation between obesity and OA was estimated using linkage disequilibrium score regression (LDSC). Two-sample Mendelian randomization (MR) was applied to assess causal effects using genome-wide association study (GWAS) summary statistics for BFP and OA. Transcriptome-wide association studies (TWAS) and colocalization analyses were performed to identify candidate genes. Mediation MR was conducted to verify their mediating roles. Obesity defined by BMI combined with BFP was significantly associated with OA (OR = 1.421, 95 %CI: 1.048-1.925, P = 0.025), and was independent of age, race, and various comorbidities. MR analysis confirmed a unidirectional causal effect of obesity on OA (IVW OR = 2.349, 95 %CI: 2.012-2.743, P < 0.001), with no reverse causality detected. TWAS and colocalization identified MAPK3, RBM6, and PRMT6 as potential mediators. Mediation MR confirmed significant effects of MAPK3 (β = 0.991, P = 0.015) and RBM6 (β = 2.740, P < 0.001) in the obesity-OA pathway. Obesity exerts a causal effect on OA, partially mediated by the downregulation of MAPK3 and RBM6. These genes represent potential targets for the prevention and treatment of obesity-related OA. Show less
Intracerebral hemorrhage (ICH) has a high rate of death and disability. LncRNA-TUG1 is essential for the pathological changes secondary to ICH. The purpose of this work was to investigate the possible Show more
Intracerebral hemorrhage (ICH) has a high rate of death and disability. LncRNA-TUG1 is essential for the pathological changes secondary to ICH. The purpose of this work was to investigate the possible mechanism by which TUG1 inhibits neural repair subsequent to ICH through adjusting miR-381-3p/brain-derived neurotrophic factor (BDNF). After the ICH model was created, miR-381-3p agomir and pcDNA-TUG1 were injected. The neural function of rats was estimated using the modified neurological severity score. To quantify the expression of genes and proteins, western blotting, immunohistochemistry, and qRT-PCR were used. To confirm the interaction between TUG1 and miR-381-3p and between miR-381-3p and BDNF mRNA, a luciferase reporter assay was employed. In rats treated with miR-381-3p agomir, a trend of improvement in neurological dysfunction was observed, while the pcDNA-TUG1-treated ones showed deterioration. Furthermore, miR-381-3p agomir increased, while pcDNA-TUG1 reduced the expression level of BDNF in ICH rats. TUG1 and BDNF mRNA were validated to attach directly to miR-381-3p. Overexpressing TUG1 inhibited the level of BDNF by sponging miR-381-3p and antagonized its protective effect on neural repair in ICH rats. Our study suggests that TUG1 can sponge miR-381-3p to downregulate BDNF expression and inhibit neural repair following ICH, demonstrating a potential signaling pathway that is conducive to a better understanding of the pathological mechanisms of ICH. Show less