👤 Siqi Lu

Defective Wnt/β-catenin signaling is closely associated with the pathogenesis of Alzheimer's disease (AD), thus validating this pathway as a therapeutic target for AD. ISX9 is a potent agonist of the Wnt/β-catenin pathway. However, it remains unknown whether ISX9 exerts anti-AD effects by enhancing the Wnt/β-catenin signaling pathway. We therefore explored the neuroprotective potential of ISX9 using both hippocampal neuron-derived HT22 cells and 5×FAD transgenic mouse model of AD. In HT22 cells, we employed the SuperTOPFlash reporter gene, Co-IP and Western blot assays to investigate the mechanism by which ISX9 activates the Wnt signaling pathway. The effects of ISX9 on the biological behavior of HT22 cells were further evaluated through MTT, BrdU and IF staining. To study the therapeutic effect of ISX9 on AD, six-month-old 5×FAD transgenic mice were randomly divided into four groups: WT, WT/ISX9, AD and AD/ISX9. The mice were intraperitoneally injected with ISX9 or vehicle at an interval of one day for 2 months. Behavioral tests were conducted to evaluate the cognitive and learning abilities of mice, while the expression levels of Aβ peptides, Tau-related proteins, neuroinflammatory factors, blood-brain barrier (BBB)-related proteins and the components of Wnt/β-catenin signaling were investigated. Our results demonstrated that ISX9 potently activated Wnt/β-catenin signaling by promoting the association of LRP6 with AXIN1, and increased the viability and proliferation of hippocampal cells. At the behavioral level, ISX9 improved learning and memory abilities in 5×FAD mice, and ameliorated hippocampal neuronal damage. Furthermore, ISX9 treatment effectively reduced the expression of Aβ peptides, total Tau, and phosphorylated Tau (S404) proteins in the AD mice. Mechanistically, ISX9 exhibited its neuroprotective effects, activating the Wnt/β-catenin signaling pathway via potentiating the interaction of LRP6 with AXIN1, upregulating the expression of BBB-related proteins and downregulating neuroinflammatory factors in AD mice. Our findings indicate that ISX9 potently activates the Wnt/β-catenin signaling pathway and confers cognitive protection in hippocampal cells and AD mice. This compound may serve as a promising therapeutic agent for the treatment of AD. Show less

Bazi Bushen (BZBS), a Traditional Chinese Medicine (TCM) formula, is composed of fourteen herbal ingredients, including classic tonics such as Ginseng Radix et Rhizoma and Cistanches Herba. Traditionally used to combat fatigue and promote vitality in aging individuals, BZBS is rooted in TCM principles of kidney essence replenishment and brain function enhancement. Recent pharmacological studies have begun to validate its efficacy in age-related cognitive decline, but its effects and mechanisms in Alzheimer's disease (AD) remain unclear. This study aimed to evaluate the potential therapeutic effects of BZBS in 5 × FAD transgenic mice, a commonly used Alzheimer's disease model, and to shed light on its possible mechanisms of action. Four- and six-month-old 5 × FAD mice were treated with BZBS to examine how it might influence cognitive performance. Behavioral assessments were carried out using Y-Maze and the Morris Water Maze. To investigate the biological changes and uncover the mechanisms involved, we used a range of techniques-Thioflavin S staining, immunofluorescence, Western blotting, and qPCR-to look at Aβ plaque accumulation, Amyloid Precursor Protein C-terminal Fragments (APP-CTF) and β-secretase 1 (BACE1) expression levels, markers of inflammation, and indicators of cellular aging in hippocampus and motor cortex. In the 4-month group, where treatment was started before severe pathology developed, BZBS improved learning and memory performance. It also reduced amyloid deposition in the cortex and hippocampus, and lowered the levels of APP-CTFs and BACE1. In addition, we observed decreased mRNA expression of IL-1α, IL-6, and NF-κB, along with reduced microglial activation in the hippocampus of BZBS-treated mice. Similarly BZBS downregulated key markers of cellular senescence, including p16, p21, and senescence-associated β galactosidase (SA-β-gal) activity. In the 6-month group, which already showed signs of amyloid pathology, BZBS still had beneficial effects-improving cognition, lowering Aβ load, and reducing microglial activity-suggesting that it may be effective even after disease onset. These findings demonstrate that BZBS exerts significant therapeutic effects in 5 × FAD mice, including improved cognitive improvement, reduced Aβ deposition, suppressed microglial activation, and attenuated hippocampal cellular senescence. Notably, BZBS was effective whether administered from the early stage of pathology (at four months of age) or after established amyloidosis (at six months of age), highlighting its dual potential as both a preventive and disease-modifying intervention for Alzheimer's disease (AD). Show less

RNA G-quadruplexes (rG4s), formed through guanine self-recognition into stacked tetrads, serve as critical regulators of gene expression, yet their comprehensive mapping and dynamic regulation in physiological contexts remain technically challenging. Here, we develop Ultra-low-input rG4-seq (ULI-rG4-seq), enabling precise rG4 detection enabling precise rG4 detection with ∼140 bp resolution in samples as small as 100 oocytes, and reveal notable enrichment of rG4s near crucial regulatory regions, particularly transcription start sites and end sites. This technological advance, combined with Trim-away or oocyte-specific knockout of DHX36 (also known as G4R1 or RHAU), an rG4-specific helicase, reveals acute and chronic loss of DHX36 leads to opposing effects on rG4 levels. This observation extends beyond the traditional view of helicases as unwinding enzymes and suggests sophisticated cellular mechanisms maintaining RNA structural homeostasis. Through integrated analysis of rG4 landscapes and DHX36-binding profiles, we demonstrate coordination between cytoplasmic rG4 regulation and nuclear gene expression, revealing how RNA structure dynamics orchestrate RNA stability and translation, thereby influencing transcriptional elongation, genome stability, and alternative splicing. Finally, we show that deletion of DHX36 resulted in decreased oocyte quality, premature ovarian failure and complete female infertility due to transcriptional defects and genome instability related to R-loop accumulation. These technological and conceptual advances not only deepen our understanding of RNA-based regulation but also open new therapeutic possibilities for diseases involving RNA structure. Show less

Primary resistance to chimeric antigen receptor (CAR) T-cell therapies has limited their widespread application. Our prior genome-wide CRISPR/Cas9 screening revealed that the loss of CD58, a crucial intrinsic resistance factor in tumors, resulted in insufficient immune synapse formation and impaired CAR T-cell activation and cytotoxicity. However, the specific signaling pathway and transcriptional changes associated with CAR T-cell dysfunction have not been addressed. Here, we revealed that AP-1-mediated activation was attenuated in CAR T cells impaired by tumor CD58 loss, driving a decrease in mitochondrial biogenesis, metabolic kinetic impairment, mitochondrial membrane potential loss and ROS accumulation. Moreover, this AP-1 attenuation triggered death receptor-independent apoptosis through the intrinsic mitochondrial pathway. In seeking therapeutic strategies, we pharmacologically and genetically blocked three distinct inhibitory phosphatases positioned upstream of AP-1 signaling. Multifaceted validation has demonstrated that dual specificity phosphatase 6 (DUSP6) blockade is an effective approach to supplement AP-1 signaling while notably reducing CAR T-apoptosis and enhancing mitochondrial fitness, proliferation and long-term cytotoxicity. The transcriptomic profiles of DUSP6-ablated CAR T cells revealed markedly upregulated T-cell activation signatures and enriched metabolic pathways. Clinically, bulk and single-cell RNA-seq analyses revealed that DUSP6 was downregulated in patients who responded to T-cell-based immunotherapy, implying its relevance to patient outcomes. Our findings repositioned CD58 not merely as an immune synapse component but also a metabolic checkpoint in CAR T-cell biology, the loss of which triggers AP-1-dependent mitochondrial derangement and creates a permissive landscape for intrinsic apoptosis, which can be ameliorated by ablation of the inhibitory phosphatase DUSP6. Crucially, DUSP6 ablation represents a promising engineering target to potentiate CAR T-cell efficacy in broader applications. Show less

To explore the genetic etiology of 46 Chinese pedigrees affected with Hereditary multiple exostoses (HME) and provide genetic counseling and reproductive intervention. Whole-exome sequencing and Sanger sequencing were carried out on 87 patients from the 46 pedigrees to analyze the variants of EXT1 and EXT2 genes. Pathogenicity of the variants was assessed based on the guidelines from the American College of Medical Genetics and Genomics and Association for Molecular Pathology (ACMG/AMP). Prenatal diagnosis and preimplantation genetic testing (PGT) were provided for couples with identified pathogenic mutations. This study was approved by the Medical Ethics Committee of the hospital (Ethics No.: LL-SC-SG-2014-010). In total 17 and 22 pathogenic variants were respectively identified in the EXT1 and EXT2 genes, among which 5 EXT1 and 12 EXT2 variants were unreported previously. Three patients with no family history were found to harbor de novo variants of the EXT1 gene. Twenty nine couples had opted for PGT or underwent prenatal diagnosis following natural conception, and 17 healthy babies were born. This study has clarified the genetic etiology of 45 HME pedigrees and identified 17 novel variants, which has enriched the mutational spectrum of the EXT1 and EXT2 genes. Reproductive intervention through PGT and prenatal diagnosis have prevented the recurrence of HME in these families. Show less

Gout is an acute inflammatory arthritis triggered by monosodium urate (MSU) crystal deposition and activation of innate immune responses. In addition to inflammasome signaling, emerging evidence suggests that metabolic reprogramming of arachidonic acid (AA) pathways amplifies inflammatory responses during gout flares. However, the contribution of upstream fatty acid desaturation processes that regulate endogenous AA availability remains poorly defined. 1,2,3,4,6-Penta-O-galloyl-β-D-glucose (PGG) is a naturally occurring polyphenol with reported anti-inflammatory activity, but its effects on MSU-induced fatty acid metabolism and gouty inflammation have not been well established. Publicly available bulk and single-cell transcriptomic datasets from human and mouse gout studies were analyzed to assess dysregulation of AA-associated pathways. MSU-induced inflammatory responses were examined in mouse bone marrow-derived macrophages and in a murine MSU-induced gout model. Macrophages were treated with PGG prior to MSU stimulation, and inflammatory cytokine production, phagocytosis, and expression of fatty acid desaturases were assessed. Lipidomic analysis of macrophages and plasma was performed using gas chromatography-mass spectrometry (GC-MS) to quantify arachidonic acid and related fatty acids. In vivo disease severity, cytokine expression, and anti-inflammatory markers were evaluated following PGG treatment. Analysis of public datasets revealed consistent dysregulation of arachidonic acid-associated inflammatory pathways during gout flares. In macrophages, MSU stimulation increased expression of fatty acid desaturases FADS1 and FADS2 and promoted accumulation of arachidonic acid, concomitant with robust production of pro-inflammatory cytokines. PGG treatment significantly suppressed MSU-induced FADS1, FADS2 and arachidonic acid levels, and attenuated pro-inflammatory cytokine production. PGG also markedly impaired macrophage phagocytosis of MSU crystals. In vivo, PGG treatment significantly reduced clinical disease severity in an MSU-induced gout model, suppressed fatty acid desaturation and arachidonic acid accumulation in plasma, decreased pro-inflammatory cytokine expression, and enhanced anti-inflammatory markers. These findings identify fatty acid desaturation as an important metabolic contributor to gouty inflammation and demonstrate that PGG suppresses MSU-induced inflammation by limiting endogenous arachidonic acid availability, reducing inflammatory amplification, and impairing MSU crystal phagocytosis. Targeting upstream fatty acid metabolism represents a potential therapeutic strategy for modulating acute gout flares beyond conventional anti-inflammatory approaches. Show less

The intramuscular fat content and the unsaturated fatty acid (UFA) composition are both critical indicators of buffalo meat quality. While microRNAs regulate fatty acid metabolism, their specific roles in buffaloes remain unclear. Our previous WGCNA identified bta-miR-30f as a hub miRNA positively correlated with UFA levels. In the present study, bta-miR-30f was found to be highly expressed in sternum subcutaneous adipose tissue and mature adipocytes. Functional studies indicated that bta-miR-30f increased lipid accumulation via enhanced adipogenesis and UFA levels, upregulating key genes including Show less

Myelin debris accumulation after spinal cord injury (SCI) drives persistent neuroinflammation, lysosomal dysfunction, and lipid overload in macrophages, ultimately impairing tissue repair. Here, we identify fibroblast growth factor 4 (FGF4) as a previously unrecognized regulator of macrophage-mediated myelin debris clearance. Endogenous FGF4 transiently increased in the early phase of SCI but rapidly declined. Using in vitro models, we demonstrate that exogenous FGF4 markedly enhances myelin debris phagocytosis through activation of the FGFR1-PI3K/AKT signaling pathway, leading to upregulation of Clec10a, a C-type lectin receptor not previously linked to myelin debris processing. Silencing Clec10a significantly mitigated the phagocytic and neuroprotective benefits of FGF4, supporting Clec10a as an important mediator of this response. D-GalNAc competitive inhibition assays showed that Clec10a does not rely on the conserved carbohydrate-recognition domain to bind to myelin debris. FGF4 enhanced the maturation and degradative efficiency of the endolysosomal system, driving internalized myelin debris through Rab5 The online version contains supplementary material available at 10.1186/s12974-026-03743-0. Show less

Aberrant fibroblast growth factor receptor 3 (FGFR3) activation drives bladder carcinogenesis in humans, but currently approved pan-FGFR inhibitors lack FGFR3 isoform selectivity and fail to counter clinically acquired resistance mutations (e.g., FGFR3 V555M/L). Herein, we report the structure-based drug design of 4-(1-methyl-1 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 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

Left ventricular noncompaction cardiomyopathy (LVNC; OMIM No. 604169) is anatomically characterized by excess trabeculation and deep intertrabecular recesses. It is the third most prevalent pediatric cardiomyopathy. Despite its clinical significance, the pathogenesis of LVNC remains uncertain. We examined Numb expression in epicardial cells (EpiCs) and epicardial-derived cells (EPDCs) using a mCherry::Numb knock-in mouse line; used Numb is enriched in EpiCs and EPDCs. In EDKO hearts, EPDCs displayed abnormal differentiation, and their migration was arrested at the outer compact zone, resulting in the absence of EPDCs in the inner compact zone and trabeculae. The EDKO hearts displayed LVNC, and inducible EpiC-specific Ablation of NFPs (Numb family proteins) in EpiCs disrupted the invasion and differentiation of EPDCs and the communication between cardiomyocytes and other cells, and caused LVNC. The epithelial-mesenchymal transition and compaction defects can be partially rescued by exogenous Fgf2 supplementation. Our findings highlight an essential role for the epicardial NFPs-Fgf/Fgfr axis in regulating ventricular compaction. Show less

Breast cancer (BC) progression is intricately linked to the dysregulation of transfer RNA-derived fragments (tRFs). Through comprehensive analysis of The Cancer Genome Atlas (TCGA) data, it is demonstrated that 5'tRF-GlyGCC is overexpressed in BC tissues and negatively associated with patients' survival. Mechanistically, 5'tRF-GlyGCC binds to lactate dehydrogenase A (LDHA), enhancing its enzymatic activity and promoting glycolysis, which drives BC cell malignancy. This binding is mediated by the phosphorylation of LDHA at tyrosine 10, and facilitated by fibroblast growth factor receptor 1 (FGFR1), through the formation of a ternary complex that amplifies oncogenic signaling. Furthermore, 5'tRF-GlyGCC/LDHA axis induces macrophage infiltration and polarization toward an M2 phenotype, mediated by the chemokine CCL7, thereby reshaping the tumor microenvironment. Additionally, it is uncovered that the biogenesis of 5'tRF-GlyGCC is regulated by ALKBH3 and ANG, which also modulate LDHA activity. In vivo, targeting 5'tRF-GlyGCC/LDHA signaling significantly suppresses tumor growth and enhances the efficacy of immunotherapy. Collectively, these findings elucidate the pivotal role of 5'tRF-GlyGCC in BC progression, highlighting its potential as therapeutic target for BC treatment. Show less

Osteosarcoma, the most common primary malignant bone tumor with poor prognosis, underscores the need for a deeper understanding of its molecular mechanisms. Recent studies have highlighted the importance of RNA modifications, including 5-methylcytosine (m5C), in cancer progression, yet the m5C modification landscape in osteosarcoma remains unexplored. Here, we performed transcriptome-wide profiling of m5C modifications in osteosarcoma using meRIP-seq and RNA-seq, analyzing four pairs of osteosarcoma and adjacent normal tissues. Furthermore, through conjunction analyses of meRIP-seq and RNA-seq data, we identified 637 genes with significant changes in both the m5C modification and mRNA levels. Among these, GPRC5B emerged as a key prognostic gene, with its high expression and m5C hypermethylation significantly associated with poor survival in osteosarcoma patients. Functional experiments demonstrated that GPRC5B suppresses apoptosis and promotes osteosarcoma cell proliferation and migration. Mechanistically, NSUN2-mediated m5C modification upregulates GPRC5B expression, and the anti-apoptotic effects of NSUN2 are primarily dependent on its ability to modulate GPRC5B m5C modification and expression. Knockdown of GPRC5B partially rescues the anti-apoptotic effects of NSUN2, highlighting the critical role of GPRC5B in osteosarcoma survival. Our study identified an m5C-dependent NSUN2-GPRC5B regulatory axis, providing insights into osteosarcoma progression and revealing its therapeutic potential. Show less

The high prevalence of cancer immunotherapy resistance, coupled with substantial tumor heterogeneity, underscores the urgent need for innovative therapeutic targets. A deeper understanding of immunoregulatory mechanisms would provide new targets and combination therapeutic strategies for tumor therapy. In this study, we demonstrate that HSD17B12 enhances anti-tumor immunity and represents a promising therapeutic target. Mechanistically, HSD17B12 promotes lysosome-dependent degradation of PD-L1 via the VAC14 and ESCRT complexes across various malignancies, regardless of its 3-ketoacyl-CoA reductase activity. HSD17B12-deficient cells displayed PD-L1 accumulation in both tumor cells and exosomes, reducing T cell-mediated cytotoxicity. Notably, we found a significant negative correlation between HSD17B12 and PD-L1 expression in colorectal cancer tissues. Furthermore, high HSD17B12 expression in CRC correlated with increased infiltration of cytotoxic T cells. Based on these findings, we designed a peptide, HSD-CC1-NPGY, which effectively reduces PD-L1 expression in cells and suppresses tumor growth in a mouse model. Overall, our results establish HSD17B12 as an important regulator of anti-tumor immunity and a promising therapeutic target for cancer treatment. Show less

Steroid-refractory (SR) disease develops in a substantial fraction of patients with grade II-IV acute graft-versus-host disease (aGvHD) and is associated with poor long-term survival. Improved mechanistic insight is needed to identify reliable predictors of steroid resistance. We retrospectively profiled peripheral blood collected prior to glucocorticoid treatment from allogeneic hematopoietic cell transplantation recipients without aGvHD, with steroid-sensitive aGvHD, and with SR-aGvHD using an integrated multi-omics approach, and validated findings in an independent multicenter cohort. Mass cytometry revealed expansion of activated CD28+ CD8+ effector-memory T (Tem) cells in SR-aGvHD. Absolute counts of these cells at neutrophil engraftment predicted subsequent steroid resistance in the multicenter cohort and performed comparably to established clinical classifiers. This phenotype was associated with a proinflammatory milieu enriched for IL-2, IL-27, and IFN-γ. Single-cell RNA sequencing and functional assays implicated a STAT1-glucocorticoid receptor (GR) regulatory axis in which inflammatory cytokines induce STAT1 phosphorylation and suppress GR expression, consistent with intrinsic glucocorticoid resistance. JAK inhibition rescued cytokine-induced steroid resistance in vitro, while in SR-aGvHD patients, clinical response to ruxolitinib was accompanied by reduced STAT1 activation, restoration of GR expression, and contraction of the expanded CD8+ Tem pool. These findings identify immune dysregulation at SR-aGvHD centered on CD8+ Tem cells with a STAT1-dependent GR deficit and support a mechanistic link to steroid refractoriness. CD28+ CD8+ Tem cell counts may serve as a biomarker of SR-aGvHD and inform development of pre-emptive, pathway-targeted strategies. Show less

Psoriasis and atopic dermatitis (AD) are two prevalent inflammatory skin disorders, each characterized by distinct adaptive immune responses. However, recent evidence suggests that these diseases may share overlapping immune mechanisms, especially concerning keratinocyte function. The specific cytokines that coordinate these inflammatory pathways remain largely undefined. The expression of IL-27 and its receptor was analyzed using data derived from GEO datasets. Imiquimod-induced psoriasis-like and MC903-induced AD-like skin inflammation models were established in wild-type and Il27ra knockout littermates. Skin inflammation was evaluated using clinical scoring, histology, and immunostaining. Flow cytometry was employed to characterize immune cell populations in skin. Expression of relevant cytokines and signaling molecules was assessed using quantitative PCR, bulk RNA sequencing, and Western blotting. We found significantly elevated expression of the IL-27 receptor in the lesional skin of patients with psoriasis or AD. IL-27 receptor-deficient mice exhibited markedly reduced skin inflammation in both psoriasis-like and AD-like murine models. Mechanistic investigations revealed that IL-27 induces tumor necrosis factor-α production via signal transducer and activator of transcription 1 activation in keratinocytes, thereby potentiating inflammatory responses. Our findings identify IL-27 signaling in keratinocytes as a pivotal regulator of skin inflammation in both psoriasis and AD. This highlights IL-27 as a promising therapeutic target for inflammatory skin diseases. Show less

The purposes of this study were to identify different psychological capital subtypes among college students through latent profile analysis (LPA) and to explore the associations of psychological capital subtypes, internet usage duration and physical exercise frequency with on both depression and anxiety. Cross-sectional study design was implemented. A cross-sectional survey was conducted using the "Questionnaire Star" platform. The questionnaires of Psychological Capital Scale, PHQ-9, and GAD-7 were administered to 1089 college students from a university in Zhengzhou, China. Latent profile analysis was applied to identify latent subtypes of psychological capital. Multivariate regression analysis was performed to investigate the associations of psychological capital subtypes with both depression and anxiety. Three psychological capital latent profiles were identified: low self-efficacy (11.7%), moderate (57.8%), and high psychological capital (30.5%) in Chinese college students. High psychological capital group showed significantly higher scores of self-efficacy, resilience, hope, and optimism than other two groups (P < 0.001). Internet usage time and physical exercise frequency exhibited positive associations with psychological capital subtypes. Compared with the low self-efficacy group, the moderate and high latent groups had significantly lower scores of both depression and anxiety. Older students had higher scores of both depression and anxiety than younger. Three latent profiles, low self-efficacy, moderate, and high psychological capital, were identified in Chinese college students. Self-efficacy is the key dimension distinguishing between the different subtypes. Adequate internet use and physical exercise frequency improved psychological capital profile. High psychological capital levels effectively reduced the scores of both depression and anxiety. Show less

Given that abnormal lipid metabolism is a hallmark of metabolic dysfunction-associated steatotic liver disease (MASLD), this study seeks to investigate the relationship between serum lipoprotein(a) [Lp(a)] levels and the progression or regression of MASLD. A total of 12,962 participants undergoing transient elastography at the Health Promotion Center of the First Affiliated Hospital of Nanjing Medical University were included in the first cross-sectional study (Study 1). The longitudinal study (Study 2) included 17,661 individuals from the same center, each with at least two health check-ups involving abdominal ultrasonography. Another cross-sectional study (Study 3) included 5,927 individuals from the UK Biobank cohort who had undergone both magnetic resonance imaging proton density fat fraction (MRI-PDFF) and Lp(a) testing. Cross-sectional analysis (Study 1) revealed that elevated Lp(a) levels were inversely correlated with the severity of both hepatic steatosis and fibrosis. Longitudinal data (Study 2) further demonstrated that baseline serum Lp(a) levels were decreased in participants with the incident of MASLD, while increased in participants with the regression of MASLD during the follow-up period. A lower baseline Lp(a) level was an independent factor for new-onset MASLD and non-regression of MASLD: the fully adjusted hazard ratios (HR) were 0.895 (95%CI 0.834-0.962, Serum Lp(a) levels are inversely associated with both the progression and regression of MASLD, indicating its potential role in reflecting disease dynamics. 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 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

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

To identify latent classes based on symptom clusters and to explore the association between these distinct symptom experience subtypes and social isolation in older adults with comorbid diabetes mellitus (DM) and coronary heart disease (CHD). A cross-sectional study was conducted among 337 older adults with DM and CHD recruited from the Department of Endocrinology and Cardiology of Nantong Sixth People's Hospital between February 2023 and October 2025. Data were collected using a general information questionnaire, the Chinese version of the Memorial Symptom Assessment Scale (MSAS), and the Lubben Social Network Scale-6 (LSNS-6). Exploratory factor analysis (EFA) was used to identify symptom clusters. Latent profile analysis (LPA) was then employed to classify patients into different symptom experience subtypes based on the symptom cluster scores. One-way ANOVA, Chi-square tests, and multiple linear regression were used to analyze the association between latent classes and social isolation. EFA extracted three symptom clusters (cardiopulmonary-fatigue, emotional-perceptual, and metabolic), accounting for 62.3% of the total variance. LPA identified three distinct latent classes: Class 1 "Low Burden-Balanced Pattern" (45.4%), Class 2 "Psycho-Somatic Co-dominant Pattern" (31.8%), and Class 3 "Metabolic-Physical Dominant Pattern" (22.8%). Univariate analysis revealed significant differences in social isolation scores (LSNS-6) across the three classes ( The findings reveal significant heterogeneity in symptom experiences among older adults with comorbid DM and CHD, which can be categorized into distinct latent classes. The subtype characterized by a Psycho-Somatic Co-dominant Pattern shows the strongest association with social isolation. In clinical practice, early identification of this high-burden subgroup may facilitate the provision of integrated interventions that address physical, psychological, and social dimensions. Show less

Myopia is a critical public health issue; however, the roles of multidimensional psychological resources (i.e., resilience and emotion regulation) and potential gender differences remain underexplored. This cross-sectional study aimed to investigate the association between latent psychosocial profiles and myopia severity, and to examine the moderating role of gender in this association among adolescents. In total, 1008 Chinese seventh-grade students completed assessments of psychological resilience, emotion regulation, and depressive and anxiety symptoms. Myopia was measured as spherical equivalent refraction (SER). Latent profile analysis (LPA) was used to identify distinct psychological profiles, and moderation analysis tested gender's role in the profile-myopia association. LPA revealed three distinct psychosocial profiles: "Low-Resource", "Emotion-Driven", and "Balanced-Adaptive". The Low-Resource profile exhibited the highest levels of depression, anxiety, and myopia severity. A significant moderating effect of gender was found. Among females, both the Emotion-Driven and Balanced-Adaptive profiles were associated with significantly less myopia severity compared to the Low-Resource profile-an association not observed in males. Specific psychological resource profiles were linked to myopia severity, a relationship that was significantly moderated by gender and was prominent only in female adolescents. These findings highlight the importance of person-centered approaches and gender-specific considerations in understanding the psychosomatic pathways of myopia. Show less

Nurses' voice behavior is critical for patient safety and organizational improvement. However, its manifestation is not uniform among nurses. This study aimed to identify latent profiles of nurses' voice behavior using Latent Profile Analysis (LPA) to understand this heterogeneity and explore its influencing factors, with a specific focus on differences across work motivation dimensions (rooted in Self-Determination Theory, SDT). A multicenter cross-sectional design was adopted. Data from 701 clinical nurses across six hospitals in Guangxi Province were analyzed: LPA identified four distinct profiles, and Multinomial Logistic Regression was used to examine predictors. Work motivation was measured by the Multidimensional Work Motivation Scale (MWMS), and voice behavior by the Voice Behavior Scale (VBS). LPA identified four distinct profiles (Conservative, 5.42%; Balanced Risk-Taker, 26.39%; Transitional, 34.38%; Challenging, 33.8%), and Multinomial Logistic Regression was used to examine predictors. Work motivation was measured by the Multidimensional Work Motivation Scale (MWMS), and voice behavior by the Voice Behavior Scale (VBS). Results showed autonomous motivation (e.g., intrinsic drive) strongly predicted active voice behavior, while amotivation predicted conservative profiles. Nurses exhibited high work motivation (MWMS: 93.02 ± 21.09) and moderately high voice behavior (VBS: 39.27 ± 8.736). The research found that nurses exhibited high work motivation and moderately high voice behavior, with autonomous motivation being a pivotal predictor. Differentiated strategies targeting intrinsic motivation enhancement are critical for fostering nursing innovation and improving care quality. Show less

Flourishing is a key positive psychological construct that has been linked to favorable health-related outcomes in patients with inflammatory bowel disease in prior research. However, current research often overlooks the variations in flourishing levels within this population, as well as the mechanisms through which flourishing interacts with disease progression. This study aimed to identify latent categories of flourishing among patients with inflammatory bowel disease and to analyze the potential influencing factors. This study employed a cross-sectional, descriptive exploratory design involving 316 patients diagnosed with inflammatory bowel disease. Data collection was carried out using a general information questionnaire, the Flourishing Scale (FS), the IBD Self-Efficacy Scale (IBD-SES), the Resilience Scale for Inflammatory Bowel Disease (RS-IBD), and the Social Support Rating Scale (SSRS). Latent profile analysis (LPA) was utilized to identify potential subgroups exhibiting flourishing, while multiple logistic regression analysis was conducted to evaluate the influencing factors. The flourishing of individuals with inflammatory bowel disease was classified into three latent groups: the low flourishing-low support beneficiary group ( Patients with inflammatory bowel disease demonstrate three distinct latent categories of flourishing. Healthcare professionals should implement more accurate and targeted intervention measures based on the characteristics and influencing factors of different potential categories, in order to improve the flourishing levels of patients with inflammatory bowel disease. Show less

Lipoprotein(a) [Lp(a)] and diabetes mellitus (DM) are independent risk factors for worse outcomes in coronary artery disease (CAD) patients. Evidence of their joint association is limited. We aimed to investigate the combined effect of elevated Lp(a) and DM on survival outcomes in CAD patients. This study included 65 547 CAD patients (62.6 ± 10.7 years, 27.7% female) from CIN-II and RED-CARPET cohorts. Patients were stratified into four groups by Lp(a) levels (< or ≥ 30 mg/dL) and DM status. Multivariable Cox regression models estimated associations with cardiovascular and all-cause mortality, examining additive and multiplicative interactions. During a median follow-up of 5.5 years, 10 686 (16.3%) patients died from all causes and 5106 (7.8%) died from cardiovascular causes. Patients with Lp(a) ≥ 30 mg/dL and DM were independently associated with cardiovascular mortality (adjusted hazard ratio [aHR]: 1.28, 95% CI: 1.20-1.35; aHR: 1.53, 95% CI: 1.44-1.62, all p < 0.001, respectively). Compared to patients with Lp(a) < 30 mg/dL without DM, the aHRs were 1.26 (95% CI: 1.16-1.36, p < 0.001), 1.51 (95% CI: 1.40-1.62, p < 0.001) and 2.00 (95% CI: 1.83-2.18, p < 0.001) for those with Lp(a) ≥ 30 mg/dL without DM, Lp(a) < 30 mg/dL with DM and Lp(a) ≥ 30 mg/dL with DM, respectively. Significant additive interaction between elevated Lp(a) and DM on cardiovascular mortality was observed, with 12% of the excess risk attributed. Similar associations were observed in all-cause mortality. In patients with CAD, elevated Lp(a) and DM act synergistically to increase the risk of cardiovascular and all-cause mortality, suggesting that both risks should be considered to integrate management. Show less

From a positive psychology perspective, this study aimed to identify the latent profiles of spiritual well-being and analyze the serial mediation mechanism of family care and spiritual coping in the relationship between spiritual well-being and health-related quality of life (HRQoL). The findings are intended to inform strategies for improving the spiritual well-being of maintenance hemodialysis (MHD) patients. A cross-sectional design was employed with 220 MHD patients recruited from two tertiary hospitals in Guangdong, China (August 2023-January 2024). Assessments were conducted using the Functional Assessment of Chronic Illness Therapy-Spiritual Well-Being Scale (FACIT-SP-12), Family Care Index, Spiritual Coping Questionnaire (SCQ), and Short Form-12 Health Survey (SF-12). Latent profile analysis (LPA) was employed to identify heterogeneous subgroups based on spiritual well-being. A chain mediation model was then used to examine the mediating effects of family care and spiritual coping. HRQoL scores averaged 56.50 ± 22.29. Significant correlations emerged: spiritual well-being ( Spiritual well-being indirectly influences the quality of life in MHD patients through the serial mediation of family care and spiritual coping. Clinicians should recognize the heterogeneity in spiritual well-being and integrate routine spiritual screening into nursing assessments to identify patients with low spiritual well-being. It is recommended to develop family-based education and support programs, along with interventions that combine family care and spiritual coping strategies, so as to improve patients' long-term health outcomes. Show less

This study employed a latent profile analysis (LPA) to identify distinct subgroups of learned helplessness among Chinese breast cancer chemotherapy patients and examined influencing factors. Through convenience sampling, 260 breast cancer chemotherapy patients aged 18-74 years from a tertiary hospital in Henan Province were recruited between May 2024 and January 2025. Data were collected using a general demographic questionnaire, the Learned Helplessness Scale, the Brief Illness Perception Questionnaire, the Social Support Rating Scale, and the General Self-Efficacy Scale. An LPA was applied to classify learned helplessness patterns, followed by a multivariate logistic regression to determine the influencing factors. The latent profile analysis revealed three distinct profiles of learned helplessness among breast cancer patients undergoing chemotherapy: a "low helplessness-low hopelessness stable profile" (17.0%), a "moderate helplessness-moderate hopelessness fluctuating profile" (52.0%), and a "high helplessness-high hopelessness profile" (31.0%). The multivariable logistic regression revealed that age range 18-44 years, low monthly household income per capita, fatigue, and illness perception were significantly associated with the "high helplessness-high hopelessness profile" (P < 0.05). Conversely, the age range 45-59 years was significantly associated with the "moderate helplessness-moderate hopelessness fluctuating profile" (P < 0.001). Furthermore, experiencing ≤2 chemotherapy-related side effects, a higher level of perceived social support, and greater self-efficacy were significant predictors of membership in the "low helplessness-low hopelessness profile" (P < 0.05). Breast cancer chemotherapy patients were categorized into three distinct subgroups, which were influenced by age, income, fatigue, treatment side effects, illness perception, self-efficacy, and social support. Show less